Evidence Report /Technology Assessment 

Number 61

Management of Cancer Symptoms: Pain, 

Depression, and Fatigue 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

2101 East Jefferson Street 

Rockville, MD 20852 

www.ahrq.gov 

Contract No. 290-97-0019

Prepared by: 

New England Medical Center EPC, Boston, MA 

Investigators 

Daniel Carr, M.D. 

Leonidas Goudas, M.D., Ph.D. 

Donald Lawrence, M.D. 

William Pirl, M.D. 

Joseph Lau, M.D., EPC Director

Deirdre DeVine, M. Litt., Project Manager 

Bruce Kupelnick, B.A., Research Associate 

Kimberly Miller, B.A., Research Assistant 

AHRQ Publication No. 02-E032 

July 2002 
This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation:

Carr D, Goudas L, Lawrence D, et al. Management of Cancer Symptoms: Pain, Depression, and 

Fatigue. Evidence Report/Technology Assessment No. 61 (Prepared by the New England 

Medical Center Evidence-based Practice Center under Contract No 290-97-0019). AHRQ 

Publication No. 02-E032. Rockville, MD: Agency for Healthcare Research and Quality. 

July 2002. 

This report may be used, in whole or in part, as the basis for development of clinical 

practice guidelines and other quality enhancement tools, or a basis for reimbursement and 

coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement 

of such derivative products may not be stated or implied. 

AHRQ is the lead Federal agency charged with supporting research designed to improve 

the quality of health care, reduce its cost, address patient safety and medical errors, and 

broaden access to essential services. AHRQ sponsors and conducts research that provides 

evidence-based information on health care outcomes; quality; and cost, use, and access. 

The information helps health care decisionmakers—patients and clinicians, health system

leaders, and policymakers—make more informed decisions and improve the quality of 

health care services.

ii
Preface

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The reports and assessments provide organizations 

with comprehensive, science-based information on common, costly medical conditions and new 

health care technologies. The EPCs systematically review the relevant scientific literature on 

topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to 

developing their reports and assessments. 

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

We welcome written comments on this evidence report. They may be sent to: Director, 

Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 

6010 Executive Blvd., Suite 300, Rockville, MD 20852. 

Carolyn M. Clancy, M.D. 

Acting Director 

Agency for Healthcare Research and Quality 

Robert Graham, M.D. 

Director, Center for Practice and 

 Technology Assessment 

Agency for Healthcare Research and Quality 

The authors of this report are responsible for its content. Statements in the report should not be 

construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. 

Department of Health and Human Services of a particular drug, device, test, treatment, or other 

clinical service. 

iii
 
Abstract 

Objective. Despite dramatic advances in cancer biology and a widening array of treatment 

options, cancer continues to cause devastating suffering not only in the hundreds of thousands of 

patients who die of it each year in the United States, but also in some patients who are 

successfully treated and become cancer survivors. This evidence report on the topic of

Management of Cancer Symptoms: Pain, Depression, and Fatigue was produced on request from

the Office of Medical Applications of Research, National Institutes of Health, and the National 

Cancer Institute for a Consensus Development Conference. 

Search Strategy. Studies used in this evidence report were identified through searches 

of the English language literature published between 1966 and September 2001 in MEDLINE®, 

CANCERLIT®, and the Cochrane Controlled Trials Registry. The searches were supplemented 

with reviews of bibliography of selected references and of published meta-analyses for selected 

topics. 

Selection criteria. We accepted all studies of patients with a diagnosis of cancer who 

suffered from pain, depression, or fatigue due to cancer or treatment of cancer and addressed the 

issues of prevalence, assessment, or treatment. We placed no restrictions on the patients’ age, 

gender, ethnicity, and stage of the primary disease or presence of metastases. 

Data Collection and Analysis. We incorporated more than 200 English-language 

articles in the evidence report. Specific inclusion criteria and methods of synthesis were 

developed for each of the topics. Relevant data from each article were abstracted into evidence 

tables. Information from the evidence tables was synthesized into summary tables describing the 

findings of each study. 

Main Results. The prevalence of cancer pain varied from 14 to 100 percent, depending 

on the setting. More than 100 scales or instruments have been used to assess pain. Studies 

published in the interim since our earlier evidence report on the management of cancer pain do 

not change the conclusions of that report. Randomized controlled trials establish that many 

current treatment modalities can individually reduce cancer pain. Treatment trials rarely separate 

efficacy according to putative mechanism of pain. For specific problems such as postherpetic 

neuralgia and oral mucositis, there are sufficient trials upon which to base specific treatment 

recommendations. 

The prevalence rates for major depressive disorder and clinically significant depressive 

symptoms are about 10 to 25 percent. Although a clinical interview is the standard for assessing 

depression, many instruments are available for screening and the assessment of severity for 

depressive symptoms. There is currently no evidence on how widely they are used clinically or 

to suggest that they affect clinical care and outcomes. The benefit of psychosocial interventions 

for cancer-related depression seems to be modest. All medication trials that use antidepressants 

and lasted at least 5 weeks demonstrated some efficacy. There are no controlled trials of the 

effect of alternative treatments on cancer-related depression. Extremely wide prevalence rates of

fatigue (4 to 91 percent) were found in association with chemotherapy, radiation therapy, and 

v 
other treatments. The prevalence of fatigue in the palliative setting was 48 to 75 percent and in 

cancer survivors 17 to 56 percent. Most studies used multi-item, multidimensional assessment 

instruments. Clinical interpretation of results is problematic due to the heterogeneity of

assessment methods. There are few randomized, controlled trials of treatments for cancer-related 

fatigue. Only one of these strongly supports a specific intervention for fatigue, i.e., treatment 

with epoetin alfa in anemic patients receiving chemotherapy. 

Conclusions. Pain, depressive symptoms, and fatigue are common problems in patients 

with cancer. Despite numerous instruments having been developed to assess these symptoms, 

optimal and standardized methods for the assessment of these symptoms in clinical practice have 

not been determined. Even in areas where efficacious treatment options exist, there are few highquality randomized trials to guide the selection of optimal treatment alternative. 

Additional studies are needed to measure the prevalence and impact of these symptoms in 

cancer, to determine the clinical significance of these measurements, and to define factors that 

correlate with these symptoms. For cancer-related fatigue, current treatment options are limited 

unless reversible factors contributing to fatigue can be identified and corrected. 

For all of the topics examined in this evidence report, there is a paucity of studies in the 

pediatric population and research in children is urgently needed to address the symptoms of pain, 

depression, and fatigue. 

vi
Contents 

Abstract......................................................................................................................................... v

Summary....................................................................................................................................... 1 

Evidence Report 

Chapter 1. Introduction................................................................................................................ 9

Overview.............................................................................................................................. 9

Symptoms in Cancer Patients.............................................................................................. 9 

 Cancer-related Pain.............................................................................................................. 11

Prevalence of Cancer-related Pain.............................................................................. 12 

Assessment of Cancer-related Pain............................................................................. 12 

Treatment of Cancer-related Pain............................................................................... 13 

 Cancer-related Depression................................................................................................... 14

Prevalence of Cancer-related Depression................................................................... 14 

Assessment of Cancer-related Depression.................................................................. 15 

Treatment of Cancer-related Depression.................................................................... 16 

 Cancer-related Fatigue......................................................................................................... 17

Prevalence of Cancer-related Fatigue......................................................................... 18 

Assessment of Cancer-related Fatigue........................................................................ 18 

Treatment of Cancer-related Fatigue.......................................................................... 19 

Chapter 2. Methodology............................................................................................................... 21

Questions Formulated by the Planning Committee for the Conference.............................. 21 

Topics Addressed in this Evidence Report.......................................................................... 21 

General Approach of this Evidence Report......................................................................... 22 

Literature Search.................................................................................................................. 22

Cancer-related Pain..................................................................................................... 22 

Cancer-related Depression.......................................................................................... 23 

Cancer-related Fatigue................................................................................................ 23 

 Selection of studies.............................................................................................................. 23

Patient Population Studied.......................................................................................... 23 

Cancer-related Pain..................................................................................................... 24 

Key questions addressed in the Management of Cancer Pain Evidence 

Report.............................................................................................................. 24

Cancer-related Depression.......................................................................................... 24 

Cancer-related Fatigue................................................................................................ 25 

Reporting the Data............................................................................................................... 25

Updates of the Management of Cancer Pain Evidence Report Key Questions.......... 26 

Grading of the Evidence for Randomized Controlled Trials............................................... 26 

Internal Validity.......................................................................................................... 27 

Applicability................................................................................................................ 27

 Study size............................................................................................................................ 27

Magnitude of the Treatment Effect of Cancer-related Pain Studies........................... 28 

Chapter 3. Results........................................................................................................................ 29

Prevalence............................................................................................................................ 29

vii 
Prevalence of Cancer-related Pain.............................................................................. 29 

Summary of Findings...................................................................................... 29 

Summaries of Epidemiological Studies.......................................................... 31 

Prevalence of Cancer-related Depression................................................................... 38 

What is the Prevalence of Major Depression in Patients with Cancer?.......... 38 

What is the Prevalence of Significant Depressive Symptoms in Patients 

with Cancer?................................................................................................... 40 

What is the Prevalence of Depression in Children with Cancer?................... 41 

Incidence......................................................................................................... 42

What is the Incidence of Major Depression in Cancer?.................................. 42 

What is the Incidence of Significant Depressive Symptoms in Cancer 

Patients?.......................................................................................................... 42

What is the Incidence of Depression in Children with Cancer?..................... 44 

Prevalence of Cancer-related Fatigue......................................................................... 44 

Measures and Definitions of Fatigue.............................................................. 48 

Prevalence of Fatigue During Chemotherapy and/or Radiation Therapy....... 48 

Fatigue in Cancer Survivors............................................................................ 50 

Fatigue in the Palliative Care Setting.............................................................. 50 

Patterns and Correlates of Fatigue.................................................................. 50 

Assessment........................................................................................................................... 52

Assessment of Pain..................................................................................................... 54 

Assessment of Depression.......................................................................................... 56 

How do Various Instruments for Screening for Depression Compare?.......... 56 

Assessment of Fatigue................................................................................................ 56 

Treatment............................................................................................................................. 59

Treatment of Cancer-related Pain............................................................................... 59 

What is the relative efficacy of current analgesics for cancer pain?............... 59 

What are the efficacy and side effects of the adjuvant analgesics in 

the management of cancer pain?......................................................... 60 

Adjuvants – Breakthrough Pain.............................................. 61 

Adjuvants – Spinal Local Anesthetics and Other Agents....... 62 

Are different formulations and routes of administration associated with 

different patient preferences or different efficacy rates?............................... 64 

What are the patients preferences, efficacy, costs, and side effects 

of different routes of opioid administration (e.g., sustained release 

opioid versus transdermal delivery)?.................................................. 64 

Opioids versus Opioids........................................................... 66 

What is the relative analgesic efficacy of palliative pharmacological 

(chemotherapy, bisphosphonates or calcitonin) and non-pharmacological 

cytotoxic or static (radiation therapy or radionuclide) therapy?..................... 67 

What is the efficacy of bisphosphonates in treating metastatic bone 

pain?.................................................................................................... 67

Bisphosphonates...................................................................... 68 

What is the efficacy of chemotherapeutic drugs in treating cancer 

pain (e.g., emcitabine)?...................................................................... 69 

Chemotherapeutic Agents....................................................... 70 

viii 
What is the efficacy of external-beam radiation and radionuclides in 

treating cancer pain?........................................................................... 71 

Individual Summaries on External-beam Radiation Therapy 

for Cancer Pain........................................................................ 72 

What is the relative efficacy of current adjuvant (non-pharmacological/ 

non-invasive) physical or psychological treatments (relaxation, massage, 

heat and cold, music, exercise, and so on) in the management of cancerrelated pain?.................................................................................................... 73 

Reflexology............................................................................. 74

Acupuncture............................................................................ 74

What is the efficacy of cognitive behavioral interventions in 

treating cancer pain?........................................................................... 75 

Individual Summaries............................................................. 75 

Oral Mucositis-Related Pain....................................................................................... 76 

Results............................................................................................................. 83

Meta-analysis.................................................................................................. 84

Outcome: severe oral mucositis, clinician assessments.................................. 85 

Discussion....................................................................................................... 85

Acute Herpes Zoster and Postherpetic Neuralgia (PHN) in Cancer Patients.............. 86 

Treatment of Cancer-related Depression.................................................................... 88 

What are the Effects of Medications on Depression in Cancer Patients?....... 88 

Are Psychosocial Interventions Effective in Treating Depressive Symptoms 

in Cancer Patients?.......................................................................................... 92 

Are Alternative Treatments Effective for the Treatment of Depressive

Symptoms in Cancer Patients?........................................................................ 93 

Treatment of Cancer-related Fatigue.......................................................................... 93 

Chapter 4. Conclusions............................................................................................................... 99

Prevalence............................................................................................................................ 99

Cancer-related Pain..................................................................................................... 99 

Cancer-related Depression.......................................................................................... 99 

Cancer-related Fatigue................................................................................................ 100

Assessment........................................................................................................................... 100

Cancer-related Pain..................................................................................................... 100

Cancer-related Depression.......................................................................................... 101

Cancer-related Fatigue................................................................................................ 101

Treatment............................................................................................................................. 102

Cancer-related Pain..................................................................................................... 102

Cancer-related Depression.......................................................................................... 103

Cancer-related Fatigue................................................................................................ 104

Chapter 5. Future Research.......................................................................................................... 105

Prevalence............................................................................................................................ 105

Cancer-related Pain..................................................................................................... 105

Cancer-related Depression.......................................................................................... 105

Cancer-related Fatigue................................................................................................ 105

Assessment........................................................................................................................... 106

Cancer-related Pain..................................................................................................... 106

ix
Cancer-related Depression.......................................................................................... 107

Cancer-related Fatigue................................................................................................ 107

Treatment............................................................................................................................. 107

Cancer-related Pain..................................................................................................... 107

Cancer-related Depression.......................................................................................... 108

Cancer-related Fatigue................................................................................................ 109

Concurrency and Interactions between Pain, Depression and Fatigue................................ 109

References and Bibliography........................................................................................................ 111

Evidence Tables............................................................................................................................ 133

Evidence Table 1. Epidemiology of Cancer Pain – A Literature Update 1998-May 

2001..................................................................................................... 135

Evidence Table 2. Cross-Sectional Studies on Prevalence of Major Depressive 

Disorders (MDD) Using DSM Criteria............................................... 139

Evidence Table 3. Cross-Sectional Studies on Prevalence of Significant Depressive 

Symptoms in Adults Using the HADS............................................... 143

Evidence Table 4. Depressive Symptoms in Children with Cancer................................. 149

Evidence Table 5. Incidence of Depressive Symptoms in Adult Cancer Patients – 

HADS.................................................................................................. 151

Evidence Table 6. Prevalence of Fatigue in Cancer Patients............................................ 153

Evidence Table 7. Assessment of Depression in Adults: Direct Comparison of 

Instruments to Each Other or Standardized Interviews....................... 163

Evidence Table 8. Assessment of Fatigue in Cancer Patients.......................................... 167

Evidence Table 9. Randomized Controlled Trials on Drug Treatments for the 

Management of Cancer Pain............................................................... 193

Evidence Table 10. Randomized Controlled Trials on the Efficacy of Bisphosphonates 

for the Management of Cancer Pain................................................... 225

Evidence Table 11. Randomized Controlled Trials on the Efficacy of Chemotherapeutic 

agents for the Management of Cancer Pain........................................ 231

Evidence Table 12. Randomized Controlled Trials on the Efficacy of Radiation 

Treatments for the Management of Cancer Pain................................. 239

Evidence Table 13. Randomized Controlled Trials on Cognitive Behavioral and Other 

Interventions for the Management of Cancer Pain............................. 247

Evidence Table 14. Psychopharmacologic Studies of Treatment of Depression in 

Cancer. Double-blind Randomized Control Trials............................ 253

Evidence Table 15. Meta-analyses on Effects of Psychological Interventions on 

Depressive Symptoms in Cancer Patients........................................... 261

Evidence Table 16. RCTs of Treatment of Fatigue in Cancer Patients.............................. 263

Appendixes.................................................................................................................................... 271

Appendix A. Abbreviations 273

Appendix B. Glossary 277

Figures 

Figure 1. Relationship between some factors that contribute to the occurrence of cancer 

symptoms, methods of assessment, and prevalence of symptoms............................ 10 

x 
Tables 

Table 1a. Summary of epidemiological studies reporting on the prevalence and/or incidence 

of cancer-related pain................................................................................................ 29 

Table 1. Prevalence of Major Depressive Disorder (MDD). 12 Cross-sectional Studies on 

Prevalence of MDD using DSM Criteria.................................................................. 38 

Table 2. Prevalence of significant depressive symptoms in adults. Cross-sectional studies 

using the HADS........................................................................................................ 40 

Table 3. Prevalence of Depressive Symptoms in Children with Cancer................................ 41 

Table 4. Incidence of Depressive Symptoms in Adult Cancer Patients.................................. 43 

Table 5. Prevalence of Fatigue in Cancer Patients.................................................................. 44 

Table 6. Assessment Scales for Pain, Depression, and Fatigue.............................................. 52 

Table 7. Assessment Scales by Cancer Type.......................................................................... 53 

Table 8. Most Frequently Used Assessment Tools, Cited in Management of Cancer Pain: 

Evidence Report........................................................................................................ 55 

Table 9. Frequency of Use, Fatigue Assessment Scales......................................................... 57 

Table 10. Frequency of Use, Assessment Instruments by Cancer Type................................... 58 

Table 11. Grading of randomized controlled trials comparing an NSAID with another 

NSAID or to placebo................................................................................................. 59 

Table 12. Summary table of randomized controlled trials evaluating adjuvant analgesics in 

the management of cancer pain................................................................................. 60 

Table 13. Grading of randomized controlled trials evaluating adjuvant analgesics in the 

management of cancer pain....................................................................................... 60 

Table 14. Summary of the evidence from randomized controlled trials comparing the 

efficacy of one opioid with another (or a different formulation of the same) 

opioid, administered through the same of different route and/or the same or 

different dosing schedules......................................................................................... 64 

Table 15. Summary of comparisons performed in randomized controlled trials reporting on 

efficacy and/or adverse effects, comparing an opioid with another opioid.............. 65 

Table 16. Grading of individual randomized controlled trials reporting on the effects of 

opioid with another (or the same) opioid, administered through the same or 

different routes/modes/schedules of administration.................................................. 65 

Table 17. Summary of the evidence from randomized controlled trials reporting on the 

relative efficacy of bisphosphonates (various doses) or bisphosphonates versus 

placebo...................................................................................................................... 68 

Table 18. Grading of individual randomized controlled trials reporting on the relative 

efficacy of bisphosphonates (various doses) or bisphosphonates versus placebo.... 68 

Table 19. Summary of evidence from randomized controlled trials reporting on the efficacy 

of chemotherapeutic drugs in the management of cancer pain................................. 69 

Table 20. Grading of individual randomized controlled trials reporting on the efficacy of 

chemotherapeutic drugs in the management of cancer pain..................................... 69 

Table 21. Summary of the evidence from randomized controlled trials reporting on the 

efficacy of external-beam radiation in the management of cancer pain................... 71 

Table 22. Grading of individual randomized controlled trials reporting on the efficacy of 

external-beam radiation in the management of cancer pain...................................... 71 

xi
Table 23. Grading of individual randomized controlled trials reporting on the efficacy of 

various physical treatments (reflexology and acupuncture) in the management of 

cancer pain................................................................................................................ 74 

Table 24. Summary of the evidence from randomized controlled trials reporting on the 

efficacy of cognitive behavioral interventions in the management of cancer pain... 75 

Table 25. Grading of individual randomized controlled trials reporting on the efficacy of 

cognitive behavioral interventions in the management of cancer pain..................... 75 

Table 26. Comparisons of active treatment versus placebo/no treatment for treatment of 

mucositis (absent vs. present)................................................................................... 80 

Table 27. Comparisons of active treatment versus placebo/no treatment for treatment of 

mucositis (grade 0-2 versus 3+)................................................................................ 80 

Table 28. Grading of individual randomized controlled trials reporting on the effects of 

prophylactic antiviral treatments against zoster pain and PHN................................ 87 

Table 29. Summary of randomized controlled trials comparing various treatments of herpes 

with respect to zoster pain and Postherpetic Neuralgia (PHN) in cancer 

patients...................................................................................................................... 87 

Table 30. Psychopharmacologic Studies of Treatment of Depression in Cancer. Doubleblind randomized controlled trials............................................................................ 88 

Table 31. RCTs of Treatment of Fatigue in Cancer Patients.................................................... 94 

xii 
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.

2
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

3
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

4
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.

5
AHRQ Pub. No. 02-E031

July 2002

ISSN 1530-440X
Chapter 1. Introduction 

Overview 

The Office of Medical Applications of Research (OMAR) at the National Institutes of Health 

requested that the Agency for Healthcare Research and Quality (AHRQ), through its Evidencebased Practice Center (EPC) program, produce an evidence report for a State-of-the-Science 

conference on the topic of Management of Cancer Symptoms: Pain, Depression, and Fatigue. 

EPCs review relevant scientific literature on assigned clinical care topics and produce 

evidence reports and technology assessments, conduct research on methodologies and the 

effectiveness of their implementation, and participate in technical assistance activities. The 

purpose of an evidence report is to search for and summarize evidence on several key questions 

on a specific topic. EPCs collaborate with science partners to formulate specific key questions. 

As specified by AHRQ in the EPC program, evidence reports do not make specific clinical 

recommendations; however, recommendations for future research are typically provided. Public 

and private sector organizations may use the reports and assessments as the basis for their own 

clinical guidelines and other quality improvement activities. 

This evidence report summarizes the evidence on the prevalence, methods of assessment, and 

management of the following symptoms in patients with cancer: pain, depression, and fatigue. 

The symptoms and key questions were identified by the State-of-the-Science Conference 

planning committee composed of staff from OMAR, National Cancer Institute, national experts 

on this topic, as well as the EPC staff. 

Symptoms in Cancer Patients 

Despite remarkable advances in cancer biology and a widening array of treatment options, 

cancer continues to cause devastating suffering not only in the hundreds of thousands of patients 

who die of it each year in the United States, but also in 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 for them. 

Pain, depression, and fatigue are complex subjective experiences. They are not directly 

measurable. To be studied, they must be defined operationally and estimated using patient selfreport instruments. The development of tools that capture the multidimensional aspects of these 

symptoms has been an important clinical and research advance. 

Figure 1 depicts the relationships between various factors that may contribute to the occurrence 

of cancer symptoms. Heterogeneity of the factors involved in each study is further compounded by 

heterogeneity of instruments or scales used to assess these symptoms. Studies that employ different 

designs, rely upon different inclusion and exclusion criteria, and use different assessment tools will 

likely report different rates of occurrence of symptoms. Hence, the interpretation and comparison 

of results from such diverse studies is difficult. 

9
Prevalence

(observed)

True rate of

occurrence

of

symptoms

Phase of

illness

Type of

cancer

Age,

gender,

culture

Treatment

Comorbidities

Settings

Assessment method

(instruments, scales,

observers)

Genetics

Figure 1. Relationship between some factors that contribute to the occurrence of cancer symptoms, 

methods of assessment, and prevalence of symptoms. 

Dramatic progress in pain research has resulted from extensive laboratory investigations 

leading to increasingly detailed models of the fundamental mechanisms of pain. These advances in 

the understanding of the physiology of pain have led to clinically testable hypotheses regarding 

pain mechanisms and new treatments. There is, unfortunately, little fundamental research on 

depression in cancer. Its mechanisms may differ from non-cancer-related depression, but it is 

reasonable to assume that there is overlap and therefore a rationale for testing interventions found 

effective outside the context of cancer. Mechanisms of cancer-related fatigue remain generally 

unexplored despite its prevalence and impact. The dearth of information of the pathophysiology of 

cancer-related fatigue is reflected in the paucity of treatment trials for this condition. 

The studies reviewed in this report provide evidence of progress in a number of other areas of 

symptom research. Large-scale, population-based studies of symptoms in cancer have been 

performed, providing estimates of symptom prevalence that are more generalizable than those 

obtained from small cohort studies. Some of the practical difficulties of accruing and retaining 

research subjects, who are depressed, fatigued, or in pain, have begun to be addressed. An 

impressive amount of data has been accumulated and some important insights have been gained 

about pain, depression, and fatigue in cancer. Using sophisticated assessment tools, investigators 

have measured the burden of pain, depression, and fatigue, and the factors that correlate with them, 

in a wide variety of settings: during curative or palliative treatments, in long-term survivors, and 

near the end of life. Some randomized controlled trials have led to the adoption of new treatments 

to relieve symptoms and ameliorate suffering. Given the scope and complexity of the problems, 

much remains to be done. 

10
Overviewed in this chapter are the three cancer-related symptoms identified by the planning 

committee as the focus for the conference. The prevalence, assessment, and treatment for each of 

these symptoms are discussed. 

Cancer-related Pain 

Intractable pain is a complication dreaded by many patients with cancer. “Cancer pain” 

comprises acute pain, chronic pain, tumor-specific pain, and treatment- (including procedure-) 

related pain. Pain is a major cause of impaired quality of life (including decreased patient 

functionality and caregiver burden) in patients with cancer, and intensifies the distress and 

suffering commonly evoked in patients from diagnosis onwards (Bonica, 1990; Chapman and 

Garvin, 1999; Loeser and Melzack, 1999). New pain symptoms that prompt the diagnosis of cancer 

may provoke acute physiological responses and evolve into chronic pain. When a new pain appears 

in a patient known to have cancer, it may remain noticeable despite analgesic therapy and hence 

perpetuate fatigue due to interference with sleep, or distress in an anxious or depressed host. Pain 

caused by poorly controlled underlying or advancing pathophysiology heralds a demoralizing loss 

of control over one’s body that typifies the clinical course of progressive disease. Pain is a reminder 

of cancer-related mortality, and is experienced within a personal, social, cultural and religious 

framework (Field and Cassel, 1997). 

Inflammatory mediators associated with cancer include prostaglandins, cytokines, tumor 

necrosis factors, interleukins, growth factors and other tumor-derived algesic molecules such as 

endothelin (Davar, Hans, Fareed, et al., 1998), each of which can excite nociceptors (Schwei, 

Honore, Rogers, et al., 1999). Some cancers induce endogenous antibodies and others are treated 

by therapeutic administration of exogenous antibodies; both types of agents may evoke painful 

neuropathies (Sorkin, 2000). Preclinical research on bone pain in cancer suggests a distinctive 

neurochemical and histological “signature” in afferent nerves and their spinal cord connections in 

animal models of neoplasia (Schwei, Honore, Rogers, et al., 1999). Several elements within a 

spectrum of possible pain mechanisms may be active in a single patient with cancer pain (Woolf, 

Bennett, Doherty, et al., 1998). Cancer-related and non-cancer pains may involve neuropathic 

components, in which the nervous system is damaged (Woolf and Mannion, 1999), and nociceptive 

components, in which injury to non-neural tissue is conveyed through an undamaged nervous 

system. Pain may originate from visceral organs due to tumor infiltration or obstruction of a viscus, 

from pathology involving the surface of the body and conveyed via the somatic nerves that 

innervate the body surface. Clinicians have delineated a number of cancer pain syndromes. Some

of these syndromes are due to tumor-specific patterns of local or distant metastasis, others reflect 

diffuse neuropathies from tumor products or chemotherapy, and still others involve localized neural 

damage such as nerve plexus injury from radiation therapy or infiltration by tumor. 

The total experience of cancer pain encompasses not just pain intensity but also includes 

family, spiritual, behavioral, psychosocial and financial dimensions (Ferrell and Ferrell, 1996; 

Lang and Patt, 1994; McGuire, 1995). For this reason, and also because cancer and cancer 

treatment produce use cancer and cancer treatment produce a variety of related non-pain sedation, a 

consensus has emerged that optimal care for patients with cancer employs a multidimensional 

palliative framework that addresses multiple symptoms and patient concerns are simultaneously. 

11
Prevalence of Cancer-related Pain 

Cancer has a profound impact around the world because of its prevalence and associated 

morbidity and mortality (The World Health Organisation Global Programme For Cancer 

Control, 1993; Wolff, 1997). Poorly controlled pain is key to the impaired quality of life (QOL) 

that patients with cancer may suffer. Work in the 1970s and 1980s by Bonica (1985), Twycross 

(1976), Foley (1985), Daut and Cleeland (1982) and Stjernsward (The World Health 

Organisation Global Programme For Cancer Control, 1993) established the importance of cancer 

pain control and showed that about three-quarters of patients with advanced cancer experience 

pain. Surveillance data gathered in developed countries in order to characterize the incidence, 

prevalence, and in some studies the nature and severity of pain have enrolled about 60,000 

patients. This global experience indicates that one-third to one-half of all patients undergoing 

active cancer treatment experience pain, and that the likelihood of pain is influenced by type of 

tumor, stage of disease, and extent of metastases (Bonica, 1985; Daut and Cleeland, 1982). 

Of the over one million Americans diagnosed annually with cancer, 1500 die daily from this 

cause (Landis, Bolden, and Wingo, 1999). Nearly 10 million Americans now have or previously 

had cancer. During the past 25 years, age-adjusted incidence rates pooled across ages, race, and 

cancer type have increased significantly (about 20 percent) in the United States (Landis, Bolden, 

and Wingo, 1999; National Cancer Institute, 1999). In parallel with a global trend throughout 

developed countries, the population of the United States has on average grown older, and 

numbers of elderly have risen (U.S. Bureau of the Census, 1999). Although cancer is the second 

leading cause of death (after accidents) in children younger than 14 years in the United States, 5-

year survival rates have improved substantially for many childhood cancers since the 1970s 

(Landis, Bolden, and Wingo, 1999). Unfortunately, despite calls for assigning a high priority to 

alleviating cancer pain in children (Schechter, Berde, and Yaster, 1993), many children who die 

of cancer have substantial suffering at the end of life (Wolfe, Grier, Klar, et al., 2000). The 

incidence and prevalence and hence impact of cancer increases dramatically with age. The 

cancer incidence rate is less than 50 cases per 100,000 in those under 25, and rises steadily with 

age to over 200 cases per 100,000 in the 40 to 44 age group. Pooled data for all ages from birth 

to 54 yield an incidence of just over 100 cases per 100,000; this rate increases 10-fold to over 

1000 cases per 100,000 in the 55 to 64 age group, and further doubles in those over 65 to greater 

than 2000 cases per 100,000 (National Cancer Institute, 1999). Correspondingly, the cumulative 

percentage of the US population experiencing invasive cancers during their lifetime increases 

sharply from below 2 percent in the 0 to 39 age group, to just under 10 percent in the 40 to 59 

age group, to about 30 percent in those older than 60 (Landis, Bolden, and Wingo, 1999; 

National Cancer Institute, 1999). 

The aging and overall growth of the population plus the increased incidence and prevalence 

of cancer in those over 60 ensure that the national disease burden of cancer will increase at least 

in the near term, and that this burden will continue to fall disproportionately on the elderly 

(Ferrell BR and Ferrell BA, 1996). 

Assessment of Cancer-related Pain 

Patients with cancer may experience acute or chronic pain related to their primary diagnosis, 

from treatment, or from unrelated, even pre-existing disorders. Because of the multiple, often 

changing origins of pain and the importance of its control, the Joint Commission for the 

Accreditation of Healthcare Organizations requires that pain be assessed initially and serially 

thereafter during each clinical encounter in patients at risk for undertreated pain (2000). The 

12
subjective nature of pain requires patient participation in its assessment. Therefore the mere act 

of probing this aspect of a patient’s personal, internal experience validates that experience 

(Morris DB, 1998) and demonstrates a patient-centered point of view (Gerteis, Edgman-Levitan, 

Daley, et al., 1999). A comprehensive approach to pain assessment in cancer care extends 

beyond nociceptive evaluation to encompass comorbid medical and psychosocial problems, the 

meaning and impact of pain upon the patient and significant others, and its effect upon quality of 

life (The World Health Organisation Global Programme For Cancer Control, 1993). 

Initial evaluation of any patient with cancer-related pain is expected to include the essentials 

of any symptom history (location, intensity, quality, temporal characteristics, exacerbating and 

relieving factors, and responses to prior treatments), together with psychosocial assessment, 

physical examination, and appropriate diagnostic studies (Jacox, Carr, Payne, et al., 1994). 

Psychosocial assessment addresses the mood of the patient, his or her coping skills, family 

support structure, signs and symptoms of anxiety or depression, and expectations regarding pain 

management. Initial evaluation seeks to establish a pathophysiological mechanism for each pain, 

if possible as a recognized syndrome with well-described key features, natural history, and 

treatments of choice (Caraceni, Portenoy, and a Working Group of the IASP Task Force on 

Cancer Pain, 1999; Portenoy and Lesage, 1999). The determination that pain is primarily 

neuropathic or nociceptive helps guide initial selection of drug or non-drug therapy such as 

surgery or radiation therapy. Neuropathic pain can result from many potential disorders such as 

deafferentation, mono- or polyneuropathies, or a complex regional pain syndrome (Woolf and 

Mannion, 1999). Nociceptive pain may be due to somatic or visceral pathology (Cervero and 

Laird JMA, 1999). 

Failure to assess cancer pain intensity serially using a standard, validated scale makes it 

difficult to judge the effectiveness of any analgesic regimen, or to compare one regimen with 

another (Jadad-Bechara AR, 1994; Max, 1996; McQuay and Moore, 1998). The 0-10 visual or 

verbal analog scales, or variants such as a thermometer, are validated, easy to administer, and 

widely used. Unless the patient is asked to rate pain at its lowest, average or highest intensity 

during a specific time interval, analog scale measurements provide only an instantaneous 

“snapshot” of pain intensity that is an incomplete picture of pain with activity, across days or 

weeks, or that prevents sleep at night. The Brief Pain Inventory (Daut and Cleeland, 1982) 

therefore captures data on pain intensity across tie as well as at the moment of completion of this 

instrument. Recognition that pain may impair other dimensions of quality of life and 

functionality has prompted inclusion of health-related quality of life (HRQOL) measures into 

clinical analgesic trials, and some clinics to monitor HRQOL during routine care. 

Treatment of Cancer-related Pain 

Undertreatment of cancer pain occurs over a third of the time even in wealthy, industrialized 

nations (Cleeland, Gonin, Hatfield, et al., 1994). The basis for such undertreatment is 

multifactorial. Inadequacy of clinicians' knowledge of effective pain assessment and 

management, negative attitudes of patients and clinicians toward the use of drugs for pain relief,

regulatory issues that promote healthcare providers’ concerns about regulatory scrutiny and 

unwarranted investigation (Joranson et al., 1998; Joranson et al., 2002) and problems of cost and 

reimbursement for effective pain management (Cleeland, 1987) each contribute. 

Present day practical therapeutic options overlap substantially with those applied to treat 

noncancer-related pain. A generic approach to pain management involves beginning an NSAID 

with or without an adjuvant, adding a weak opioid for persistent or unresponsive pain, then 

13
exchanging the weak opioid for a strong opioid such as morphine. In this context, adjuvant refers 

to medications that treat concurrent symptoms that exacerbate pain, such as nausea or insomnia; 

augments or treats a side effect of opioid analgesia; or can diminish specific types of pain such 

as neuropathic pain (e.g., an anticonvulsant or a tricyclic antidepressant). This approach, 

developed and disseminated by the World Health Organization (WHO) as a three-step staircase 

or ladder whose therapeutic escalation is driven by persistent or unresponsive pain, is widely 

applied to treat cancer-related and noncancer pain in primary through tertiary care practice 

settings (Carr, Jacox, Chapman, et al., 1992). Because cancer pain provokes biopsychosocial 

responses in addition to purely nociceptive reactions, the effective management of cancer pain 

normally requires a multidisciplinary approach that includes behavioral interventions (similar to 

the approach to rehabilitation of patients with chronic pain not due to cancer). The “low-tech” 

WHO approach to pain control relies primarily upon the oral route of drug administration but 

requires no essential modification when alternate routes such as rectal, sublingual, subcutaneous, 

topical or transdermal are used for drug delivery (Bruera, Brenneis, Michaud, et al., 1988). 

Whether or not they suffer from cancer, patients whose pain fails to respond adequately to the 

WHO method may be offered, in settings with suitable infrastructures, more invasive 

interventions such as intravenous or intrathecal drug administration. Additional measures to 

control cancer pain that are rarely if ever used to treat noncancer pain include the use of 

biphosphonates, radionuclides, and chemical or surgical neurolysis. 

Cancer-related Depression

Unfortunately, depression is sometimes viewed as being an “appropriate” symptom in cancer 

patients. However, it is never appropriate for cancer patients to suffer with significant 

depression. Cassem, (1997) notes that although massive bleeding is an “appropriate” sequela of a 

ruptured spleen, it is unthinkable to just stand by and allow a patient bleed to death. 

Depression in cancer patients is treatable. Untreated, it can lead to decreased compliance 

with medical care, prolonged hospital stays, increased morbidity, and perhaps increased 

mortality (Herrmann, Brand-Driehorst, Kaminsky, et al., 1998; Richardson, Shelton, Krailo, et 

al., 1990; Spiegel and Kato, 1996). Depressed cancer patients are more likely to request 

euthanasia or physician-assisted suicide and are more likely to commit suicide (Emanuel, 

Fairclough, Daniels, et al., 1996; Henderson and Ord, 1997; Chochinov et al., 1999). 

Prevalence of Cancer-related Depression 

It is estimated that 20 to 25% of all cancer patients will experience depression during the 

course of their illness (Bottomley, 1998). People with cancer are three times more likely than the 

general population and almost twice as likely than other medically hospitalized patients to 

develop depression (Arolt, Fein, Driessen, et al., 1998; Kessler, McGonagle, Zhao, et al., 1994). 

The prevalence of depression in cancer patients is even higher in those with the greatest 

disability and distressing physical symptoms, especially uncontrolled pain. 

There is great variation in the reported frequencies of depression in cancer populations. 

These varying estimates of depression in cancer patients may result from differing definitions of 

“depression,” differing assessment tools, and different cancer populations with different 

significant variables such as timing of the assessment, physical debilitation, and concurrent 

treatment. Many of the retrieved studies do not employ the criteria for major depression 

described in the American Psychiatric Association’s Diagnostic and Statistical Manual for 

14
Mental Disorders and appear instead to be measuring depressive symptoms (American 

Psychiatric Association, 1994). 

Assessment of Cancer-related Depression 

Given the seriousness of its impact, it is important for caregivers to recognize and treat 

depression. Past studies have shown that oncologists and primary care providers have difficulty 

recognizing depressive symptoms in cancer patients (Newell, Sanson-Fisher, Girgis, et al., 1998; 

Passik, Dugan, McDonald, et al., 1998). Major depression is a clinical entity with specific signs, 

symptoms, and treatments. It is more than just sadness. 

“Depression” in comparison to pain or fatigue can be a set of symptoms or clinical 

syndromes. Depressive symptoms are present in several psychiatric disorders, with the most 

common ones in cancer patients being major depressive disorder, adjustment disorder, and 

depression secondary to a medical condition. Depressive symptoms can also be present in the 

absence of a psychiatric disorder. 

Depression is more complicated and difficult to distinguish from symptoms of the underlying 

disease in cancer patients. The psychiatric diagnosis of major depressive disorder is defined by a 

set of criteria in the American Psychiatric Association’s Diagnostic and Statistical Manual of 

Mental Disorders, Fourth Edition (DSM-IV)(American Psychiatric Association, 1994). The 

DSM defines depression as having at least five of the following symptoms for at least 2 weeks: 

1) depressed mood most of the day; 2) loss of interest or pleasure; 3) change in appetite and/or 

change in weight; 4) insomnia or hypersomnia; 5) psychomotor retardation or agitation; 6) loss 

of energy; 7) feelings of worthlessness or guilt; 8) poor concentration; and 9) thoughts of death 

or suicidal ideation. In order to meet the criteria for major depressive disorder, one of the 

patient’s symptoms must be either depressed mood or loss of interest/pleasure, and the individual 

must also be experiencing distress or impairment in social, occupational, or other areas of 

functioning. Major depressive disorder is usually distinguished from an adjustment disorder by 

the degree, duration, or amount of symptoms. 

Making the diagnosis of depression can be a challenge with the cancer patient. Many 

neurovegetative symptoms of depression—especially loss of energy, loss of appetite, and sleep 

disturbance—overlap with common symptoms of cancer or other medical illnesses, and with the 

side effects of medical treatments used in cancer patients. 

Because these symptom-based diagnostic criteria may not be specific for depression in the 

context of medical illness, a set of psychological criteria has been suggested in their place. 

Endicott suggested substituting the psychological symptoms of self-pity, brooding, crying spells, 

and pessimism for the neurovegetative symptoms that overlap with cancer (Endicott, 1984). 

Some clinicians highlight the importance of the cognitive symptoms of depression, such as 

depressed thoughts, hopelessness about all aspects of their lives, guilt or worthlessness, and 

suicidal ideation. 

Additionally, many medical factors in patients with cancer can contribute to, exacerbate, or 

even mimic depressive symptoms. These include uncontrolled pain, hypercalcemia, anemia, 

endocrinologic abnormalities, cancer involvement of the central nervous system, glucocorticoids, 

interferon, and some other chemotherapeutic agents (Roth and Holland, 1994). 

The diagnosis of major depression is further entangled with patients’ reactions to being 

diagnosed with cancer. Holland and Massie have described the natural history of emotions 

following the diagnosis of cancer (Massie, Speigel, Lederberg, et al., 1995). When confronted 

with a diagnosis of cancer, most patients experience a period of shock and disbelief. The second 

15
phase that follows is characterized by more visible distress: sadness, depressed mood, insomnia, 

anxiety, anorexia, and irritability that can last up to 2 weeks. During this time there is a sense of

sadness and uncertainty about the future, and patients are often preoccupied with thoughts of 

illness, death, and losses. All of these feelings are within the normal limits of reacting at the time 

and do not constitute an episode of depression. However, some patients may have difficulty 

carrying out daily activities and have trouble concentration and processing information. Within a 

few weeks, however, most patients have adapted to their diagnosis, their depressive symptoms

resolve, and treatment begins with some optimism and hope for the future. 

 Although clinical evaluation specifically for psychiatric symptoms is generally thought to be 

the best assessment, several instruments, both self-report and clinician-administered are being 

used to assess depressive symptoms. These instruments include three main types: standard 

psychiatric assessments (such as the Beck Depression Inventory or Hamilton Depression 

Inventory); instruments designed to assess symptoms in a medically ill population (such as the 

Hospital Anxiety and Depression Scale and the Brief Symptom Inventory); and rapid assessment 

instruments (such as The Distress Thermometer). Some of these instruments are currently being 

used in clinical settings to screen for depressive symptoms.

Treatment of Cancer-related Depression 

Recognizing the importance of psychological symptoms that accompany cancer, the National 

Comprehensive Cancer Network (NCCN) published its consensus guidelines for the 

management of psychosocial distress in cancer patients (National Comprehensive Cancer 

Network, 1999). Depressive symptoms fall under the umbrella of psychosocial distress and are 

thought to be common in patients with cancer. 

The NCCN guidelines contain three main components for management: screening, 

assessment, and treatment. Part of the assessment process is determining an appropriate 

treatment or referral. Depending on the severity of symptoms and the presence of suicidal 

ideation, the NCCN has algorithms for treatment. 

As with depression in non-cancer populations, treatment for depression in cancer patients can 

take the form of psychosocial interventions and psychotherapy, medications, or alternative 

treatments. Many times patients receive a combination of these treatments. 

Much of the research on treatment for depression in cancer patients has been on psychosocial 

interventions. Support groups, group therapy, psycho-education, cognitive-behavioral therapy, 

and individual counseling are all psychosocial interventions that are being used clinically and 

have been studied. In contrast to non-cancer populations and based on the high prevalence rates 

of depression in cancer patients, there have been many preventative trials of psychosocial 

interventions on depressive symptoms. 

There has been considerably less research on the effects of psychopharmacologic 

interventions on depression in cancer patients. This may be due at least in part to some of the 

special challenges that an oncology sample would pose compared to a standard psychiatric 

sample in a clinical trial. Holland, Romano, Heiligenstein, et al., (1998) have cited some of these 

challenges: finding treatment groups that are homogeneous enough to obtain meaningful results, 

recruitment of large numbers of subjects to achieve adequate power to detect differences, and 

difficulties with retention and completion, often complicated by medical morbidity and 

mortality. 

16
Increasing general interest in alternative treatments in both oncology and psychiatry has 

prompted many clinicians and patients to try these therapies. Although there is less data 

available on these treatments, research in this area is also increasing. 

Cancer-related Fatigue 

Fatigue associated with cancer and cancer treatment appears to be qualitatively and 

quantitatively distinct from the fatigue that is experienced intermittently by healthy individuals. 

Although the experience of fatigue probably varies greatly among individual patients, common 

themes in the subjective accounts of patients with cancer are the persistence of fatigue despite 

rest and sleep, and its interference with physical and mental function. Cancer-related fatigue 

probably encompasses a number of distinct syndromes, including muscle weakness, lack of 

stamina, and loss of ability to concentrate. Imprecision in the terminology of fatigue may 

sometimes mask important distinctions between these syndromes. Fatigue may be the final 

common pathway arising from a complex combination of physical syndromes and psychological 

states that is different in each oncology patient. Nonetheless, the term fatigue is useful because it 

represents an experience that is universally recognized. 

Although fatigue is at least as prevalent and debilitating as pain in many contexts, it may 

often go unrecognized unless specifically addressed by caregivers. Even when recognized, 

treatment options are limited unless reversible conditions that contribute to fatigue can be 

addressed. 

Fatigue in cancer patients is both a side effect of treatment and a consequence of the biologic 

effects of the cancer itself. The direct effects include (but are certainly not limited to) metabolic 

and nutritional disturbances, endocrine dysfunction, neurologic, psychological, neuromuscular, 

and cognitive effects. The mechanisms of many of these effects are poorly understood. Fatigue 

has been ascribed to the abnormal production of inflammatory cytokines in the setting of cancer, 

but the specific evidence for the role of cytokines in cancer-related fatigue is fragmentary. 

Methodological difficulties in the study of the mechanisms of cancer-related fatigue include 

the ability to determine whether elevated levels of biologic factors such as cytokines cause 

symptoms or are merely associated with them. Also, the development of animal models of 

cancer-related fatigue is problematic due to the inherent subjectivity of the symptom and the 

difficulty of establishing objective, behavioral correlates of fatigue. Voluntary, motivated 

activity has been proposed as one such correlate in animals (Ottenweller, Natelson, Gause, et al., 

1998). In human subjects, patterns of rest and activity as measured continuously by a wrist 

actigraph were found to correlate with subjective self-reports of fatigue (Berger, 1998). 

In addition to the direct effects of cancer and the various modes of cancer treatment, a wide 

variety of other phenomena contribute to fatigue in cancer patients. The best studied of these 

(and the most amenable to available interventions) is anemia due to chemotherapy. The impact 

of depression in cancer is outlined elsewhere in this study, and while depression undoubtedly 

contributes to fatigue in cancer patients, the interaction of fatigue and depression has not been 

well studied. A variety of other cancer symptoms, including dyspnea, fever, nausea, and pain 

probably contribute to fatigue. In addition, sedation is a common side effect of the medications 

used to treat cancer symptoms, notably the opioid analgesics and anti-emetics, another factor that 

may contribute to fatigue. 

17
Prevalence of Cancer-related Fatigue 

Reported prevalence rates of fatigue in cancer patients and survivors are extremely variable, 

reflecting both the heterogeneity of the populations studied, the variety of techniques used to 

measure fatigue, and the absence of consensus on criteria for the definition of fatigue. There is 

reason to suspect, however, that many studies systematically underestimate the degree of fatigue 

experienced by cancer patients, since the most fatigued patients may decline to participate in 

studies or may be unable to attend academic referral centers where most studies were performed. 

Thus, there are potential biases involved in the use of small, non-random cohorts in studying the 

prevalence of cancer-related fatigue. There are only two true population-based studies (Cella, 

Davis, Breitbart, et al., 2001; Vogelzang, Breitbart, Cella, et al., 1997). They assessed the 

prevalence of fatigue in telephone surveys of cancer patients and survivors recruited from large, 

representative samples of households in the United States, rather than in non-random or 

convenience samples as were used in many other studies. 

Each study assessed fatigue over a short time period, for example during a course of 

radiation therapy and shortly after its completion (Irvine, Vincent, Graydon, et al., 1998), or in 

survivors at one time point after treatment (Woo, Dibble, Piper, et al., 1998). We were unable to 

identify longitudinal studies of fatigue reporting its prevalence and patterns over the entire 

course of illness using uniform methodology. 

Assessment of Cancer-related Fatigue 

The NCCN has developed practice guidelines for cancer-related fatigue reflecting currently 

accepted approaches to assessment and treatment (Atkinson, Barsevick, Cella, et al. 2000). That 

report emphasizes the high prevalence of fatigue at all stages of cancer and the need for 

screening and assessment of fatigue as an integral part of cancer care. Since fatigue is subjective, 

patient self-reports are central to its assessment. Information provided by family members can 

offer a perspective on the behavioral consequences of fatigue. The medical history, physical 

examination, and laboratory data may also be useful in the assessment of fatigue. The NCCN 

guideline has recommended the routine use of a quantitative or semi-quantitative screening 

device, such as a 0-10 numeric scale. For those with moderate or severe fatigue, a focused 

evaluation is performed to assess the characteristics of the fatigue and to determine whether 

contributing factors such as pain, emotional distress, anemia, sleep disturbance or endocrine 

dysfunction are present. If such factors are not identified a more comprehensive evaluation is 

recommended, including a review of systems, review of medications, assessment of 

comorbidities, nutritional and metabolic assessment, and assessment of activity. 

The assessment of cancer-related fatigue in the context of clinical research has a somewhat 

different emphasis than the clinical guidelines promulgated by the NCCN. The foci of 

assessment in fatigue research have been: 1) to quantify the prevalence, pattern and severity of 

fatigue in a variety of settings 2) to determine factors that predict or correlate with fatigue, 

including other symptoms, biological parameters (e.g., cytokine or hormone levels), disease and 

treatment variables, and demographics, and 3) to assess the response of fatigue to interventions. 

For these purposes, a number of patient self-report instruments have been developed, and an 

epidemiology of fatigue is beginning to emerge as described in this report. A number of issues 

remain to be addressed regarding the assessment of cancer-related fatigue, however. These 

include the clinical significance of measurements of fatigue, the development of objective, 

measurable physiologic correlates of fatigue, methods for comparing measurements obtained by 

different fatigue instruments, and the degree to which cancer-related fatigue can be attributed to 

18
specific etiologic factors such as the effects of chemotherapy and radiotherapy, anemia, and 

depression. 

Treatment of Cancer-related Fatigue 

There is limited evidence to support specific interventions to ameliorate cancer-related 

fatigue, with the exception of epoetin alfa for the treatment of anemia and its symptoms during 

chemotherapy (Littlewood, Bajetta, Nortier, et al., 2001). This is perhaps not surprising given the 

fragmentary understanding of the fundamental physiology of fatigue, and its probable 

multifactorial basis in most patients. The initial approach advocated by the NCCN panel is 

therefore to assess regularly and address the common, potentially remediable factors that may 

contribute to fatigue, such as anemia, sleep disturbances, medication effects, electrolyte 

abnormalities and hypothyroidism. The degree to which cancer-related fatigue can be attributed 

to such reversible causes is unknown, but it is fairly clear that there is an enormous burden of 

fatigue that is not attributable to such specific causes or persists despite appropriate treatment for 

them. When specific, reversible causes of fatigue cannot be identified, or fatigue fails to respond 

to appropriate intervention for them, the NCCN panel of experts advocates a more 

comprehensive assessment, education and counseling, and consideration of a number of 

interventions. These include non-pharmacologic approaches such as exercise, stress 

management, and energy conservation, and pharmacologic approaches such as corticosteroids, 

psychostimulants, and antidepressants. These recommendations were the result of a consensus 

based on clinical experience, rather than evidence from randomized clinical trials. As reviewed 

below, a small number of randomized controlled trials have evaluated psychosocial 

interventions, exercise programs, and other methods of treatment for fatigue. The data on 

exercise is promising, but in general unless a specific etiology of fatigue (e.g., anemia or 

depression) can be identified and treated, there is extremely limited evidence from clinical trials 

to support any interventions for cancer-related fatigue. 

19
Chapter 2. Methodology 

This evidence report is based on a systematic review of the literature. It is produced to 

provide background information for the NIH Office of Medical Applications of Research 

(OMAR) and the National Cancer Institute for use in a Consensus Development Conference, 

July 2002. Meetings and teleconferences of the EPC staff with technical experts were held to 

identify specific issues central to this report. A comprehensive search of the medical literature 

was conducted to identify relevant studies. We compiled evidence tables of study characteristics 

and results, appraised the methodological quality of the studies, and summarized their results. 

The planning committee acknowledged that many symptoms are relevant to the care of 

cancer patients but the current conference can only address a limited number of topics. Pain, 

depression, and fatigue were selected as the focus of this conference. The planning committee 

identified the prevalence, assessment, and treatments as the key issues to be addressed for each 

of the three chosen symptoms. 

The purpose of an evidence report is to summarize information from relevant studies 

addressing specific key questions. Due to the large number of topics and the broad nature of 

some of these topics, it is beyond the scope of this evidence report to cover all possible related 

issues on the topics covered in this conference. In addition to information summarized in our 

evidence report, speakers have been invited to the Consensus Development Conference to cover 

specific issues. 

Questions Formulated by the Planning Committee for the Conference 

The following questions were formulated by the planning committee for the Consensus 

Development Conference: 

1. What is the occurrence of pain, depression, and fatigue, alone and in combination, in 

people with cancer? 

2. 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?

3. What are the treatments for cancer-related pain, depression, and fatigue, and what is the 

evidence for their effectiveness?

4. What are the impediments to effective symptom management in people diagnosed with 

cancer, and what are optimal strategies to overcome these? 

5. What are the directions for future research? 

Topics Addressed in this Evidence Report 

Several conference questions are very broad in scope and cover many interrelated issues. 

Addressing them fully is beyond the scope of this evidence report. The various combinations of 

symptoms and issues yielded nine distinct topics. Thus, we structured this evidence report in the 

following manner: 

1. Prevalence of cancer-related pain 

2. Prevalence of cancer-related depression 

3. Prevalence of cancer-related fatigue

4. Assessment of cancer-related pain 

5. Assessment of cancer-related depression 

21
6. Assessment of cancer-related fatigue

7. Treatment of cancer-related pain 

8. Treatment of cancer-related depression 

9. Treatment of cancer-related fatigue 

For some of these topics, in particular the treatment of cancer pain, there are multiple 

questions and subquestions. 

General Approach of this Evidence Report 

Our evidence-based practice center produced an evidence report on the Management of 

Cancer Pain based on a literature search conducted in December 1998 (Goudas, Carr, Bloch et 

al., 2001). For cancer-related pain topics in the present evidence report, we updated the key 

questions addressed in the previous report. At the request of the conference planning committee, 

we added two new topics to the treatment of cancer-related pain: oral mucositis and post-herpetic 

neuralgia. We summarize the methodological approach and report the new results in the present 

evidence report. Readers are referred to the earlier evidence report for detailed information about 

the methodological approach and the results. We conducted new systematic reviews for the 

symptoms of cancer-related depression and cancer-related fatigue. 

Literature Search 

Three separate literature searches were conducted for this evidence report. The National 

Library of Medicine (NLM), as a partner in the Consensus Development Conference process, 

with input from the EPC staff, performed the literature search for cancer-related depression and 

cancer-related fatigue. The general approach for all three symptoms, including cancer-related 

pain, was to identify human studies published in English language. 

Cancer-related Pain 

For cancer pain, we applied the same search strategy used in our Management of Cancer 

Pain evidence report (Goudas, Carr, Bloch et al., 2001) to identify new studies published in the 

period from December 1998 through June 2001. This methodology is only briefly summarized 

below since it is already provided in detail in the earlier evidence report. We performed literature 

search in the MEDLINE® and CANCERLIT® databases. Overlapping reports between the 

MEDLINE® and CANCERLIT® databases were excluded from the CANCERLIT® search. We

also searched the Cochrane Controlled Trials Registry and consulted technical experts and 

examined references of published meta-analyses and selected review articles for additional 

studies. 

Separate literature searches were conducted for oral mucositis and postherpetic neuraligia. 

We identified published reports of randomized clinical trials on prevention and treatment of oral 

mucositis by using a search strategy in MEDLINE® between 1966 and November 2001. The 

search strategy consisted of the keywords "Stomatitis," "Mouth Mucosa," "Radiation Injuries," 

"Neoplasms," and "cancer," and was limited to "human and English language" and to 

"prospective studies" or "randomized" or "random allocation" or "clinical trials" or "double blind 

method." This search strategy yielded 660 reports from which we selected 114 RCTs and 2 

systematic reviews pertinent to the question at hand. We performed supplemental hand searches 

based on the literature cited in these articles. The supplemental searches added no qualified 

22
randomized trial to this report. The abstracts of these reports were screened to select appropriate 

articles for inclusion in the present synthesis. 

We performed a systematic review of the literature aiming to address the questions of 

prevalence of acute zoster related pain and postherpetic neuralgia and of the relative efficacy of 

available treatments for herpes for acute zoster pain and postherpetic neuralgia in cancer patients. 

We identified published randomized clinical trials reporting on acute zoster pain and postherpetic 

neuralgia following treatment of acute herpes infection. We searched MEDLINE® between 1966 

and November 2001. The search strategy consisted of combinations of the keywords 

"Neuralgia," "Herpes Zoster," "Pain," "neoplasia," and "Neoplasms," and was limited by the 

keywords "human," "English language," and "controlled clinical trial." We performed 

supplemental hand searches based on the literature cited in these articles. The supplemental 

searches added no qualified randomized trial to this report. The abstracts of these reports were 

screened to select appropriate articles for inclusion in the present synthesis. 

Cancer-related Depression 

NLM staff performed the literature search for cancer-related depression articles in November 

2001. Several search strategies were evaluated. The initial search was conducted in PUBMED®

and used broad medical subject headings including: neoplasms combined with depression OR 

depressive disorder OR antidepressive agents. Letters, news, editorials, and non-English citations 

were eliminated. PsycInfo, CINAHL®, and BIOSIS® were also searched using depression and 

neoplasms as major headings. The initial search strategy yielded over 3,000 citations. The final 

search strategy that we used limited the retrieval to those citations that had the term depression as 

a descriptor or in the title. This strategy yielded about 1,000 articles, and the domain expert of 

this evidence report screened them. Additionally, bibliographies of review articles or chapters 

were used to identify relevant studies. 

Cancer-related Fatigue 

NLM staff performed two separate but linked searches in September 2001, one from

MEDLINE® and another from several databases (EMBASE, PsychInfo, BIOSIS®, NTIS, 

CINAHL®, and Allied and Complementary Medicine) to identify English-language articles that 

dealt with assessment, prevalence, and treatment of fatigue in cancer patients. The searches 

yielded 1,137 abstracts, and they were screened for relevance to the specific topics. One hundred 

seventy-six abstracts were selected for retrieval. Screening of these articles resulted in the 

elimination of almost half, and ultimately 56 papers were judged to be relevant. 

Data were subsequently and systematically extracted, and their elements were the following: 

population and setting of the cancer patients, size of trial, age, range and percentage of 

male/female, types of cancer studies, scales used to assess the symptoms of fatigue, time points 

of measurement, the results and conclusions of the authors. 

Selection of Studies 

Patient Population Studied

We accepted all studies of patients with a diagnosis of cancer who suffered from pain, 

depression, or fatigue due to cancer or cancer treatment. We 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 

23
trajectory of disease, including but not limited to, periods of active treatment and at the end of 

life. 

Cancer-related Pain 

In this report, we retrieved studies presenting data on three broad categories of patients: 

• Patients with pain resulting from direct tumor involvement, from either local disease or 

distant metastases, and involving sites such as bone, soft tissue, or neural structures.

• Patients with pain resulting from a therapeutic, diagnostic, or palliative intervention 

(procedural pain), such as chronic post-mastectomy or lumbar puncture pain. 

• Patients with pain resulting from the side effects of anti-tumor treatment, such as acute 

herpes zoster or postherpetic neuralgia or oral mucositis pain.

We did not review and summarize randomized controlled trials already included in the 

previously published evidence report on management of cancer pain, or included in published 

systematic reviews that were retrieved during the present search process. Instead, we 

summarized results of those systematic reviews we deemed comprehensive. Studies on acute 

postsurgical pain in patients were excluded. We placed no restriction on article inclusion 

according to etiology, nature, or mechanism of pain as classified according to any cancer-related 

pain classification system. 

Key Questions Addressed in the Management of Cancer Pain Evidence Report 

Reproduced here are the key questions addressed in the Management of Cancer Pain

evidence report. Readers are referred to this report for a more detailed description of the specific 

questions. 

Question 1. What are the epidemiological characteristics of cancer-related pain, including 

pain caused by cancer, by the side effects of cancer treatment, and by procedures used to treat 

cancer? 

Question 2. What is the relative efficacy of current analgesics for cancer pain? 

Question 3. Are different formulations and routes of administration associated with different 

patient preferences or different efficacy rates?

Question 4. What is the relative analgesic efficacy of palliative pharmacological 

(chemotherapy, biphosphonates or calcitonin) and non-pharmacological cytotoxic or -static 

(radiation therapy or radionuclide) therapy?

Question 5. What is the relative efficacy of current adjuvant (non-pharmacological/non

invasive) physical or psychological treatments (relaxation, massage, heat and cold, music, 

exercise, and so on) in the management of cancer-related pain? 

Question 6. What is the relative efficacy of current invasive surgical and non-surgical 

treatments, such as acupuncture, nerve blocks, and neuroablation, on the treatment of cancerrelated pain? 

Cancer-related Depression 

Because the search for depressive symptoms in cancer produced several thousand citations, a 

second more selective search was performed. In order to focus the scope, we limited our 

literature review to studies that specifically assessed depressive symptoms rather than including 

more general quality of life (QOL) data from every cancer clinical trial. Not only would 

reviewing all of the QOL studies be beyond the scope of this report, but also there is some

evidence that the mental health domains of QOL scales may not be sensitive for clinically 

24
significant depressive symptoms in oncology populations. We also did not include studies that 

compared QOL outcomes between different cancer treatments. 

Because “depression” was not limited to major depressive disorder, choices were made 

regarding the definition of “depression” and the scope of the review. Unlike pain and fatigue, 

depression can be both a set of symptoms and clinical syndromes. Depressive symptoms are 

present in several psychiatric disorders with the most common in cancer patient being major 

depressive disorder, adjustment disorder, and depression secondary to a general medical 

condition. Because major depressive disorder is the most described in this population, we 

focused the review on studies of major depressive disorder. 

However, limiting the review to major depressive disorder does not capture the prevalence of 

depressive symptoms in cancer patients, regardless of diagnosis. We also chose to review 

studies that assessed the presence of depressive symptoms. Because of the numerous 

instruments used to assess depressive symptoms and psychological distress in people with 

cancer, the most frequently used instrument was chosen to review in order to allow some

comparability of data. 

Similarly, the assessment of depression would include the assessment of major depressive 

disorder as well as depressive symptoms. However, again because of the numerous instruments 

used to assess psychological distress in people with cancer, we chose to only review papers that 

directly compared instruments. 

The bulk of treatment studies for depression in cancer patients has used psychosocial 

interventions. Because there have been hundreds of studies and published meta-analyses were 

identified, we limited our review of these interventions to the meta-analyses. The reviews of 

treatment studies using psychopharmacologic and alternative interventions were limited to 

controlled trials. 

Cancer-related Fatigue 

This report summarized the scientific evidence on the assessment, prevalence, and treatment 

of fatigue in cancer patients. It was not limited to certain types of malignancy or treatment 

modalities, but occurred in patients with all types of cancer, from early to advanced stages, 

receiving chemotherapy, radiation therapy, hormonal therapy, biologic therapy, bone marrow or 

stem cell transplantation, or combined modality treatments. 

There were many studies that included the assessment of one or more cancer-related 

symptoms, more than we can evaluate in this evidence report. To address the topic of the 

prevalence of cancer-related fatigue, we accepted studies that assessed fatigue as the primary 

purpose of the study. We accepted both retrospective and prospective studies. We excluded 

studies that used general health QOL measurements and also clinical trials that measured fatigue 

as part of the outcomes. We accepted only randomized controlled trials for the topic of treatment 

of cancer-related fatigue.

Reporting the Data

Full articles for selected abstracts were retrieved and examined in detail for possible data 

abstraction and inclusion in the evidence tables. We summed up the evidence in the literature 

using three complementary approaches. Evidence tables provided detailed information about the 

study design, patient characteristics, inclusion and exclusion criteria, intervention or test 

evaluated, and the outcomes of all the studies examined in each of the nine topics in this 

evidence report. 

25
The evidence tables were condensed into summary tables to provide a more succinct 

impression of the study quality and results. Where appropriate, we graded the studies according 

to the methodological quality and applicability of the study. The study size and the effect or test 

performance are also reported in the summary tables. Summarizing the data this way makes it 

easier to compare studies. 

We summarized the published meta-analyses when we used them to address specific topics. 

Finally, for several topics, we provide an overall summary of information presented in various 

related tables. A narrative description of individual studies along with an evidence-grading 

scheme is employed to summarize the evidence used to address each of the topics. 

Updates of the Management of Cancer Pain Evidence Report Key Questions 

For the updates to the previously published Management of Cancer Pain evidence report, 

we followed the same format and used the same key question numbers in reporting the new 

evidence. In general, we grouped studies that met the inclusion criteria according to six broad 

treatment categories derived from the earlier Management of Cancer Pain Clinical Practice 

Guideline (Jacox, Carr, Payne, et al., 1994): 

• primary pharmacological interventions (opioids, acetaminophen, and NSAIDs, local 

anesthetics)

• secondary pharmacological interventions or adjuvant analgesics (psychostimulants, 

alpha-2 agonists, tricyclic antidepressants, etc.) 

• nonpharmacological interventions (physical, psychosocial, and educational interventions, 

e.g., hypnosis, massage, TENS, music, relaxation, and acupuncture) 

• nonpharmacological invasive interventions (neuroaugmentation, neurolytic block) 

• antineoplastic interventions (radiotherapy, chemotherapy, biphosphonates) 

• other various treatments interventions (not under previous categories) 

Data from studies addressing the same question were included in the same category of 

evidence table. Variables that generally apply to any clinical trial (e.g., study design) as well as 

more specific variables (e.g., therapy for breakthrough pain) that apply only to studies on cancer 

pain management were considered in selecting variables to be included in the evidence tables

(see the Evidence Tables for these variables). 

Grading of the Evidence for Randomized Controlled Trials 

Grading of evidence can be useful in appreciating the overall “quality” of a group of studies 

addressing a question. Over two dozen scales have been proposed to evaluate the quality of 

randomized controlled trials (Moher, Jadad, Nichol, et al., 1995). While it may be desirable to 

have a simple evidence grading system using a single quantity, the “quality” of evidence is 

multidimensional and a single metric cannot fully capture information needed to interpret a 

clinical study (Ioannidis and Lau, 1998). 

The evidence tables contain detailed information about the study characteristics, population 

and disease characteristics, patient demographics, treatment comparisons, and outcome 

measures. We used this information to derive an evidence-grade to provide an indication of 

“quality” for each of the randomized controlled trials used to address the key questions. This 

evidence-grading scheme captures four dimensions of a study that are important for the proper 

interpretation of the evidence: internal validity, applicability, magnitude of treatment effect, and 

the size of the study. This evidence-grading scheme is used as part of the reporting of the results. 

26
Internal Validity

Internal validity addresses the design, conduct, and reporting of the clinical trial. Some of the 

items belonging to this entity have been widely used in various “quality” scales and usually 

include items such as concealment of random allocation, treatment blinding, and handling of 

dropouts. In this evidence report, we define a four category internal validity scale: A (least bias), 

B (susceptible to some bias), C (likely to have large bias), I (unable to assess due to lack of 

reported information). 

A. Double-blinded, well-concealed randomization, few drop outs, and no (or only minor) 

reporting problem of the trial that is likely to cause significant bias. 

B. Single-blinded only, unclear concealment of randomization, or has some inconsistency in 

the reporting of the trial but is unlikely to result in major bias. 

C. Unblinded study, inadequate concealment of random allocation, high dropout rate, or has 

substantial inconsistencies in the reporting of the trial such that it may result in large bias. 

I. Inadequately reported (very often trials do not report certain data; this may occur by 

intent or due to oversight.) 

Applicability

Applicability, also known as generalizability or external validity, addresses the issue of 

whether the evidence from the study population is sufficiently broad as to be able to generalize to 

the population at large. Individual studies are often unable to achieve broad applicability due to 

restricted study population characteristics and a small number of study subjects (Lau, Ioannidis, 

Schmid, 1997). We define the applicability grade as below: 

A. Patients enrolled in the trial represent a broad spectrum of the population (high degree of 

applicability). Typically this would be a large study, although a large study in itself does 

not guarantee a high degree of generalizability. 

B. The study included only a narrow/restricted study population, but the result is relevant to 

similar types of patient population (restricted applicability). Typically this would be a 

small study, but may also be a large study of a very homogeneous population. 

C. Studied outlier population that is not immediately relevant to the study question (very 

limited direct applicability or not applicable), or where the study reported only limited 

information. 

I. Not reported or insufficient information to assess external validity issues (uncertain 

applicability). 

Because the efficacy of pain treatments may depend on the baseline level of pain, we also 

extracted data on baseline pain intensity of the study population to assist in the interpretation of 

results. We report in the evidence grading tables, along with the applicability rating, the baseline 

pain intensity expressed as VAS (visual analog scale) of 0-10cm (or 0-100mm) when this data is 

reported in the study. Studies that did not provide 0-10cm VAS data but reported qualitative 

descriptions or other scale are so noted in the tables. 

Study Size 

The study size is used as a measure of the weight of the evidence. Some studies have a high 

drop out rate due to deaths from the underlying cancer; we provide both the enrolled and 

evaluable number of patients, when these data are reported. A large study provides a more 

precise estimation of the treatment effect but does not automatically confer broad applicability 

27
unless the study included a broad spectrum of patients. Very small studies, taken individually, 

cannot achieve broad applicability. But several small studies that enrolled diverse populations, 

taken together, may have broad applicability. The study size is included as a separate dimension 

used to assist the assessment of applicability. For summarizing all studies, this would be the 

number of studies and the total number of patients in these studies. 

Magnitude of the Treatment Effect of Cancer-related Pain Studies 

In each of the result tables, “effect size” reflects the difference between outcomes in the 

treatment arms of the study, not pre- versus post comparisons in the experimental group. For 

example if an experimental opioid were compared with morphine, and both treatments were 

found to have a large effect upon pain scores, then the effect size assigned to this study would be 

a “±”. 

The following effect size scale is employed for studies that provide consistent reporting of a 

pain-related outcome: 

+++ large difference in effect (>20 mm on 0-100 mm VAS between control and 

experimental group) 

++ modest difference in effect (10-20 mm on 0-100 mm VAS between control and 

experimental group) 

+ small difference in effect (5-10 mm on 0-100 mm VAS between control and 

experimental group) 

± no difference in effect (0-4 mm on 0-100 mm VAS between control and 

experimental group) 

- negative (harmful) effect (applicable only to placebo trial) 

It should be noted that large difference in effect does not necessarily imply a statistically 

significant difference. 

The outcomes reported by available studies on some of the questions were heterogeneous and 

were not amenable to categorizing the effect size on the same scale. This group of heterogeneous 

outcomes includes drug consumption, pain relief, and QOL-related indices. These studies were 

evaluated by pain management experts and assigned a qualitative score for the effect size. 

+++ large beneficial effect 

++ modest beneficial effect 

+ small beneficial effect 

± no beneficial effect 

28
Chapter 3. Results 

Findings for Specific Topics 

Prevalence 

Prevalence of Cancer-related Pain

Summary of Findings 

We identified and summarized the findings of 29 epidemiological studies reporting on the 

prevalence and/or incidence of cancer-related pain. These were nationwide or multicenter 

surveys including as many as 35,000 patients, and hospital or clinic-based surveys including a 

few hundred or fewer patients. More than half of these studies were conducted in the United 

States. The majority of the remaining studies are from Europe (Finland, France, Germany, 

UK/Ireland). No single survey identified a pain prevalence rate below 14% of the patients 

surveyed. Based on these surveys no correlation could be devised between the prevalence or 

incidence of pain and patient factors, disease characteristics, the setting in which care is provided 

(e.g., primary care or specialized oncology or pain treatment clinics), or specific treatments 

directed towards the underlying disease and its associated pain.

Table 1a. Summary of epidemiological studies reporting on the prevalence and/or incidence of

cancer related pain (N=29) 

Author, 

Year 

Identifier

Country

Setting N Site of cancer 

Incidence or

prevalence of pain 

(summary) 

Daut 1982 

87097307 

USA 

hospital clinic

667 Breast, prostate, colon/rectal, 

cervix/uterus/ ovary 

14% to 64% 

Ahles 1984 

84242554 

USA 

Clinic 

208 Breast Lung Lymphoma Colon 

Other 

51% 

Gilbert 1986 

87097307 

USA 

Clinic 

162 Non-Hodgkin’s lymphoma,

breast, liver, lung, myeloma, 

colon 

21% 

Miser 1987 

87230445 

USA 

hospital 

Clinic

139 Leukemia, soft tissue sarcoma, 

Ewing’s sarcoma, 

osteosarcoma, lymphoma, other 

26%-54% 

Miser 1987 

87230446 

USA hospital 

Clinic

92 Soft tissue sarcoma 

Ewing’s sarcoma 

Osteosarcoma

Leukemia Lymphoma 

Neuroblastoma 

52.2% - 100% 

Greenwald 

1987 

88026644 

 USA hospital 536 Lung, prostate, 

uterus/cervix, 

pancreas) 

38.0% - 60.0%

Coyle1990 

90270702 

USA 

Pain service 

90 Lung, colon, breast, head & 

neck, gynecologic, others 

100% 

29
Author, 

Year 

Identifier

Country

Setting N Site of cancer 

Incidence or

prevalence of pain 

(summary) 

Portenoy 

1990 

90356275 

USA 

Pain service 

63 Genitourinary, head/neck,

gastrointestinal, lung, sarcoma 

100% 

breakthrough pain 

Hiraga 1991 

92100649 

Japan nationwide 

hospitals 

35,683 (31.6%

of all 

hospitalized 

patients at the 

time of survey) 

Stomach, liver/biliary/pancreas, 

lung, colon/rectal, 

oral/pharynx/larynx, 

ovary/cervix/corpus, GU, 

lymphoma/leukemia, breast 

32.6% 

Brescia 

1992 

92092056 

USA 

specialty 

hospital for 

advanced 

cancer

1,103 Lung, breast, colon, colonrectum, other 73% 

(at admission) 

Vuorinen 

1993 

94162760 

 Finland 

pain 

clinic 

378 

(240 evaluable) 

Genitourinary, GI, breast, 

hematological, lung, skin 

28% 

Portenoy 

1994 

94313536 

USA 

hospital 

Clinic

151 Ovaries 42% to 62% 

Cleeland 

1994 

94134141 

USA 

54 oncology 

clinics 

1,308 Breast, GI, lung, GU, lymphoma, 

Gynecological 

No data available 

Larue 1995 

95245216 

France 

20 cancer 

services

605 Breast, GI, genitourinary, lung, 

head & neck, lymphoma, other 

57% 

Stevens 

1995 

95372100 

USA 

16 

ambulatory 

care services

435 Breast (postmastectomy) 15% 

Vainio 1996 

96280298 

Switzerland 

(data from

UK, 

Switzerland, 

Finland, USA

and 

Australia) 

Hospices

1,640 Lung, breast, colorectal, head & 

neck, stomach, prostate, 

gynecological, Lymphohematological, esophagus, other 

43% - 80% 

Grond 1996 

97020892 

Germany 

pain service 

2,266 GI, genitourinary, head & neck, 

breast, lung, lymphatichematopoetic, skin, bone, 

connective tissue 

30% - 39% 

Tasmuth 

1996 

97134848 

Finland 

University

Hospital 

105 Breast (postmastectomy) 23% - 36% 

Higginson 

1997 

97367049 

UK, 

Ireland 

Multidisciplin

ary palliative 

care centers

(6 in 

England, 5 in 

London) 

695 Lung/ENT, GI, genitourinary, 

Breast/bone, 

Lymph/hematopoetic, other 

63% - 90% 

30
Author, 

Year 

Identifier

Country

Setting N Site of cancer 

Incidence or

prevalence of pain 

(summary) 

Bernabei 

1998 

98296015 

USA 

1492 nursing 

homes 

13,625 Not provided 27.38%

reported daily pain. 

age >85 

Ger 1998 

98318902 

Taiwan

3 outpatient 

oncology 

clinics 

296 Lung, upper GI, colorectal, head 

& neck, other 

38% 

Petzke 1999 

10388244 

Part I 

Germany 

Outpatient 

Clinic

243 GI, GU, head/neck, breast, other 54% - 92% 

Same as

above 

Part II 

Germany 

Clinic as 

above 

55 Comparable to those in Part I. 47% 

transitory pain 

Chang 2000 

10699909 

US 

VA Medical 

Center

240 Solid tumors, hematologic 52% 

Zepetella 

2000 

10989246 

UK 

Hospice

245 Lung, breast, prostate and 

unknown primary 

89% 

breakthrough pain 

Meuser 

2001 

11514084 

Germany 

Pain Service

593 GI, lung, GU, head/neck, other 94.3% (used 

opioids) 

Beck 2001 

11576747 

South Africa 

2 healthcare 

facilities 

Phase I 

263 

All types ~45% 

Same as

above 

Phase II

479

Prostate, lung, head/neck and 

esophagus accounted for 50.5%, 

in females breast and cervix, 

lymphoma, colorectal and 

esophageal 

57.4% 

Summaries of Epidemiological Studies 

Daut and Cleeland (1982) reported their observations on the frequency, severity, and 

disruptiveness of pain in a population of 667 cancer patients. These patients were evaluated at a 

comprehensive cancer center and had cancers of the breast (43.3%), colon and rectum (19%), 

prostate (7.2%), cervix (13.6%), uterus (4%), and ovaries (12%). The authors found that the 

proportion of patients with pain varied according to primary site and degree of progression of the 

disease (non-metastatic versus metastatic cancer). When pain was present, its intensity was 

moderate and was reported by patients to interfere with their activity and enjoyment of life to a 

moderate to severe extent. Interference with activity and enjoyment of life correlated better with 

pain due to cancer than pain due to another cause. 

Ahles, Ruckdeschel, Blanchard (1984) examined 208 consecutive ambulatory patients with 

cancer and found that approximately half (47.9%) reported no pain during the preceding week, 

31
while 33.5% had pain directly related to cancer and 6.7% had pain related to the treatment of 

cancer. In a small group (11%) pain was attributed to a source unrelated to cancer. Significantly 

more patients with bone metastases reported cancer-related pain as compared to patients with 

local and regional disease (p<0.001). Among different diagnostic categories, patients with 

lymphoma reported the lowest presence of cancer-related pain. 

Gilbert and Grossman (1986) surveyed medical records of patients admitted to the oncology 

service of the Johns Hopkins Oncology Center over a 3-month period aiming to determine the 

incidence and nature of major neurologic problems on the inpatient service of a university-based 

comprehensive cancer center. The type of cancer in this population was non-Hodgkin’s 

lymphoma in 26/162 (16.0%), breast cancer in 17/162 (10.5%), hepatoma in 15/162 (9.2%), 

small cell lung cancer in 13/162 (8.0%), multiple myeloma in 13/162 (8.0%), colon in 10/162 

(6.1%), and other types in less that 10%. Seventy-two of 162 (46%) of patients admitted had 

tumor invading or compressing the nervous system, pain, seizures, or some change in their 

mental status. Of the most common problems pain was encountered in 34/162 (21%). Based on 

their observations the authors predict that evaluation or treatment of a neurologic problem will be 

the most common reason for hospital admission in patients with disseminated cancer. 

Miser, Dothage, Wesley et al. (1987) reported on the incidence and nature of pain in a mixed 

pediatric and young adult population of 92 newly diagnosed patients with cancer at the Pediatric 

Branch of the National Cancer Institute over a 6-month period. One hundred and thirty-nine 

patients were evaluated during 161 inpatient days and 195 outpatient clinic visits. Pain was 

present in 54% of total inpatient population and 26% of outpatient population. In 46% pain was 

due to tumor alone, in 14% pain was associated with both tumor and therapy, and in 40% pain 

was related to cancer treatment. Cancer-related pain was due to bone invasion in 68%, cord 

compression in 5%, and from multiple causes in 11%. Pain was associated with decreased 

functional status (Karnofsky score). Interestingly, during the study period, seven patients were 

identified with chronic pain that persisted more than one year following eradication of all known 

tumor from the site of pain. 

Miser, McCalla, Dothage et al. (1987) reported on the incidence and nature of pain in a 

mixed pediatric and young adult population of 92 patients newly diagnosed with cancer at the 

Pediatric Branch of the National Cancer Institute over a 26-month period. At the time of initial 

evaluation, 72 of the 92 patients were experiencing pain that had been present for a median of 74 

days (range 3-821 days) prior to initiation of cancer treatment. In 57 patients, pain had been an 

initial symptom of cancer. Pain was associated with a lower functional status (Karnofsky score). 

Greenwald, Bonica, and Bergner (1987) reported on the prevalence of pain in four cancers 

(lung, prostate, cervix/uterus and pancreas) in 536 patients evaluated in community as well as 

specialized treatment centers. In their survey the authors included measures of several distinct 

features of pain. The prevalence of pain ranged from 50.7% in lung cancer to 60% in pancreatic 

cancer. Their findings indicate that serious pain may occur in all cancer stages, and often 

represents an ongoing medical problem. 

In a review of 90 terminal cancer patients, Coyle, Foley, Adelbert et al. (1990) found that 

over half experienced fatigue and pain (58% and 54% respectively) in the last 4 weeks of life. 

Persistence of these and multiple concurrent symptoms, with fluctuations in both severity and 

impact on the family unit, mandate ongoing monitoring and adjustments in treatment. Although 

the majority of these patients used less than 300 morphine equivalent mg/day, eight used 900-

35,164 morphine equivalent mg/day. Supportive or palliative care programs offer the flexibility 

32
needed for managing individual pain and symptom control in dying patients, while encouraging 

family involvement. 

Portenoy and Hagen (1990) retrospectively assessed the prevalence and characteristics of 

breakthrough pain in 63 cancer patients with chronic pain managed with opioid drugs. The 

authors extracted chart data during a 3-month period from consecutive patients who reported 

moderate or lower pain intensity for more than 12 hours daily and stable opioid dosing for a 

minimum of 2 consecutive days. In this report of a total of 63 patients surveyed, 41 (64%) 

reported breakthrough pain, transient flares of severe or excruciating pain. Fifty-one different 

pains were described (median 4 pains/day; range 1-3600). Pain characteristics were extremely 

varied. Twenty-two (43%) pains were paroxysmal in onset; the remainder were more gradual. 

The duration of breakthrough pain varied from seconds to hours (median/range: 30 min (range,1-

240 min), and 21 (41%) were both paroxysmal and brief (lancinating pain). Fifteen (29%) of the 

pains were related to the fixed opioid dose, occurring solely at the end of the dosing interval. 

Twenty-eight (55%) of the pains were precipitated; of these, 22 were caused by an action of the 

patient (incident pain), and 6 were associated with a non-volitional precipitant, such as 

flatulence. The pain was believed to be somatic in 17 (33%), visceral in 10 (20%), neuropathic in 

14 (27%), and mixed in 10 (20%). Pain was related to the tumor in 42 (82%), the effects of 

therapy in 7 (14%), and neither in 2 (4%). 

Hiraga, Mizuguchi and Takeda (1991) reported the findings of a nation-wide survey in Japan 

in the year 1987 of patients with cancer pain. The incidence of pain in the terminal stage was in 

the range of 68 to 72% without any significant difference between hospitals. They also reported 

that regardless of the stage of illness, an analgesic effect was obtainable with oral/parenteral use 

of opioids. They report that the rate of complete pain relief increased from 37.8% in 1986 to 

42.7% in 1987 and 48.6% in 1988 for all stages, especially in the terminal stage. They suggest 

that the propagation of the WHO cancer pain guideline for cancer pain treatment led to this 

improvement in pain relief during the terminal stage. The reported overall incidence of pain in 

patients with cancer in this nation-wide survey was 32.6%. 

Portenoy, Miransky, Thaler et al. (1992) evaluated the epidemiology and impact of pain in 

patients undergoing active therapy of cancer in a prospective survey of 398 ambulatory patients 

with lung (46.4%) or colon (55.6%) cancer. The authors used a methodology based on face-toface interviews by trained quality assurance analysts, a multifaceted assessment instrument, and 

multivariate statistical analysis. They found that "persistent or frequent" pain during the previous 

2 weeks was reported by 57 of 145 (39.3%) patients with lung cancer and 52 of 181 (28.7%) 

patients with colon cancer; 91 of these patients (47 lung and 44 colon) were interviewed in 

detail. One-third of the surveyed patients had more than one discrete pain and the median 

duration of pain was 4 weeks (range, less than 1 week-468 weeks), with moderate average pain 

intensity. Ninety percent of patients experienced pain more than 25% of the time. In half of the 

patients pain interfered moderately or more with general activity and work while more than half

reported moderate or greater pain interference in sleep, mood, and enjoyment of life. Based on 

these observations the authors conclude that pain is prevalent among well-functioning 

ambulatory patients and substantially compromises function in approximately 50% of the 

patients who experience it. 

Brescia, Portenoy, Ryan et al. (1992) aimed to develop a clinical data base for patients with 

advanced cancer and to collect survey data to determine (1) pain severity at admission, (2) opioid 

use at admission, (3) change in opioid use during the hospital stay, and (4) survival in the 

hospital. They prospectively surveyed data on 1,103 patients admitted and on 1,017 patients who 

33
died within 6 months of the study's end. Seventy-three percent of patients had pain on admission. 

Specific primary sites of cancer associated with severe pain were cervix (68%), prostate (52%) 

and rectal/sigmoid (49%). In addition, they found that severe pain was more likely to occur in 

those patients with bone metastasis, those admitted from home, and in those younger than 55 

years of age. The authors found that the majority (71.7%) of patients had a stable analgesic 

dosing pattern, and only 4.2% required dose increases of at least 10% per day. 

Vuorinen (1993) investigated the prevalence and causes of pain at the early stages of cancer 

by surveying 378 newly diagnosed (0 to 6 months from diagnosis) unselected cancer patients. 

240 of 378 patients (64%) responded to this survey. Of these, 66 patients (28%) reported pain. 

Thirty patients had pain directly related to tumor growth, and 44 had pain secondary to cancer or 

its treatment. Only in 12 of 66 patients, the pain was unrelated to cancer. 

Cleeland, Gonin, Hatfield et al. (1994) in a multicenter study from 54 treatment locations 

affiliated with the Eastern Cooperative Oncology Group (ECOG) evaluated a total of 1308 

outpatients with metastatic cancer. They rated the severity of their pain during the preceding 

week, the degree of pain-related functional impairment and the relief provided by analgesics. 

Sixty-seven percent of the patients (871 of 1308) reported that they had had pain or had taken 

analgesic drugs daily during the week preceding the study, and 36 percent (475 of 1308) had 

pain severe enough to impair their ability to function. Forty-two percent of those with pain were 

inadequately managed. 

Mercadante, Armata and Salvaggio (1994) followed until death 60 consecutive lung cancer 

patients referred to a palliative care service to obtain information about the prevalence, 

characteristics and localization of pain. The prevalence of pain was reported to be almost 90%. 

Chest and lumbar pain were the most common sites with a clear correlation between site and 

metastases for the chest. 

Portenoy, Kornblith, Wong et al. (1994) reported on the prevalence, characteristics, and 

impact of pain and other symptoms in 111 inpatients and 40 outpatients with ovarian cancer. 

They utilized a comprehensive pain questionnaire, the RAND Mental Health Inventory, the 

Functional Living Index -- Cancer, and the Memorial Symptom Assessment Scale. The median 

patient age was 55 years (range, 23-86). Eighty-two percent had Stage III or IV disease at 

presentation, and 69% had active disease at the time of the survey. In this report sixty-two 

percent (N = 94) described a pain syndrome that preceded the onset or recurrence of the disease, 

and 42% (N = 63) reported "persistent or frequent pain" during the preceding 2 weeks. The most 

common site of pain was the abdominopelvic region (80%); pain was frequent or almost constant 

(66%), and its intensity was moderate to severe. Interference of pain with functional variables 

was moderate. Specifically, pain interfered with particular activities (68%), mood (62%), work 

(62%), and overall enjoyment of life (61%). The authors conclude that pain is strongly associated 

with impaired performance status. 

Kelsen, Portenoy, Thaler, et al. (1995) evaluated the prevalence of pain and depression, their 

correlation, and their effect on quality of life in 189 patients with recently diagnosed 

adenocarcinoma of the pancreas (PC) using validated instruments. These included the Memorial 

Pain Assessment Card (MPAC), Beck Depression Inventory (BDI), Hopelessness Scale (BHS), 

and Functional Living Index-Cancer (FLIC). At the time of study entrance, 37% of patients had 

no pain and an additional 34% had pain that was mild or less severe. Only 29% of patients had 

moderate, strong, or severe pain. They found a significant correlation between increasing pain 

and depressive symptoms among those who experienced pain. Patients who had moderate or 

greater pain had significantly impaired functional activity (P = .03) and poorer quality-of-life 

34
scores (P = .02) when compared with those with lesser degrees of pain. The authors conclude 

that moderate or severe pain and symptoms of depression are not as prevalent in recently 

diagnosed patients with pancreatic adenocarcinoma as was generally believed. 

Larue, Colleau, Brasseur et al. (1995) in a multicenter study aimed to describe the treatment 

of cancer pain in France and to evaluate the predictive factors for inadequate management using 

a cross-sectional survey in 20 treatment centers (cancer centers, university hospitals, state 

hospitals, private clinics, and a homecare setting). Patients rated the prevalence and severity of 

their pain and functional impairment related to their pain. Physicians reported patients' cancer 

characteristics, performance status, pain severity, and analgesic drugs ordered. According to this 

study 57% (340/601) of patients with cancer reported pain due to their disease, and, of those with 

pain, 69% (224/325) rated their worst pain at a level that impaired their ability to function. Thirty 

percent (84/279) of patients were reported as not receiving drugs for their pain. Of the 270 

patients in pain for whom information on treatment was available 51% (137/270) were not 

receiving adequate pain relief, according to a pain management index based on the World Health 

Organization's guidelines. French physicians were found to underestimate the severity of their 

patients' pain. The authors conclude that the assessment and treatment of cancer pain in France 

remain inadequate, emphasizing the need for changes in patient care. 

Stevens, Dibble and Miaskowski (1995) evaluated postmastectomy pain (PMP) in 95 women 

who had undergone breast cancer surgery in a cross-sectional descriptive study. They 

investigated the prevalence, characteristics, and impact of the PMP syndrome by reviewing 

medical records, and administering a patient information questionnaire, a cancer pain 

questionnaire and the McGill Pain Questionnaire. They found a prevalence of PMP of 20%. The 

women who were experiencing the syndrome reported chronic stable pain of long duration that 

began shortly after surgery. They described paroxysms of lancinating pain against a background 

of burning, aching, tight constriction in the axilla, medial upper arm, and/or chest that 

significantly interfered with the performance of daily occupational and domestic activities. 

Grond, Zech, Diefenbach et al. (1996) studied prospectively 2266 cancer patients to assess 

the localization, etiologies and pathophysiological mechanisms of the pain syndromes. They 

found 30% of patients presented with one, 39% with two and 31% with three or more distinct 

pain syndromes. Pain was associated with cancer (85%) or antineoplastic treatment (17%), and 

was unrelated to cancer in 9% of the patients. Nociceptive pain originated from bone (35%), soft 

tissue (45%) or visceral structures (33%). Pain was classified as neuropathic in origin in 34%. 

Pain was located in the lower back (36%), abdominal region (27%), thoracic region (23%), lower 

limbs (21%), head (17%), and pelvic region (15%). 

Tasmuth, von Smitten and Kalso (1996) surveyed and assessed pain, neurological symptoms, 

edema of the ipsilateral arm, and anxiety and depression in 93 women treated surgically for nonmetastastic breast cancer, as well as the impact of these symptoms on daily life during a 1-year 

follow-up (1993-94). They assessed patients before surgery and at follow-up 1, 6, and 12 months 

postoperatively during 1993-1994. The authors performed sensory testing and evaluated 

handgrip force and measured the circumference of the arm. Anxiety and depression were 

evaluated as well. The authors reported that one year after surgery, 80% of the women had 

treatment-related symptoms in the breast scar region and virtually all patients had symptoms in 

the ipsilateral arm. They observed a nonsignificant higher incidence of chronic post-treatment 

pain after conservative surgery than after radical surgery (breast area: 33% vs 17%, NS; 

ipsilateral arm: 23% vs 13%, NS). They reported numbness in 75% of the patients, and edema of 

the ipsilateral arm in over 30% of the patients after both radical and conservative surgery. 

35
Phantom sensations in the breast were reported by 25% of the patients. Anxiety and depression 

scores were highest before surgery and decreased with time. These correlated significantly with 

preoperative stressful events. 

Vainio and Auvinen (1996) aimed to estimate the prevalence of pain and eight other common 

symptoms in 1840 patients with advanced cancer in a multicenter survey performed in Europe, 

the United States, and Australia and to assess the differences in prevalence of the symptoms by 

primary site. They collected data using structured data collection sheets provided by the World 

Health Organization's (WHO) Cancer and Palliative Care Unit. They found a prevalence of 

moderate to severe pain of 51% (range, 43% in stomach cancer to 80% in gynecological 

cancers). The authors comment that population-based follow-up studies are needed to document 

the incidence and prevalence of symptoms throughout the course of the disease. 

Higginson and Hearn (1997) collected data on 695 patients with cancer in a multicenter study 

in Ireland and South England. In this sample 70% (486/695) had pain at the time of referral to 

the pain service. A significant reduction (P < 0.0001) in the levels of pain experienced by 

patients had occurred by two weeks after referral. The authors' findings suggest that the 

prevalence of pain in patients with advanced cancer cared for in the community is as high as that 

observed in other settings, and that improved pain control is associated with specialist 

consultation. 

Bernabei, Gambassi, Lapane et al. (1998) report the findings of a retrospective crosssectional study on the adequacy of pain management in elderly and minority patients with cancer 

admitted to 1492 nursing homes in 5 U.S. states. They studied a group of 13,625 patients with 

cancer aged 65 years and older, discharged from the hospital to any of the sampled facilities 

between 1992 and 1995. The authors found that a total of 4003 patients (24%, 29%, and 38% of 

those aged 85 years or older, 75 to 84 years, and 65 to 74 years, respectively) reported daily pain. 

Variables associated with pain were age, gender, race, marital status, physical function, 

depression, and cognitive status. In this group of patients, 16% received a WHO level 1 drug, 

32% a WHO level 2 drug, and only 26% received morphine. 

Ger, Ho, Wang et al. (1998) conducted an interview with 269 newly diagnosed cancer 

patients admitted during an 18-month period to the Tri-Service General Hospital in Taiwan. 

Admission was to evaluate the prevalence and severity of cancer pain, its treatment, and impact 

on patients during the week before the interview. The majority of patients (69%) were 

interviewed within 14 days of their definitive diagnosis of cancer. The authors reported that 38% 

(N = 113) of the patients had cancer-related pain. Of these 113 patients, 65% had "significant 

worst pain" (worst pain level at or above five on a 0-10 scale) and 31% had "significant average 

pain" (average pain level at or above five most of the time). Sixty-nine percent received no pain 

medication at all or inadequate medication (not "by the ladder"), and 23% had pain medication 

that was not administered at a fixed interval (not "by the clock"). 

Petke, Radbruch, Zech et al. (1999) surveyed patients suffering from chronic cancer pain to 

determine the subjective characteristics of transient pain (TP). In this study TP was reported by 

243 (39%) patients. The authors found that neuropathic baseline pain was associated with a 

higher prevalence of TP (P < 0.0001). According to site and mechanism, TP was somatic in 39%, 

visceral in 22%, and neuropathic, in 36% of patients. TP intensity was severe or worse in 92% of 

patients. The duration of TP was shorter and its frequency was higher in patients with 

neuropathic TP. Spontaneous occurrence of TP occurred in 40% of the patients, while TP related 

to movement in 36%, to the analgesic regimen in 35%, to coughing in 11%, and to various other 

factors in 18% of the patients. Only half of the movement-related TP episodes were predictable. 

36
Chang, Hwang, Feuerman et al. (2000) conducted a survey in 240 consecutive out- and 

inpatients to assess symptom prevalence and intensity and their relation to quality of life in 

medical oncology patients at a Veterans Affairs medical center. The authors utilized the 

Functional Assessment Cancer Therapy (FACT-G), Memorial Symptom Assessment Scale 

(MSAS), and the Brief Pain Inventory instruments. Symptoms were then analyzed by their 

relation to Karnofsky performance status (KPS) and quality of life. The authors found a median 

number of 8 symptoms per patient (range, 0-30 symptoms). The 5 most prevalent symptoms

were lack of energy (62%), pain (59%), dry mouth (54%), shortness of breath (50%), and 

difficulty sleeping (45%). Patients with moderate intensity pain had a median number of 11 

symptoms and patients with moderate lack of energy had a median number of 13 symptoms. The 

number of intense symptoms increased as the KPS decreased (P < 0.001). 

Zeppetella, O'Doherty and Collins (2000) prospectively surveyed 414 consecutive patients 

admitted to a hospice to determine the prevalence and characteristics of breakthrough pain in 

patients with cancer admitted to a hospice. Of these patients, 33 were confused or too unwell to

participate and 136 were pain-free. The remaining 245 (64% of 381) reported 404 pains (range 1-

5 per patient). Of these 245 patients, 218 (89%) had breakthrough pain and identified 361 pains 

(range 1-5 per patient). Breakthrough pain was classified as somatic (46%) visceral (30%), 

neuropathic (10%) or of mixed etiology (16%). Thirty-eight percent of pains were severe or 

excruciating. The average number of daily breakthrough pain episodes was 7 (range 1-14); 49% 

occurred suddenly. Most (59%) were unpredictable, and 72% lasted less than 30 minutes. A 

significant 75 percent of patients were dissatisfied with their pain control. 

Beck and Falkson (2001) aimed to assess the prevalence and patterns of cancer pain 

management in the Republic of South Africa by screening 263 patients. A total of 94 patients 

(37% of the sample) experienced cancer-related pain. Inpatients had a higher prevalence of pain 

than did outpatients. The authors found a significant difference in the prevalence of pain in 

blacks (56.1%) compared to whites (56.1% versus 29.4%, respectively; P<0.005). In a second 

phase, 426 patients with cancer pain from different settings were asked to complete a 

questionnaire (that included the Brief Pain Inventory) designed to learn about their pain and how 

it was managed. The authors found that nearly one-third of the entire sample experienced 'worst 

pain' of severe intensity. In this sample 81% of non-whites experienced “worst pain” of moderate 

to severe intensity as compared to 65% of whites (P<0.001). In this survey, only 21% of patients 

reported that they had achieved 100% pain relief. 30.5% of the entire sample had a negative 

score on the Pain Management Index, a comparison of the most potent analgesic used by a 

patient relative to their worst pain. Of this group, 58.1% were experiencing severe “worst pain.” 

Meuser, Pietruck, Radbruch et al. (2001) conducted a survey to assess symptom prevalence, 

etiology and severity in 593 patients with cancer who were treated by a pain service according to 

the WHO method for cancer pain relief. Symptoms other than pain were systematically treated 

with appropriate adjuvant drugs. The authors measured pain and symptom severity by patient 

self-assessment, and assessment by the physicians of the pain service. Symptom etiology and the 

severity of confusion, coma and gastrointestinal obstruction were assessed at each visit. Patients 

were treated for an average period of 51 days. The reported treatment efficacy was good in 70% 

of the patients, satisfactory in 16% and inadequate in 14% of patients. Prevalence and severity of 

anorexia, impaired activity, confusion, mood changes, insomnia, constipation, dyspepsia, 

dyspnoea, coughing, dysphagia and urinary symptoms were significantly reduced; those of 

sedation, other neuropsychiatric symptoms and dry mouth were significantly increased and those 

of coma, vertigo, diarrhea, nausea, vomiting, intestinal obstruction, erythema, pruritus, and 

37
sweating remained unchanged. The most frequent symptoms were impaired activity (74% of 

days), mood changes (22%), constipation (23%), nausea (23%), and dry mouth (20%). The 

highest severity scores were associated with impaired activity, sedation, coma, intestinal 

obstruction, dysphagia and urinary symptoms. Of all 23 symptoms, only constipation, erythema, 

and dry mouth were assessed as being most frequently caused by the analgesic regimen. 

Prevalence of Cancer-related Depression 

Because “depression” was not limited to major depressive disorder, choices were made 

regarding the definition of “depression” and the scope of the review. Unlike pain and fatigue, 

depression can be both a set of symptoms and clinical syndromes. Depressive symptoms are 

present in several psychiatric disorders with the most common in cancer patient being major 

depressive disorder, adjustment disorder, and depression secondary to a general medical 

condition. Depressive symptoms may also be present in the absence of a psychiatric diagnosis. 

Because major depressive disorder is the most described in this population, we first focused the 

review on studies of major depressive disorder. 

However, limiting the review to major depressive disorder does not capture the prevalence of 

depressive symptoms in cancer patients, regardless of diagnosis. We also reviewed studies that 

assessed the presence of clinically significant depressive symptoms. 

What is the prevalence of major depression in patients with cancer? 

Eleven studies that used DSM criteria to diagnose major depression were identified and 

reviewed. All of the studies used interviews that incorporated DSM criteria, except for Breitbart 

and Pirl who used the SCID. 

Table 1. Prevalence of Major Depressive Disorder (MDD) 

12 Cross-sectional Studies on Prevalence of MDD using DSM Criteria 

Author 

Year 

UI N Population/Setting

Mean Age 

(Range) & % Male Cancer Type Prevalence 

Derogatis

1983 

215 Multicenter, new

inpatients and 

outpatients 

50.3±15.5 

49% M 

All: 20% lung; 

18% breast; 

11% lymphoma 

13% depressive 

class;

5.5% MDD 

Bukberg 

1984 

62 Oncology inpatients 51 (23-70) 

53% M 

All: 38% 

leukemia/ 

lymphoma; 21% 

GU, 13% lung 

42%; 

24% severe 

Morton 

1984 

48 Patients treated in last 

3 years, no evidence 

of disease 

>60 

100% M 

Head and neck 

cancers

39.6% 

38
Author 

Year 

UI N Population/Setting

Mean Age 

(Range) & % Male Cancer Type Prevalence 

Evans 

1986 

83 Oncology inpatients 53.1±15.6

(20-86) 

0% M 

Gyn cancers 23% MDD; 

24% non-major 

depression

Grandi 

1987 

18 Consecutive surgical

oncology inpatients 

(29-75) 

0% M 

Breast cancer 22.2% 

Colon 

1991 

100 Routine evaluations of 

hospitalized BMT 

patients 

30 

65% M 

Acute leukemia, 

BMT 

1% MDD; 6%

Adjustment 

disorder with 

depressed 

mood 

Golden

1991 

65 Oncology inpatients 54.2±2.0

(20-86) 

0% M 

Gyn cancer 23% 

Alexander 

1993 

60 Oncology inpatients 55.0±13.3

60% M 

Various, not 

specified 

13% MDD; 

adjustment 

disorder w 

depressed 

mood 10% 

Sneeuw 

1993 

1112 Early stage, patient 

status not noted 

ND 

0% M 

Breast cancer 5.4% 

Bereard 

1998 

100 Oncology outpatients 51.8±13.3

16% M 

55% breast; 

43% lymphoma 

19% 

Breitbart 

2000 

92 Hospitalized palliative

care oncology patients

65.9±15.6 

40% M 

Various, not 

specified 

16% 

Pirl 

2002 

45 Ambulatory prostate

cancer patients

receiving androgen 

deprivation therapy 

69.4±7.4 

100% M 

100% prostate 12.8% 

Seven studies assessed major depressive disorder in hospitalized cancer patients. Three 

assessed depression in outpatients and two had mixed or unspecified hospital status. Despite 

using standardized criteria, there appears to be a wide range of reported rates. However, the 

populations are quite heterogeneous in types of cancers, hospital status, treatment, and disease 

status. If they were available, rates of other depressive syndromes were also included in the 

table. 

The majority of rates for major depressive disorder fall between 10 to 25% of patients, with 

25% of studies reporting rates below and 17% reporting rates above. From this table, it is 

difficult to draw conclusions about the effects of the variables mentioned above on rates. 

39
However, it may be noteworthy that the lowest reported rate was in the youngest population. 

Although major depressive disorder is more common in women in the general population, there 

did not appear to be a consistent strong association between female gender and depression in this 

data. 

What is the prevalence of significant depressive symptoms in patients with 

cancer? 

The Hospital Anxiety and Depression Scale (HADS) was the most commonly used 

instrument to measure depressive symptoms in citations resulting from our literature search. 

Table 2. Prevalence of significant depressive symptoms in adults 

Cross-sectional studies using the HADS 

Author 

Year 

UI N

Population/ 

Setting 

Cancer 

Type

Age (Range) 

& % Male Prevalence 

Espie 

1989 

41 Outpatients Follow

up at least 6 months 

after treatment 

Head and 

neck 

64 mean, 

(43-78 range) 

66% M 

17% 

Razavi 

1990 

210 Inpatients Various 55.30 mean, 14.50 

sd 

32.9% M 

7.8% random, 25.5% 

referred 

Hopwood

1991 

204 Consecutive

ambulatory patients 

Breast Not noted

0% M 

9% probable cases, 

1% borderline, and 

9% mixed depression 

and anxiety 

Hopwood

1991 

81 Ambulatory patients Advanced

breast, no 

brain mets 

Not noted 

0% M 

34.6% 

Maraste 

1992 

133 Ambulatory patients Breast 61 mean 

(32-84) 

0% M 

1.5% probable cases, 

3.75% borderline 

Pinder 

1993 

139 Inpatients and

outpatients 

Advanced

breast 

cancer

60.5 mean, 

(27-90) 

0% M 

12%, 

Chaturvedi 

1996 

50 New patients

undergoing 

treatment, hospital 

status not known 

Head and 

neck 

cancers

Not noted 

80% M 

62% probable cases 

of either anxiety or 

depression

Grassi 

1996 

86 Home care patients Various 45%

40
Author 

Year 

UI N

Population/ 

Setting 

Cancer 

Type

Age (Range) 

& % Male Prevalence 

Roth 

1998 

113 Outpatients Prostate ND

100% M 

15.2% 

Groenvold 

1999 

538 Ambulatory survivors Breast 55 mean age

0% M 

3.5% probable cases, 

6.5% borderline 

Newell 

1999 

195 Outpatients Various 56% are 50-69 

years 

41% M 

8% probable cases, 

15% borderline 

Chen

2000 

203 Inpatients Various Not noted

49.8% M 

20.2% probable 

cases, 

23.7% borderline 

Cliff 

2000 

164 Outpatients Prostate Mean age: 73.9 

100% M 

8.1% 

Hopwood

2000 

987 Data from 3 

multicenter treatment 

studies

Lung 

cancer

Not noted 

Not noted 

17% probable cases, 

16% borderline 

Pascoe 

2000 

504 Outpatients Various 62 median, (range 

20-93) 

45% M 

7.1% probable cases, 

11.0% borderline 

Reviewing studies that utilized the HADS scale to measure depressive symptoms, we again 

found a wide range of reported rates. Thirteen studies were identified. Two studies assessed 

depressive symptoms in hospitalized cancer patients. Seven assessed depression in outpatients 

and four included homecare, mixed, or unspecified hospital status. 

It appears that the majority of reports fall into the 7 to 21% range for probable cases of 

depression, with a higher rate for “borderline cases” of depression. Of the 14 studies quantifiable 

for depression, 14% lay below this range of rates and 14% lay above this range. 

Populations, which are heterogeneous by hospital status, cancer type, treatment, and disease 

status, complicate these reports. Even though a standardized instrument was used, different cut 

off points were chosen by different investigators to identify participants as having clinically 

significant depressive symptoms. 

What is the prevalence of depression in children with cancer? 

Few studies were identified that assessed the prevalence of major depressive disorder or 

depressive symptoms in children with cancer. Of the three studies found, two specifically gave 

rates for depressive symptoms while the other reported emotional distress. From these two 

studies, the rate of depressive symptoms appears to be somewhere between <10% and 14%. 

41
Table 3. Prevalence of Depressive Symptoms in Children with Cancer

Author 

Year 

UI N

Population/ 

Setting 

Cancer 

Type

Mean Age 

(range) & 

% Male Prevalence 

Multhern 

1994 

99 Consecutive hospitalized

children with cancer in 

remission 

Various,

41.4% 

leukemia 

12.9 median

(8-16) 

60.6% M 

Specifics not noted, 

<10% 

Suris

1996 

3139 - 162 

chronic 

illness, 39 

cancer

Random sample of Spanish 

high school students, 14-19

years old, data analyzed as

chronic illness (including 

cancer) vs. control, no 

significant difference found 

between cancer and other 

chronic illnesses 

ND (14-19)

ND 

Significantly higher 

report of depressive 

symptoms, 30.0% of 

females reported 

“emotional problems” 

with 23.5% reporting 

suicidal ideation, 

16.1% males reported 

“emotional” problems 

with 16.1% reporting 

suicidal ideation 

Von Essen 

2000 

Group 1: 16 

Group 2: 35 

2 groups of hospitalized

children with cancer

diagnosed no later than 1 

month pre-study ages 8-18

years old 

Various Group 1:

13.3±3.3 

Group 2: 

12.6±3.3 

Group 1: 69% M 

Group 2: 51% M 

14% of all subjects, 

6.3% on treatment, 

17.1% off treatment 

Incidence 

What is the incidence of major depression in cancer patients? 

No incidence studies were identified that used DSM criteria to diagnose major depressive 

disorder. 

 

What is the incidence of significant depressive symptoms in cancer patients? 

Using the same rationale as in the prevalence review of depressive symptoms, we reviewed 

studies that prospectively measured depressive symptoms with the most commonly used 

instrument, the HADS. In all studies except one, we found that the prevalence of depressive 

symptoms was greater at the endpoint than baseline. It is difficult to estimate incidence rates 

with the data in the table. These studies are complicated by the two major factors: 1) a high 

prevalence of depressive symptoms at baseline and 2) variation in depressive symptoms based on 

timing of the measurement from diagnosis or treatments. However, it appears that at least 50% 

of patients at baseline remain depressed and 1.8 to 17% of non-depressed patients develops 

significant depressive symptoms in one year. If the Hopwood study is excluded because of its 

42
outlying rate (17%) and unknown timeframe, the incidence of clinically significant depressive 

symptoms appears to be between 1.8 to 7.4% per year. 

Table 4. Incidence of Depressive Symptoms in Adult Cancer Patients 

HADS 

Author 

Year 

UI N

Population/ 

Setting 

 & Characteristics Treatment

Time 

Course

Instruments Baseline Time 1Time 2

Chadurvedi 

1996 

100, 

57, 

21 

Consecutive newly 

diagnosed patients 

starting radiation, 

various cancers 

(55% cervix),

67% < 40 years 

21% Male 

Radiation 3-4 months

posttreatment 

HADS (≥8) 4% Finishing

course of

radiation, 

44% 

3-4 

months 

post 

treatment, 

48% 

Norden 

1999 

159, 

113 

Consecutive newly 

diagnosed GI

cancers, mean age 

67 years (range 

23-89) 

51% Male 

Biopsy 3-6 months

after 

diagnosis

HADS (≥8 

for 

depression

or anxiety 

scales),

MAC, IES 

21.2% 3 or 6 

months 

later, 

12.4% 

Hjermstad 

1999 

130, 

130, 

94 

Consecutive

leukemia patients 

for stem cell 

transplantation, 

 median age 35 

(range 17-55) 

56% Male 

BMT 1 year HADS (≥8) 4.6% 2 weeks,

40% 

1 year, 

10.6% 

Hammerlid 

1999 

357, 

345, 

215 

Head and neck 

cancer patients

pre-treatment, 

mean age 63 

(range 18-88) 

72% Male 

Various,

combined 

and 

radiation in 

majority 

1 year HADS 

(≥11)

6%prob

able 

cases,

11% 

borderline 

3 month 

13% 

probable 

cases, 

11% 

borderline 

1 year, 

8% 

probable 

cases, 9%

borderline

Hopwood

2000 

987, 

718 

Lung cancer

patients in clinical 

trails, 55% poor 

prognosis 

Gender ND 

3 clinical 

trials, 3 

chemother

apy and 1 

radiation 

Time of 1st 

follow-up 

not noted 

HADS 

(≥11),

RSCL 

17%pro

bable 

cases, 

16% 

borderline 

1st follow 

up, 29% 

probable 

cases or 

borderline 

43
Five studies were identified that prospectively assessed depressive symptoms with the 

HADS. All were cancer treatment studies, with treatments including biopsy, radiation, 

chemotherapy, and bone marrow transplant. 

In all studies except one, we found that the prevalence of depressive symptoms was greater at 

the endpoint than baseline. It is difficult to estimate incidence rates with the data in the table. 

These studies are complicated by the two major factors: 1) a high prevalence of depressive 

symptoms at baseline and 2) variation in depressive symptoms based on timing of the 

measurement from diagnosis or treatments. However, it appears that at least 50% of patients at 

baseline remain depressed and 1.8-17% of non-depressed patients develop significant depressive 

symptoms in one year. 

If the Hopwood study is excluded because of its outlying rate (17%) and unknown 

timeframe, the incidence of clinically significant depressive symptoms appears to be between 1.8 

to 7.4% per year. 

What is the incidence of depression in children with cancer?

No studies were identified on the incidence of major depressive disorder or depressive 

symptoms in children with cancer. 

Prevalence of Cancer-related Fatigue

Our search strategy identified 27 studies in which a defined endpoint of the research was a 

quantitative estimation of the prevalence of cancer-related fatigue in a specified target 

population. Thirteen studies included patients with a variety of cancers. Five specifically 

focused on breast cancer, four on lung cancer, two on prostate cancer, and one each on Hodgkin's 

disease and rectal cancer. We did not include fatigue prevalence rates from studies of general 

health-related quality of life, symptom surveys, or treatment trials unless fatigue assessment was 

specified as an endpoint of the study. In addition to the tabulated studies generated by our 

search, we have reviewed a number of studies that, although they do not report a specific fatigue 

prevalence, focus on the pattern of fatigue in cancer and the various disease, treatment, and 

patient-related factors that correlate with it. 

Table 5. Prevalence of Fatigue in Cancer Patients 

Author 

Year 

UI N

Population/ 

Setting 

Mean Age 

(Range)/ 

% Male

Cancer 

Type Prevalence

King 

1985 

85242295 

USA 

96 During and postXRT (26-83) 

52% M 

Chest, head 

and neck, 

GU, GYN, 

65-93% during XRT, 14-

46% @ 3 months (% 

reported for each 

anatomic site) 

Hurny

1993 

94207627 

Switzerland 

127 Chemo trial ND

Gender ND 

SCLC 43% moderate or severe 

at baseline, 30-37% 

during chemo

44
Author 

Year 

UI N

Population/ 

Setting 

Mean Age 

(Range)/ 

% Male

Cancer 

Type Prevalence

Donnelly 

1995 

95271387 

USA 

743 palliative care

service 

(61-70) 

53% M 

Various

cancers 

48% "clinically important" 

(moderate or severe) 

Hickok

1996 

97089233 

USA 

50 Radiation therapy 63 (37-78) 

avg. 

68% M 

Lung cancer

patients 

78% experienced fatigue 

at some point during XRT 

Longman 

1996 

97158314 

USA 

307 Patients on

chemo, hormonal 

therapy or XRT 

55 (25-82)

0% M 

Breast

cancer, 

stage I-IV, 

83%; 60.2% "problematic"

Richardson 

1997 

98155331 

UK 

129 During chemo 58 (26-82) 

44% M 

Various 89% at some point during 

chemo 

Sarna 

1997 

97165457 

USA 

60 58.3 (33-80)

0% M 

Advanced

lung cancer 

56.7% had "serious" 

fatigue (>3 on 1-5 scale) 

Vogelzang 

1997 

97397931 

USA 

419 Patients who had 

received chemo or 

XRT 

65 

33% M Various

cancers

78% reported fatigue 

during their disease and 

treatment, 32% on daily 

basis

Smets

1998 

98435611 

Netherlands

250 Ambulatory

patients receiving 

XRT with curative 

intent 

64±13

59% M 

Various

cancers

During XRT 40% were

tired most of the time, 

33% sometimes, 27% 

hardly ever. 44% were 

more fatigued after than 

before XRT, 26% were 

less fatigued, 30% no 

change 

Smets

1998 

98435610 

Netherlands

154 Patients in

remission after 

XRT 

65±12

57% M 

Various

cancers

51% recalled fatigue in 

first 3 months after XRT 

(19% very much, 32% 

moderate). No significant 

differences in fatigue 

scores between cases and

controls at 9 months 

45
Author 

Year 

UI N

Population/ 

Setting 

Mean Age 

(Range)/ 

% Male

Cancer 

Type Prevalence

GastonJohansson

1999 

20152209 

USA 

127 Patients after

surgery and 

chemotherapy, 

before autologous 

stem cell or bone 

marrow transplant

45±7.6 

0% M 

Stage II, III & 

IV breast 

cancer 

91% had fatigue on VAS 

Jacobsen

1999 

20004863 

USA 

54 cases 

54 controls

Patients receiving 

adjuvant chemotherapy 

51±10

0% M 

Breast

cancer 

4% of patients had severe 

fatigue before cycle 1, 

28% before cycle 4 

(MSAS). Patients had 

significantly more fatigue 

than controls at all time 

points 

Loge 

1999 

99385422 

Norway

459 cases 

2214 

controls 

Patients after 

curative

treatment: 

38% XRT, 

14% chemo, 

47% XRT+chemo

44±12

55% M 

Hodgkin's 

Disease 

26% of Hodgkin's 

survivors were fatigue 

cases (total dichotomized

score > 4 and symptom 

duration of > 6 months) 

vs. 9% of male and 12% 

of female controls

Miaskowski 

1999 

99283638 

USA 

24 Outpatient XRT

for bone 

metastases

56.6±13

50% M 

Various

cancers 

79% had moderate or

severe fatigue at bedtime 

and 48% on awakening 

Monga 

1999 

99334561 

USA 

36 XRT 66.9 (55-79)

100% M 

Localized 

prostate 

cancer 

8% were fatigued (>6 on 

PFS) prior to XRT, 25% at 

completion of XRT 

Stone 

1999 

99202777 

UK 

95 cases 

98 controls

Palliative care 

units, no chemo or 

XRT in > 4 weeks

67 (30-89)

43% M 

Patients with 

advanced 

cancer 

75% had severe fatigue (> 

95th percentile of controls 

on FSS) 

Bower 

2000 

20139478 

USA 

1957 Breast Cancer

Survivors 1-5 

years after 

diagnosis

55 

0% M 

Breast

cancer

35% classified as fatigued 

(scores in disability/limitation range on RAND 

survey) 

Curt 

2000 

20497163 

USA 

(same as Cella 

2001) 

379 Patients postchemo or XRT 53 

21% M 

Breast

cancer (62%

of patients) 

and various 

other 

76% had fatigue at least a 

few days per month during 

most recent chemo, 30 % 

had daily fatigue 

46
Author 

Year 

UI N

Population/ 

Setting 

Mean Age 

(Range)/ 

% Male

Cancer 

Type Prevalence

Okuyama 

2000 

21408236 

Japan 

134 Post-surgery

patients (77%

mastectomy, 23% 

breastconserving) 

28.1% had had 

chemo, 8.9% XRT

55.1±10.3 

0% M 

Breast

cancer

patients 

stage 0-III, 

56% perceived

themselves as fatigued 

per the CFS. 

Servaes

2000 

21023870 

Netherlands

85 

comparison

group 

16 chronic 

fatigue 

Patients diseasefree at a mean of 

2.9 years after 

treatment 

47.5±14

56% M 

Various

cancers and

treatments, 

29% had heightened and 

19% severe fatigue (>27 

or >35 on CIS) 

Stone 

2000 

20314191 

UK 

62 Patients receiving

hormonal therapy 

69 (55-80)

100% M 

Prostate 

cancer, 

various

stages 

14% had "severe fatigue" 

at baseline, 17% at 3 

months (NS). (severe 

fatigue defined as > 95th 

percentile on FSS in 

controls without cancer) 

Stone 

2000 

20363241 

UK 

98 Patients receiving

inpatient palliative 

care

66 (30-89)

56% M 

Early breast 

or prostate 

cancer, 

inoperable 

lung cancer, 

or advanced 

cancer 

48% of cases had "severe 

fatigue" (defined as >95th 

percentile of control group 

scores) 

Stone 

2000 

20489733 

UK 

576 Patients attending

three regional

cancer centers 

over a 30 day

period 

59 (18-89)

37% M 

Various

cancers and

stages 

58% reported being 

"somewhat" or "very 

much" fatigued 

Cella 

2001 

21348064 

USA 

(same as Curt 

2000) 

379 Patients postchemo or chemo 

+ XRT 

53 

21% M 

Various

cancers

(50% breast) 

17% met proposed criteria

for cancer-related fatigue; 

37% reported > 2 weeks 

of fatigue in preceding

month 

Given 

2001 

21291233 

USA 

841 (>65)

55% M 

Breast, 

colon, lung, 

prostate 

26-33% had fatigue at 4 

time points over 1 year 

47
Author 

Year 

UI N

Population/ 

Setting 

Mean Age 

(Range)/ 

% Male

Cancer 

Type Prevalence

Okuyama 

2001 

21408236 

Japan 

157 ambulatory

patients with 

advanced lung

cancer, no

surgery, chemo or 

XRT in past 4 

weeks 

63.1 (27-80) 

71% M 

Advanced

lung cancer 

51.3% had clinical fatigue, 

defined as interfering with 

at least one domain of 

daily life 

Wang

2001 

21481486 

USA 

72 Patients receiving

pre-op chemo & 

XRT 

56±11

50% M 

Locallyadvanced 

rectal cancer

At baseline 26% had 

moderate and 18% severe

fatigue; at end of 

treatment 28% had 

moderate & 31% severe 

fatigue 

Measures and Definitions of Fatigue 

A variety of patient self-assessment instruments were used to measure cancer-related fatigue. 

In 18 of the 27 studies, a multi-item questionnaire with defined psychometric properties was 

used. The fatigue subscale of the EORTC QLQc30 was used in four studies. No other 

instrument was used in more than two studies. Other types of measures included telephone 

interviews (three studies), non-validated ad hoc questionnaires (three studies), and the 

combination of a diary and visual analog scale (one study), a visual analog scale alone (one 

study) and a single question (one study). 

Using these measurements, a variety of operational definitions of fatigue were devised, along 

with gradations ("moderate," "severe," etc.) The studies that assessed fatigue using a single 

question (Given, Given, Azzouz, et al., 2001; King, Nail, Kreamer, et al., 1985) characterized 

fatigue as present or absent. Richardson and Ream (1997) also used a binary definition based on 

fatigue present at any point according to patient diaries. Hurny, Bernhard, Joss, et al. (1993) 

utilized an early version of the EORTC QLQc30 and its fatigue and malaise subscale, but based 

their definition of fatigue on a single, Likert format item from this scale: "Were you tired?". 

Patients who responded "quite a bit" or "very much" were characterized as fatigued. Several 

other studies established criteria for fatigue based on patients' scores on various fatigue 

instruments. For example, Miaskowski and Lee (1999) used a score of > 6 on the Lee Fatigue 

Scale as their definition of severe fatigue, and Monga, Kerrigan, Thornby, et al. (1999) used a 

score of > 6 on the Piper Fatigue Scale as their cut-off for the presence of fatigue. While a 

number of valid, consistent and reliable instruments were used to assay cancer-related fatigue, 

the wide array of available instruments unfortunately renders comparisons between studies 

problematic. Descriptors such as "moderate" and "severe" are used to describe levels of fatigue, 

but these criteria are defined in a non-uniform manner. 

Case-control designs were used to define criteria for fatigue relative to normative data from

the control group. For example, Stone, Richards, A'Hern, et al. (2000) compared scores on the 

Fatigue Severity Scale between 227 cancer patients and 98 controls. Cancer-related fatigue was 

defined as a score in excess of the 95th percentile of the control group. Bower, Ganz, Desmond, 

et al. (2000) utilized the RAND Health Survey 1.0, an instrument for which national norms of 

age-matched women were available for comparison with their cohort of 1,957 breast cancer 

48
survivors. They defined patients in this cohort as fatigued if their scores fell in the 

disability/limitation range of the energy/fatigue subscale of the RAND survey. 

Prevalence of Fatigue during Chemotherapy and/or Radiation Therapy

Four studies reported prevalence rates of fatigue in patients receiving chemotherapy, five 

during radiation therapy, and four in groups receiving either one treatment or the other, or both. 

In the studies focusing on chemotherapy as the primary treatment modality, variable 

prevalence rates were reported. Richardson and Ream (1997) studied 109 patients receiving 

various types of chemotherapy using daily Visual Analogue Scales (VAS) assessing the extent of 

fatigue, the distress caused by it, and the impact of fatigue on social and work-related activities. 

They report that 89% of patients had fatigue at some point, using a daily visual analog scale. Of 

note, they found that patients used a number of self-care activities to alleviate fatigue, most 

commonly a modification of their rest and activity patterns. These self-care strategies were 

found to be fairly ineffective, with complete or near-complete relief of fatigue reported by 11.5% 

and 25.5% respectively. Using the same data set this group has reported different temporal 

patterns of fatigue in patients receiving chemotherapy continuously, weekly, or every three or 

four weeks (Richardson, Ream, and Wilson-Barnett, 1998). 

Hurney, Bernhard, Joss, et al. (1993) examined a sample of 127 patients with small-cell lung 

cancer on a chemotherapy trial. "Fatigue and malaise" were assessed using items from an 

EORTC QL questionnaire. At baseline 43% had moderate to severe fatigue. Interestingly, this 

level declined slightly to 30-37% during treatment, but all other symptoms were abolished over 

this period, presumably due to a high rate of response to chemotherapy. Fatigue was therefore 

the most prominent symptom over the course of treatment. This is one of the few studies that 

attempted to determine the extent to which fatigue was treatment-related vs. disease-related: in 

multivariate analysis, 43% of the variance in fatigue was ascribed to disease symptoms, and 35% 

to toxicity of treatment. Most other studies have reported a worsening of fatigue associated with 

cancer treatment. 

Jacobsen, Hann, Azzarello, et al. (1999) reported that fatigue prevalence increased from 4% 

before cycle 1 to 28% before cycle 4 in 54 women receiving adjuvant chemotherapy for breast 

cancer. Fatigue was greater in patients than in the controls at all time points. Gaston-Johansson, 

Fall-Dickson, Bakos, et al. (1999) found a 91% prevalence of fatigue using a visual analog scale 

in women with breast cancer after chemotherapy and before autologous stem cell or bone 

marrow transplantation. 

A number of authors have examined fatigue in the context of radiation therapy. A wide range 

of fatigue prevalence is reported in these studies, perhaps reflecting varying diseases, patient 

populations, types of radiotherapy, and the utilization of a variety of fatigue assessment 

instruments. King, Nail, Kreamer, et al. (1985) studied 96 patients with a variety of cancers. 

Depending on the type of cancer, fatigue rates ranged from 65-93% during radiation and 14-46% 

at a 3-month follow-up using a non-validated questionnaire. Hickok, Morrow, McDonald, et al. 

(1996) performed a retrospective chart review of 50 patients receiving radiation therapy for lung 

cancer. According to symptom checklists and progress notes, they found that 78% of patients 

suffered from fatigue at some point during treatment. Smets, Visser, Willems-Groot, et al. 

(1998a) assessed fatigue in 250 ambulatory patients receiving radiation therapy with curative 

intent for a variety of cancers. They found that 40% were tired "most of the time," 33% 

"sometimes," and 27% "hardly ever." Monga, Kerrigan, Thornby, et al. (1999) found that 8% of 

36 patients with localized prostate cancer were fatigued before radiation therapy and 25% at its 

49
completion. Miaskowski and Lee (1999) analyzed a cohort of 24 patients receiving radiation 

therapy for bone metastases. Seventy-nine percent had moderate or severe fatigue at bedtime, 

48% on awakening. 

In the only study of combined chemotherapy and radiation (Wang, Janjan, Guo, et al., 2001), 

72 patients with rectal cancer, the rates of moderate to severe fatigue rose from 44% at baseline 

to 59% at the end of treatment. 

In a cohort of breast cancer patients receiving chemotherapy, radiation therapy and other 

treatments, Longman, Braden, Mishel, et al. (1996) found an 83% prevalence of fatigue (60.2% 

"problematic") in stage I-IV breast cancer. 

Fatigue has also been evaluated in large, cross sectional studies of patients with many 

different cancers undergoing a variety of treatments. In a study of 841 elderly patients (> 65 

years of age) with newly diagnosed breast, colon, lung or prostate cancer, 26-33% were found to 

have fatigue over a 1-year period (Given, Given, Azzouz, et al., 2001). Stone, Richardson, 

Ream, et al. (2000) found that 58% of 576 outpatients with a variety of cancers were fatigued. 

Fatigue in Cancer Survivors 

An important subset of the fatigue literature focusing on cancer survivors has emerged in the 

last several years (Andrykowski, Curran, and Lightner, 1998; Bower, Ganz, Desmond, et al., 

2000; Broeckel, Jacobsen, Horton, et al., 1998; Cella, Davis, Breitbart, et al., 2001; Howell, 

Radford, Smets, et al., 2000; Loge, Abrahamsen, Ekeberg, et al., 1999; Okuyama, Akechi, 

Kugaya, et al., 2000; Servaes, van der, Prins, et al., 2001). Bower, Ganz, Desmond, et al. (2000) 

used a scale in which norms for healthy populations or patients with other medical conditions 

have been established (i.e., the Rand Health Survey 1.0) offering some insight into the clinical 

significance of a 35% fatigue rate in breast cancer survivors. Another advance was the use of a 

large, population-based survey by Cella, Davis, Breitbart, et al. (2001) thus avoiding some of the 

selection bias inherent in the smaller cohort studies. This group found a 17% rate of fatigue 

among 379 cancer survivors, using somewhat restrictive diagnostic criteria. In Hodgkin's 

disease, which is frequently curable and often affects young people, there is a high (26%) 

incidence of fatigue in a cohort of 459 survivors, even at a mean of 12 years after treatment. In 

these patients, fatigue correlated with psychiatric symptoms (anxiety and depression) but also 

with the late medical complication of pulmonary dysfunction (Knobel, Havard, Brit, et al., 2001; 

Loge, Abrahamsen, Ekeberg, et al., 1999; Loge, Abrahamsen, Ekeberg, et al., 2000). Okuyama, 

Akechi, Kugaya, et al. (2000) studied 134 patients with stage I-III breast cancer a mean of 789 

days after surgery, plus chemotherapy or radiation in 28.1% and 8.9% respectively. 56% of 

these patients perceived themselves as fatigued.

Fatigue in the Palliative Care Setting 

Donnelly and Walsh (1995) found a 48% rate of "clinically important" fatigue using a 

questionnaire in 43 patients on a palliative care service. A prospective, case-control study 

(Stone, Hardy, Broadley, et al., 1999) compared 95 cancer patients on a palliative unit with ageand sex-matched volunteers. 75% of the patients had severe fatigue, defined as > 95th percentile 

of the control group. 

Patterns and Correlates of Fatigue 

A number of additional studies (not included in Table 5) have examined the pattern or 

correlates of fatigue. Some of the key findings from this literature are reviewed. 

50
Not surprisingly, fatigue has been found to correlate with impairments in HQL in patients 

receiving radiation therapy (Irvine, Vincent, Graydon, et al., 1998; Lovely, Miaskowski, and 

Dodd, 1999), chemotherapy (Redeker, Lev, and Ruggiero, 2000) and in long-term survivors 

(Bower, Ganz, Desmond, et al., 2000). 

Several studies examined putative biological correlates of fatigue, with generally 

disappointing results. In patients with lung cancer undergoing radiation therapy, significant 

weight loss was observed, but neither weight loss nor a laboratory marker of impaired nutritional 

status (prealbumin) correlated significantly with fatigue (Beach, Siebeneck, Buderer, et al., 

2001). Another group with high fatigue levels, patients who have undergone autologous bone 

marrow transplants for lymphomas, were assessed for endocrine and immunologic abnormalities. 

Although gonadal dysfunction was common, it was not associated with greater fatigue; likewise, 

there was no correlation between fatigue and serum levels of inflammatory cytokines 

(interleukin-6, tumor necrosis factor, soluble tumor necrosis factor receptor) (Knobel, Loge, 

Nordoy, et al., 2000). There was also an absence of correlation between fatigue and mild leydig 

cell dysfunction in survivors of various hematologic malignancies (Howell, Radford, Smets, et 

al., 2000). Greenberg, Gray, Mannix, et al. (1993) reported that serum interleukin-1 levels rose 

between weeks one and four in men receiving radiation therapy for prostate cancer, but no 

statistical correlation was possible. 

Cancer-related fatigue has been associated with psychosocial and demographic factors, other 

symptoms, and disease and treatment variables. A common theme in many studies is an 

association between psychological distress, in particular, depression and fatigue. 

In breast cancer survivors, the variance in fatigue has been examined as a function of disease 

and treatment variables, symptoms and demographics. Bower, Ganz, Desmond, et al. (2000) 

examined correlates of fatigue in a large case-control study and found that the type of adjuvant 

treatment (chemotherapy, radiation therapy, or both) did not predict fatigue levels. The only 

significant predictors were the current symptoms of depression and pain. Similarly, Broeckel, 

Jacobsen, Horton, et al. (1998) found that demographic, disease and treatment variables were not 

significantly correlated with fatigue after adjuvant chemotherapy. Again, current symptoms and 

conditions were correlated with fatigue, in this case poor sleep, menopausal symptoms, 

catastrophizing as a coping mechanism, and psychiatric disorders. A third study (Okuyama, 

Akechi, Kugaya, et al., 2000) found the same pattern in breast cancer survivors: fatigue was 

significantly correlated with current symptoms of dyspnea, insufficient sleep and depression, but 

not disease or treatment variables. On the other hand, Mast (1998) and Woo, Dibble, Piper, et al. 

(1998) found associations between prior chemotherapy and fatigue. 

Evidence that fatigue may be related to psychological problems and other symptoms was 

presented in numerous other contexts. Irvine, Vincent, Graydon, et al. (1998) found correlations 

between symptom distress, psychological distress, and fatigue but not between disease variables 

and fatigue in 121 women receiving radiation therapy for breast cancer. Redecker, Lev and 

Ruggiero (2000) studied fatigue, psychological variables and HQL in 263 patients undergoing 

chemotherapy. Their findings suggest that fatigue is closely tied to psychological factors, 

particularly depression. Akechi, Kugaya, Okamura, et al. (1999) examined the correlates of 

fatigue in 455 ambulatory cancer patients. Cancer site and performance status did not predict 

fatigue. Aside from demographic variables, depression was the only factor correlating with 

fatigue. Hann, Garovoy, Finkelstein, et al. (1999) analyzed fatigue in 31 patients undergoing 

autologous stem cell transplants for breast cancer. There were no associations between fatigue 

and demographics, disease variables, or the transplant regimen. The factors that were associated 

51
with fatigue were time to engraftment, length of hospitalization, depressive symptoms and

anxiety. In a study of 457 Hodgkin's disease survivors, Loge, Abrahamsen, Ekeberg et al. (2000) 

found that anxiety was predictive of chronic fatigue. Bruera, Brenneis, Michaud et al. (1989) 

found that asthenia correlated with depression but not with nutritional status, lean body mass, 

tumor mass, anemia, or type of treatment in 64 patients with advanced breast cancer. 

 A common theme in these studies is the correlation of cancer-related fatigue with 

depression or, more generally, psychological symptoms. A second observation is that, in some

contexts, current physical and psychological symptoms are more significant than disease or 

treatments variables as predictors of fatigue. This appears to be the case particularly in studies 

of cancer survivors. 

Assessment

An ongoing debate is occurring about defining and measuring fatigue in cancer patients, and 

the current medical literature clearly shows that gaps in our knowledge exist. Fatigue is a 

complex phenomenon which is often incorporated into tools that measure a broad set of 

concepts, and few of these tools measure fatigue per se. In order to address the question “Which 

tools are used most often to assess fatigue (as well as pain and depression)” in recent cancer 

trials and specifically for which cancer patients, and with what degree of success, we performed 

a systematic review of the literature of the best available evidence. 

We searched Medline from 1966 through October 2001 using a sensitive search strategy for 

English language articles. Medical subject headings used were pain, fatigue, and depressive 

disorders and a saved search algorithm for controlled trials. This search yielded 469 abstracts. 

We examined each paper identified by the abstract and read thoroughly for the purpose of 

determining which common scales, if any, were used by the authors to assess the symptoms of 

pain, depression, or fatigue. We found 180 papers that employed scales in widely varying levels 

of detail: 151 to assess pain, 56 to assess depression, 26 to measure fatigue. Of these papers, 15 

assessed both pain and fatigue, 27 assessed pain and depression, 21 assessed fatigue and 

depression, and 10 assessed all three in the same publication. 

Table 6. Assessment scales for pain, depression and fatigue 

Scales 

1980-

82 

1983-

85 

1986-

88 

1989-

91 

1992-

94 

1995-

97 

1998-

2000 2001* Total

VAS 1 4 9 19 24 14 23 4 98

EORTC 2 6 8 16

HADS 1 4 1 8 14

POMS 1 2 3 8 14

FLIC 2 3 5

SF-36 2 3 5

Rotterdam 1 2 3 

CHEOPS 1 1 2

WHO 2 2

CGI 1 1

SLC 1 1

52
Scales 

1980-

82 

1983-

85 

1986-

88 

1989-

91 

1992-

94 

1995-

97 

1998-

2000 2001* Total

Piper 0

FACT 0

Total 1 5 11 21 35 27 56 5

*Search was conducted in mid-2001

The diversity of cancers was wide and comprehensive, including brain, breast, prostate, 

laryngeal, esophageal, myeloma and melanoma, leukemia and lymphoma, and over 90 papers 

which included various cancers amalgamated into a single study. The diversity of scales used 

was staggering and included most popularly EORTC (16), HADS and POMS (14 each), but there 

were as many studies (18) which used an assortment of numerical analogue intensity scales 

which ranged from 0-4, 1-5, through QLC30, to 100 point and 101 point scales. In contrast, VAS 

was cited 98 times, but in the majority of papers details were so scant or so vague that the reader 

could not determine exactly and in detail how the VAS was used, which VAS among many types 

was employed, or to assess precisely which symptoms. 

Table 7. Assessment Scales by Cancer Type 

Cancer 

VAS HADS EORTC POMS FLIC SF-36 FACT-An WHO Piper Total 

Various 54 4 2 4 1 1 66 

Breast 5 5 4 3 1 1 19 

Gynecological 5 5 

Prostate 1 1 3 1 5 

Colorectal 2 2 4 

Bone 3 3 

Pancreatic 2 1 3 

Head and Neck 2 1 2 

Hematologic 2 1 2 

Laryngeal 2 2 

Lung 2 2 

Myeloma 1 1 

RCC 1 1 

Total 74 13 10 10 3 3 2 2 1

53
Assessment of Pain

The field of pain assessment is a well-developed one. Originating in analgesic trails before 

the middle of the last century, it was brought into focus by Beecher’s 1957 monograph on the 

measurement of subjective phenomena in man. Melzack, Turk and many other colleagues from

the behavioral sciences contributed to the subsequent refinement of this field, that in recent 

decades has had an interface with the equally large and thriving discipline of quality of life 

assessment (Spilker, 1996). Every monograph on cancer pain and all general texts on pain 

assessment and management describe a comprehensive approach to pain assessment as integral 

to cancer pain control. Such assessment is uniformly depicted as following the same approach as 

the general medical assessment of any symptom: taking a detailed history, that includes 

biopsychosocial dimensions; asking about pain location, quality, frequency, severity, and 

relieving or exacerbating factors; inquiring as to prior treatments and their effectiveness; and 

physical examination targeted towards defining the etiology and mechanism of pain. For 

example, the Brief Pain Inventory is a multidimensional assessment instrument widely applied in 

cancer pain research (Daut 1983). On the other hand, in the retrieved treatment trials, the 

instruments employed were extremely diverse and the most frequently applied ones were 

narrowly focussed upon pain intensity alone. Of 21 assessment tools that were employed a 

minimum of 5 times each, the four most often used were single-point pain intensity scales. The 

diverse mechanisms of, and quality of patients’ pain were largely not reported in the retrieved 

clinical trials, and the information that was captured was gathered in a group of instruments 

sufficiently heterogeneous to preclude merging of results. Of 218 retrieved trials, there were 125 

distinct outcomes assessed. 

54
Table 8. Most Frequently Used Assessment Tools for Pain and Pain-related Quality of Life 

(including function), Cited in Management of Cancer Pain: Evidence Report NSAIDS NSAID vs Opioid 

O

pioid vs 

Opioid Opioid Adjuvants Misc. InterventionsBisphosphonatesChe

mo or 

radiotherapy Educ, B

ehav,

Ps

ychology

HypnosisN

eurolytic

C

eliac

Plexus BlockInterimRCTs T

otal Uses 

of EachTool 

Total # 

Patients 

22,793 

1102 1665 2184 416 327 3448 5403 1625 252 250 612

1 

Total # 

Studies 

218 

18 25 42 12 10 33 27 7 5 5 34

Outcome 

Scales 125 

VAS (0-100) 5 4 19 12 4 5 1 4 4 4 58

VAS 10cm 2 1 18 1 6 2 1 5 8 8 44

Pain Intensity

5pt 

3 11 3 5 1 3 26

Pain Intensity

4pt 

5 4 4 2 3 2 1 3 24

Analgesic 

Consumption 

3 3 7 1 3 4 21

McGill Pain 

Quest 

1 5 1 1 4 1 2 15

SPID 5 9 14

Pain Relief 4pt 

scale 

3 9 1 13

Integrated 

Score Method: 

5 categories 

(0-100) 

4 4 1 9

TOTPAR 2 6 1 9

Pain Relief 5pt 

scale 

3 2 1 1 1 8

Pain Intensity

Difference 

(from 

baseline) 

4 2 1 7

EORTG QLQC30 1 1 4 6

Performance 

Status (0-4) 

4 1 1 6

Daily Numeric 

Pain Scale 

(0-10) 

1 5 6

Karnofsky

Scale 

1 1 1 1 1 5

Peak Pain 

Relief 

2 1 2 5

PPID 1 4 5

Global 

Efficacy of 

Interventions 

3pt scale 

2 2 1 5

Side Effect 

Scale 4pt 

1 3 1 5

Global 

Evaluation (1-

5) 

4 1 5

55
Assessment of Depression 

The clinical standard of diagnosing major depressive disorder in patients with cancer is a 

clinical interview. Although DSM criteria for major depressive disorder contain symptoms that 

overlap with cancer and cancer treatments, the rate of diagnosing major depressive disorder in 

patients with cancer using substitute criteria is highly correlated to that with DSM Criteria 

(Kathol, Mutgi, Williams, et al., 1990).

We chose to focus this review on screening instruments for depression. 

How do various instruments for screening for depression compare? 

Studies of depressive symptoms in cancer patients utilized numerous instruments to assess 

depression. Some instruments are commonly used in psychiatric research, some are for use in 

medically ill populations, and some were created for cancer patients. 

The HADS appeared to be the most frequently used instrument in our literature review. 

Evidence table 7 compares ten instruments that were found to have direct comparisons in the 

citations. Other instruments such as the BSI, CES-D, and MAC had studies demonstrating their 

validity, internal consistency, and reliability, but no direct comparisons. Beyond the HADS, the 

Beck Depression Inventory (BDI) and Hamilton Depression Scale were other popular 

instruments that appeared to be good screening instruments. The BDI is a self-administered 

instrument that may take up to ten minutes to complete, whereas the Hamilton is a structured 

clinician-administered instrument that can take 15 to 20 minutes. 

One interesting study found a single-item screener, asking, “Are you depressed?,” to have a 

promising predictive rate for depression in terminal cancer patients (Chochinov, Wilson, Enns, et 

al., 1997). However, there have been no other studies to replicate the findings of this single-item

screener. 

Assessment of Fatigue 

Over the years, many disciplines have been involved in the study of fatigue, including 

ergonomics, nursing, physical therapy, medicine, psychology, physiology, and biochemistry. 

Fatigue is the most frequently reported symptom of patients with cancer (Glaus, Crow, and 

Hammond, 1996). It is the symptom that is reported as the most distressing and causes the 

greatest amount of interference with daily life (Richardson, 1995). To date, there remains no 

consensus regarding standard definitions of fatigue, especially cancer-related fatigue. But there 

has been progress--fatigue is beginning to earn recognition as a valid clinical diagnosis, and in 

1998, the International Classification of Disease included criteria for fatigue; in 2000, the 

National Comprehensive Cancer Network published guidelines for its management (Atkinson, 

Barsevick, Cella, et al., 2000). 

We conducted a search of the medical literature to ascertain clearer definitions of fatigue and 

to look more carefully at the development and use of instruments that assess fatigue. To this end, 

NLM staff embarked on two separate but linked searches, one from MEDLINE® and another 

from EMBASE and PsychInfo to identify English-language papers, which dealt with assessment, 

prevalence, and treatment of fatigue in cancer patients. The searches yielded 930 abstracts that 

were screened for relevance to the specific topics, and there were 176 abstracts related to the 

56
assessment of fatigue. More than 100 papers were retrieved and read thoroughly. Preliminary 

screening of these articles resulted in the elimination of almost half, and ultimately 56 papers 

were judged to be relevant. Data were subsequently and systematically extracted: population and 

setting of the cancer patients, size of trial, age, range and percentage of male/female, types of 

cancer studies, scales used to assess the symptoms of fatigue, timepoints of measurement, the 

results and conclusions of the authors. 

A majority of the papers emanated from the United States and Canada, but many European 

countries were represented including those in Scandinavia, Holland, Switzerland, England, and 

France; there are publications from Hong Kong, Japan, Greece, and Australia. The occurrence of 

fatigue crosses all diagnostic and treatment categories, at all phases of disease, in all segments of 

populations that contain a wide array of cancer patients. Almost all studies were adult, and one 

dealt with young children, aged 10-18. 

Concerning the 56 papers retained from which data were extracted, there appeared to be no 

uniformity of purpose among the publications. Table 9 describes a myriad of tools or instruments 

developed over the years to assess fatigue and remain in vogue (such as the Piper Fatigue Scale). 

There are many new instruments: CRFDS, the Fatigue Assessment Questionnaire, the Brief 

Fatigue Inventory, and the Schwartz Cancer Fatigue Scale. 

Some of the studies compare two scales or multiple instruments; some newly created scales 

attempt to validate performance or reliability in prospective clinical settings; others correlate 

their results to tools previously validated by experience. Many publications prospectively 

measured fatigue across the trajectory of cancer from diagnosis, through treatment, following 

treatment, and in the palliative setting. Other studies present correlations between severe fatigue

and markers such as pulmonary dysfunction, between severe fatigue and depression or dyspnea, 

severe fatigue and endocrinological status and various tumor necrosis factors, or low hemoglobin 

levels. 

Some of these tools are very specific to cancer-related fatigue, such as Piper Fatigue Scale 

and the Brief Fatigue Inventory. Other tools are difficult to use in the clinical setting because of 

their complexity or the length of time required to administer the tool. Reliable, clinically valid 

tools for measuring fatigue, such as numeric severity of fatigue scales, may be better suited to the 

clinical setting. 

Table 9. Frequency of use, fatigue assessment scales 

Cancers 

1985-

89 

1990-

94 1995 1996 1997 1998 1999 2000 2001* Total 

Breast 1 3 1 1 6 5 5 3 25 

Lymphoma 1 2 1 1 2 2 1 10 

Gynecological 1 1 1 1 2 3 9 

Lung 2 1 2 3 1 9 

Colorectal 1 2 2 3 8 

GI 1 1 3 1 6 

Leukemia 1 1 1 2 1 6 

Hodgkin’s 1 2 1 1 5 

Melanoma 1 1 2 1 5 

Prostate 1 2 2 5 

57
Cancers 

1985-

89 

1990-

94 1995 1996 1997 1998 1999 2000 2001* Total 

Testicular 1 2 1 4 

Head and Neck 1 1 1 3 

Liver 1 1 2 

Bladder 1 1 

Oral 1 1 

Brain 0 

Myeloma 0 

Total 4 9 5 1 5 17 19 27 12

Table 10. Frequency of use, fatigue assessment instruments by cancer type 

Cancer 

EORTC VAS MFI POMS FACT Piper GLQ-8 Rhoten S

ymptom 

Distress Yoshitake PearsonByars SF-36 Total 

Breast 5 5 4 4 1 4 1 2 1 2 1 30 

Lung 3 5 2 2 1 1 1 1 1 17 

Prostate 2 3 4 1 1 1 12 

Gynecological 2 3 2 1 1 9 

Lymphoma 1 3 1 1 1 1 1 9 

Colorectal 1 2 1 1 1 6 

GI 1 3 1 1 6 

Hodgkin’s 2 1 1 4 

Melanoma 1 1 1 1 4 

Myeloma 1 2 1 4 

Head and Neck 1 1 2 

Leukemia 1 1 2 

Brain 1 1 

Liver 1 1 

Oral 1 1 

Skin 1 1 

Stomach 1 1 

Testicular 1 1 

Bladder 0 

Total 21 21 19 17 6 6 5 5 5 3 2 1

58
Treatment

Treatment of Cancer-related Pain 

The material that follows updates the evidence published in the evidence report, Management 

of Cancer Pain (Goudas, Carr, Bloch et al., 2001). The numbering of the questions corresponds 

to those in the original report. 

What is the relative efficacy of current analgesics for cancer pain? (Question 2) 

Summary of the Evidence from Randomized Controlled Trials Comparing an 

NSAID with another NSAID. 

Table 11. Grading of randomized controlled trials comparing an NSAID with another NSAID or to 

placebo 

Author/year 

Unique Identifier 

Study

Size* 

Baseline pain 

(VAS 0-10 cm) 

Effect

Size

Internal 

Validity

Applicability

Pannuti 1999 138 2 "moderate" 

(median, VRS scale) 

5.3 cm 

(mean, VAS scale, 

range 1-10) 

± A A

.

In this literature update we identified only one new study addressing the question of relative 

efficacy of different NSAIDs in comparison to other NSAIDs or to placebo. Pannuti, Robustelli, 

Ventaffrida, et al. (1999) aimed to compare the analgesic efficacy and toxicity of the 

nonsteroidal anti-inflammatory analgesic drug, ketorolac (Toradol, Recordati spa, Milan) 10 mg

p.o. (t.i.d.) with diclofenac (Voltaren, Novartis Farma, Origglo, VA) 50 mg p.o. (t.i.d.) in cancer 

patients with moderate to severe chronic pain. The study was a multicenter randomized doubleblind cross-over trial. Each treatment lasted 7 days, after which the patients crossed over to the 

other drug. The visual analogue scale (VAS) evaluated pain intensity after the first dose and by 

the 5-point verbal rating scale (VRS) by the patient and by the physician following the 7-day 

treatment. A total of 138 advanced cancer patients were enrolled in the study. Overall, 251 

single-dose administrations (117 cross-over observations) and 257 multiple treatments (127 

cross-over experiments) were assessable. After a single administration of ketorolac and 

diclofenac, no significant difference could be observed in analgesic activity, as indicated by the 

area under the pain-intensity time curve (AUC0-8), in the maximum efficacy, or the duration of 

efficacy of the two drugs. The Westlake confidence intervals of the AUC0-8 ratio (ketorolac: 

diclofenac) (1.07; 90% CI, 0.94-1.19), of the maximum efficacy ratio (1.03; 90% CI, 0.92-1.14), 

and the duration of efficacy ratio (1.05; 90% CI, 0.97-1.11) showed the bioequivalence of the 

two drugs. Satisfactory pain relief was reported for multiple 7-day treatments, with no significant 

differences between the two therapies: according to the physician's evaluation, in 93/128 (73%; 

95% CI, 65-80%) ketorolac treatments and 91/129 (71%; 95% CI, 63-78%) diclofenac 

treatments; according to the patient's evaluation, in 83/128 cases (65%; 95% CI, 57-73%) after 

ketorolac and in 74/129 cases (57%; 95% CI, 49-66%) after diclofenac. Adverse symptoms were 

acceptable with both drugs. Interestingly, a pronounced sequence effect was found: gastric 

disturbances after ketorolac were observed mainly (10 out of 15 observed events) when the drug 

59
was given to patients pretreated with diclofenac. The results of this study reinforce the findings 

of the prior evidence report in documenting efficacy of, yet failing to find differences in the 

analgesic benefits, between different NSAIDs given for cancer-related pain. 

What are the efficacy and side effects of the following adjuvant analgesics in the 

management of cancer pain: steroids, anticonvulsants (e.g., gabapentin), 

antidepressants (e.g., selective serotonin reuptake inhibitors), local anesthetics, 

hydroxyzine, psychostimulants, (e.g., methylphenidate, cocaine), 

diphenhydramine, clonidine, and NMDA blockers (e.g., ketamine, 

dextromethorphan), alone, or as co-analgesics with opioids? (Question 2.6) 

Summary of the Evidence from Randomized Controlled Trials Evaluating 

Adjuvant Analgesics in the Management of Cancer Pain. 

Table 12. Summary table of randomized controlled trials evaluating adjuvant analgesics in the 

management of cancer pain. 

Number of

studies

Patients enrolled/evaluated Internal Validity Applicability

6 224/212(92.4% evaluable) A = 4 

B = 2 

C = 0 

A = 1 

B = 5 

C = 0 

Table 13. Grading of randomized controlled trials evaluating adjuvant analgesics in the

management of cancer pain.

Author/year 

Unique Identifier 

Study

Size* 

Baseline pain 

(VAS 0-10 cm) 

Effect Size Internal 

Validity

Applicabilit

y 

Adjuvants - Breakthrough pain (N=1) 

Portenoy et al., 

1999 99165545 

65(65) Mean (±SD) 

4.6 ± 2.5 

 (0-10 numeric scale) 

± A A

Adjuvants - Spinal local anesthetics and other agents (N=5)

Dahm et al., 2000 

20462757 

21(9) Not stated ± (more doses 

of ropivacaine 

than 

bupivacaine 

used for the 

same degree

of pain relief)

A B

60
Author/year 

Unique Identifier 

Study

Size* 

Baseline pain 

(VAS 0-10 cm) 

Effect Size Internal 

Validity

Applicabilit

y 

Lauretti, 1999

99287592 

48(48) Mean (±Variance*) 

8.5 ± 1.5 

control group

9 ± 1 

ketamine group 

8.3 ± 1.2 

neostigmine group 

9.4 ± 0.8 

midazolam group 

*the expression of 

variance is not 

mentioned 

+ 

(ketamine and

neostigmine 

better than 

control and 

midazolam) 

A B

Van Dongen, 1999 

99452099 

20(20) Mean (±SD) 

7 ± 1.3 

morphine group 

9 ± 1 

morphine/bupivacaine 

group 

7.7 ± 1.5 

+ 

(the slopes of 

regression

curves

between m 

and M plus B 

differ 

significantly 

from day 10 to 

day 45) 

B B

Mercadante, 2000 

99032200 

10(10) Mean (±SD) 

6.6 ± 0.6 

ketamine 0.25 mg/kg 

5.9 ± 0.5 

ketamine 0.5 mg/kg 

6.5 ± 0.54 

saline 

++ A B

Lauretti, 1999

99287592 

60(60) Before oral morphine 

treatment Control: 

7.6±1.9 Dipyrone: 

7.6± 

1.7 

Ketamine: 7.4±1.5 

Nitroglycerin: 7.9±1.6 

VAS>=4 at initiation of 

study drug

administration 

+ 

(oral ketamine

and 

transdermal 

nitroglycerin 

produced a 

significantly 

lower 

morphine 

consumption 

than dipyrone

or additional 

morphine 

B B

Adjuvants - Breakthrough Pain 

We identified one randomized controlled trial dealing with the management of breakthrough 

pain in cancer patients. Portenoy, Payne, Coluzzi, et al. (1999) evaluated the efficacy of oral 

transmucosal fentanyl citrate (OTFC), a novel opioid formulation in which the potent synthetic 

mu-agonist fentanyl is embedded in a sweetened matrix that is dissolved in the mouth, as a 

treatment for cancer-related breakthrough pain. To evaluate the safety and efficacy of ascending 

doses of OTFC, a novel controlled dose titration methodology was developed that applied 

blinding and randomization procedures to the evaluation of recurrent pains in the home 

61
environment. The study was a multicenter, randomized, double-blind dose titration study in 

ambulatory cancer patients. The sample comprised adult patients receiving a scheduled oral 

opioid regimen equivalent to 60-1000 mg oral morphine per day, who were experiencing at least 

one episode per day of breakthrough pain and had achieved at least partial relief of this pain by 

use of an oral opioid rescue dose. After collection of 2 days of baseline data concerning the 

efficacy of the usual rescue drug, patients were randomly treated with either 200 or 400 mcg 

OTFC unit doses in double-blind fashion. Up to two breakthrough pains each day could be 

treated with up to four OTFC unit doses per pain. OTFC in unit doses containing 200, 400, 600, 

800, 1200, or 1600 mcg of fentanyl citrate were available for the study. The unit dose was 

titrated upward in steps until the patient had 2 consecutive days on which breakthrough pain 

could be treated with the single unit dose, titration was ineffective at a 1600 mcg unit dose, or 20 

days elapsed. To maintain the double-blind, orders to titrate up were ignored one-third of the 

time according to a pre-defined randomization schedule accessible only to an unblinded study 

pharmacist. Main outcome measures include, numeric or categorical measures of pain intensity, 

pain relief, and global assessment of drug performance. Dose response relationships were found 

suggesting that the methodology was sensitive to opioid effects. Seventy-four percent of patients 

were successfully titrated. There was no relationship between the total daily dose of the fixed 

schedule opioid regimen and the dose of OTFC required to manage the breakthrough pain. 

Although the study was not designed to provide a definitive comparison between OTFC and the 

usual rescue drug, exploratory analyses found that OTFC provided significantly greater analgesic 

effect at 15, 30 and 60 min, and a more rapid onset of effect, than the usual rescue drug. Adverse 

effects of the OTFC were typically opioid-related, specifically somnolence, nausea and

dizziness. Very few adverse events were severe or serious. This study demonstrated the 

feasibility of controlled trial methodology in studies of breakthrough pain. OTFC appears to be a 

safe and effective therapy for breakthrough pain, and dose titration can usually identify a unit 

dose capable of providing adequate analgesia. If the lack of a relationship between the effective 

OTFC dose and fixed schedule opioid regimen is confirmed, dose titration may be needed in the 

clinical use of this formulation. 

 

Adjuvants - Spinal Local Anesthetics and Other Agents (N=5) 

Dahm, Lundborg, Janson, et al. (2000) aimed to determine whether intrathecal (IT)-

ropivacaine (ROP) can reduce the rate and intensity of side effects such as urinary retention, 

paresthesia, and particularly, paresis with gait impairment in a prospective, crossover, doubleblind, randomized study. Twenty-one patients were enrolled, 9 dropped out of the study, and data 

were analyzed from 12 patients. Patients were treated by insertion of IT tunneled nylon catheters, 

continuous infusion of 0.5% ROP followed by 0.5% BUP or 0.5% BUP followed by 0.5% ROP 

solutions from an external electronic pump. Each local anesthetic was infused for 7 days, and 

their order of infusion randomized. The comparative efficacy of the ROP and BUP IT infusions 

was assessed from the daily doses of IT ROP and IT BUP, oral and parenteral opioids, and daily 

scores of nonopioid analgetic and sedative drug consumption. Self-reported pain intensity (visual 

analogue scale [VAS] mean scores) and scores of Bromage relaxation, ambulation, nocturnal 

sleep pattern, rates of side-effects attributable to the IT drugs, the patients' assessment of the IT 

ROP v the IT BUP periods of the trial, and the comparative daily cost of IT ROP v IT BUP were 

recorded. The authors found that the daily doses of the local anesthetics used were 23% higher 

for ROP than for BUP. Further, the daily cost was approximately equals 3 times higher for ROP 

than for BUP. No other significant differences between IT ROP and IT BUP were found. Overall 

62
these data suggest that there is no significant benefit in the use of ropivacaine over bupivacaine 

for the management of chronic cancer-related pain. 

Mercadante, Arcuri, Tirelli, et al. (2000) evaluated the analgesic efficacy of a slow bolus of 

subhypnotic doses of ketamine (0.25 mg/kg or 0.50 mg/kg) given to 10 cancer patients whose 

pain was unrelieved by morphine in a randomized, double-blind, crossover, double-dose study. 

Pain intensity was measured on a 0 to 10 numerical scale; nausea and vomiting, drowsiness, 

confusion, and dry mouth, using a scale from 0 to 3 (not at all, slight, a lot, awful); Mini-Mental 

State Examination (MMSE) (0-30); and arterial pressure were recorded before administration of 

drugs (T0) and after 30 minutes (T30), 60 minutes (T60), 120 minutes (T120), and 180 minutes 

(T180). Ketamine, but not saline solution, significantly reduced the pain intensity in almost all 

the patients at both doses. This effect was more relevant in patients treated with higher doses. 

Hallucinations occurred in four patients, and two patients also reported an unpleasant sensation 

(“empty head”). These episodes reversed after the administration of diazepam 1 mg 

intravenously. Significant increases in drowsiness were reported in patients treated with 

ketamine in both groups and were more marked with ketamine 0.50 mg/kg. A significant 

difference in MMSE was observed at T30 in patients who received 0.50 mg/kg of ketamine. 

Ketamine can improve morphine analgesia in difficult pain syndromes, such as neuropathic pain. 

However, the occurrence of central adverse effects should be taken into account, especially when 

using higher doses. This observation should be tested in studies of prolonged ketamine 

administration. 

Lauretti, Lima, Reis et al. (1999) designed a study to evaluate the role of oral ketamine or 

transdermal nitroglycerin polymer, the latter a nitric oxide donor, as coadjuvants to oral 

morphine in cancer pain therapy. Sixty patients with cancer pain were randomized to one of four 

groups (n = 15) and studied prospectively to evaluate analgesia and any adverse effects. Pain 

intensity was evaluated by the visual analog scale (VAS, 0-10cm). All patients were regularly 

taking oral amitriptyline 50 mg at bedtime. The morphine regimen was adjusted individually to a 

maximal oral dose of 80-90 mg/day to keep the visual analog scale score less than 4. When 

patients reported pain (visual analog scale of 4 or more), despite taking 80-90 mg oral morphine 

daily, the test drug was added as follows: the control group (CG) received an additional 20 mg

oral morphine (10 mg at 12-h intervals); the nitroglycerin group (NG) received a 5-mg 

nitroglycerin patch daily; the ketamine group (KG) received 0.5 mg/kg oral ketamine at 12-h 

intervals; and the dipyrone group (DG) received 500 mg oral dipyrone at 6-h intervals. Patients 

were free to manipulate their daily morphine consumption when the test drug was introduced to 

keep their visual analog scale score less than 4. The visual analog scale scores after the test drug 

was introduced were similar among the groups. The daily consumption of oral morphine was as 

follows: on day 15: CG = DG = NG (P > 0.05), CG > KG (P = 0.036); on day 20: CG > NG = 

KG (P < 0.02) (CG > KG, P < 0.005; CG > NG, P < 0.02), DG > KG (P < 0.05); on day 30: CG 

= DG > KG = NG (P < 0.05). Patients in the CG and DG groups reported somnolence, but 

patients in the NG and KG groups did not. The authors based on these data conclude that lowdose ketamine and transdermal nitroglycerin are effective adjuvant analgesics. Lauretti, Gomes, 

Reis, (1999) aimed to examine analgesia and adverse effects of combination epidural pain 

therapy consisting of administration of morphine with either low dose of ketamine, neostigmine, 

or midazolam in terminal cancer pain patients using a randomized double-blind study design. 48 

terminal cancer patients suffering from chronic pain were randomized to one of four groups (n = 

12). Pain was initially treated with epidural morphine 2 mg twice daily (12-hr intervals) to 

maintain the VAS below 4/10. Afterwards, VAS scores > or = 4/10 at any time were treated by 

63
adding the epidural study drug (2 ml), which was administered each morning, just after the 2-mg

epidural morphine administration. The control group (CG) received 2 mg of epidural morphine 

(2 ml). The ketamine group (CG) received 0.2 mg/kg epidural ketamine (2 ml). The neostigmine 

group (NG) received 100 micrograms epidural neostigmine (2 ml). The midazolam group (MG) 

received 500 micrograms epidural midazolam (2 ml). Patients received the study drugs on a daily 

basis. Duration of effective analgesia was measured as time from the study drug administration 

to the first patient's VAS score > or = 4/10 recorded in days. The groups were demographically 

the same. The VAS pain scores prior to the treatment were also similar among groups. Only the 

patients in the KG demonstrated lower VAS scores compared to the MG (p = 0.018). Time since 

the epidural study drug administration until patient complaint of pain VAS > or = 4/10 was 

higher for both the KG and NG compared to the CG (KG > CG, p = 0.049; NG > CG; p = 

0.0163). Only the KG used less epidural morphine compared to the CG during the period of 

study (25 days) (p = 0.003). 

van Dongen, Crul, and van Egmond (1999) aimed to determine the difference in intrathecal 

morphine dose progression between a continuous intrathecal infusion of a morphine/bupivacaine 

mixture and morphine for pain relief in patients with cancer who were treated with intrathecal 

drugs in a randomized study and followed prospectively until death. Twenty patients with cancer 

were selected for intrathecal treatment because of either side effects or inadequate relief during 

conventional pain treatment. Intrathecal drug infusion rates and medication were adjusted 

according to pain relief and side effects. The main outcome was the progression of intrathecal 

morphine dose during a phase of adequate analgesia in both groups and was analyzed by 

regression analysis. Analysis of possible treatment-related side effects was also performed. The 

combination of intrathecal morphine and bupivacaine resulted in a diminished progression of the 

intrathecal morphine dose (slope of regression line = 0.0003 vs. 0.005, p = 0.0001) during a 

phase of stable analgesia in comparison with the morphine group. No serious side effects 

presented. 

Are different formulations and routes of administration associated with different 

patient preferences or different efficacy rates? (Question 3) 

What are the patient preferences, efficacy, costs, and side effects of different 

routes of opioid administration (e.g., sustained release opioids versus 

transdermal delivery)? (Question 3.1) 

Table 14. Summary of the evidence from randomized controlled trials comparing the efficacy of 

one opioid with another (or a different formulation of the same) opioid, administered through the 

same or different route and/or the same or different dosing schedules. 

Number of studies Patients enrolled/evaluated Internal Validity Applicability 

6 263/205 (77.9% evaluable) A = 4 

B = 2 

C = 0 

I = 0 

A = 2 

B = 4 

C = 0 

I = 0 

64
Table 15. Summary of comparisons performed in randomized controlled trials reporting on 

efficacy and/or adverse effects, comparing an opioid with another opioid. 

Author/year 

Unique Identifier

Opioid Control Route(s)/Modes of 

administration 

Moolenaar, 2000 

20407008 

Morphine (MSRcontrolled release 

suppository)

Morphine (MSC-oral 

tablets) 

Oral, rectal 

Heiskanen, 2000 

21075895 

Oxycodone (CR) Morphine (CR) Oral 

Hunt, 1999 

99414499 

Fentanyl Morphine Subcutaneous

Bruera, 1999 

99349918 

Morphine (CRsuppository)Morphine (CRsuppository)Rectal (different 

administration 

schedule; 12-hourly 

and once daily) 

Mercadante, 1998 

99032200 

Methadone Morphine Oral

Parris, 1998 

99019888 

Oxycodone (CR) Oxycodone (IR) Oral 

Table 16. Grading of individual randomized controlled trials reporting on the effects of opioid with 

another (or the same) opioid, administered through the same or different routes/modes/schedules 

of administration. 

Author/year 

Unique Identifier 

Study

Size* 

Baseline pain 

(VAS 0-10 cm) 

Effect Size Internal 

Validity

Applicabili

ty

Moolenaar, 2000 

20407008 

25(25) NR ± A B

Heiskanen, 2000 

21075895 

45(45) Pain intensity at 

baseline none or 

slight and escape 

analgesic doses <=2 

per day. Baseline pain 

intensity was reached 

after a titration period 

± A B

Hunt, 1999 

99414499 

30(23) NR ± A B

Bruera, 1999 

99349918 

12(6) NR ± B B

Mercadante, 1998 

99032200 

40(40) NR ++ B A

Parris, 1998 

99019888 

111(66) Mean (±SE) 

1.5 ± 0.1 

CR Oxycodone 

1.3 ± 01 

IR Oxycodone 

(0-3, 0=none,

1=slight, 

2=moderated,

3=severe) 

± A A

65
Opioids versus Opioids 

Moolenaar, Meijler, Frijlink, et al. (2000) aimed to compare the efficacy, safety, and 

pharmacokinetics of a newly developed controlled-release suppository (MSR) with MS Contin 

tablets (MSC) in cancer patients with pain. In a double-blind, randomized, two-way cross-over 

trial, 25 patients with cancer pain were selected with a morphine (M) demand of 30 mg every 12 

h. Patients were divided into two groups. Group 1 received active MSC (30 mg) and placebo 

MSR, followed by placebo MSC and active MSR (30 mg) each for a period of 5 days. Group 2 

started with active MSR and placebo MSC, followed by active MSC and placebo MSR, each for 

a period of 5 days. Twenty patients (10 patients in each group) completed the study. A 

pronounced inter-patient variability in plasma concentrations of M, M3G and M6G was observed 

after administration of both forms. Apart from the C0 and C12, no significant differences in 

AUC0-12 h, tmax and Cmax of morphine between the rectal and oral route of administration 

were found. In the case of the metabolites, it was found that AUC0-12 h and Cmax of M6G, and 

AUC0-12 h, Cmax, C0 and C12 of M3G after rectal administration were significantly lower than 

after oral administration. However, apart from the tmax of M6G, none of the pharmacokinetic 

parameters of M, M6G or M3G met the criteria for bioequivalence. There were no significant (P 

= 0.44) differences in pain intensity score between the oral and rectal forms within the two 

groups, regardless of the treatment sequence. No treatment differences in nausea, sedation or the 

demand on escape medication (acetaminophen tablets) between the rectal and oral forms were 

observed. 

Heiskanen, Ruism, Sepp, et al. (2000) examined controlled-release (CR) oxycodone and 

morphine in cancer pain. CR oxycodone and morphine were administered to 45 adult patients 

with stable pain for 3-6 days after open-label titration in a randomized, double-blind, cross-over 

trial. Twenty patients were evaluable. Both opioids provided adequate analgesia. The variation in 

plasma morphine concentrations was higher than that of oxycodone, consistent with the lower 

bioavailability of morphine. Liver dysfunction affected selectively either oxycodone or morphine 

metabolism. Three patients with markedly aberrant plasma opioid concentrations are presented. 

Significant individual variation in morphine and oxycodone metabolism may account for 

abnormal responses during treatment of chronic cancer pain 

Hunt, Fazekas, Thorne, et al. (1999) compared subcutaneous (s.c.) morphine and fentanyl 

with respect to pain control and side effects using a 6-day randomized, double-blind, cross-over 

design. Results were obtained from 23 patients (12 males and 11 females: mean age of 70.5 

years) who could tolerate morphine. Thirteen patients were randomized to receive morphine for 

the first 3 days followed by fentanyl; 10 received fentanyl first followed by morphine. There 

were no significant differences in the scores for pain between the two drugs, suggesting that 

fentanyl is equally efficacious and the conversion ratio of morphine 10 mg: fentanyl 150 

micrograms is appropriate. Patients had more frequent bowel movements during days 4-6 while 

on the fentanyl arm [t-test, df (22), P = 0.015]. Other measures for nausea, delirium, and 

cognitive function showed no differences between the two drugs. According to the authors the 

data suggests the need to further assess the role of various opioids in hospice patients, and 

emphasizes the requirement for sensitive and simple cognitive tests in this population. 

Bruera, Belzile, Neumann et al. (1999) evaluated the safety and efficacy of controlled-release 

morphine sulphate suppositories administered 12-hourly and once daily in patients with chronic 

cancer in a randomized double-blind crossover trial. Pain was assessed using a 100-mm VAS 

pain scale and a five-point ordinal pain scale. The VAS pain intensity score was 17.5+/-17.2 after 

suppositories every 12 h, versus 16.2+/-13.4 after suppositories every 24 h (difference not 

significant). The difference between the mean VAS pain scores with 12-hourly and once-daily 

66
dosing was 1.3 mm (not significant). The mean ordinal pain scores were 1.0+/-0.7 versus 1.0+/-

0.6 for 12-hourly and once-a-day dosing, respectively (not significant). A retrospective power 

analysis indicated that a difference of 5.9 mm was detectable, even with only 6 patients. Adverse 

events noted were constipation, nausea, anorexia, and dry mouth. The use of once-a-day 

controlled-release morphine suppository is a more convenient and equally effective alternative to 

twice a day dosing. 

Mercadante, Casuccio, Agnello et al. (1998) aimed to evaluate the analgesic and adverse 

effects and the doses of methadone in comparison to morphine in a prospective randomized 

study performed in 40 patients with advanced cancer who required strong opioids for their pain. 

Patients were treated with sustained-release morphine or methadone in doses titrated against the 

effect administered two or three times daily according to clinical need. Opioid doses, adjuvant 

medications, symptoms associated with opioid therapy, pain intensity, and pain mechanisms

were recorded. The opioid escalation indices in percentage (OEI%) and milligrams (OEImg) 

were calculated. The effective analgesic score (EAS) that monitors the analgesic consumptionpain ratio was also calculated at fixed weekly intervals. The authors reported no differences in 

pain intensity between the two treatments. Patients treated with methadone reported values of 

OEI significantly less than those observed in patients treated with morphine. Seven patients in 

the methadone group maintained the same initial dosage until death, whereas only one patient in 

the morphine group did not require opioid dose escalation. A more stable analgesia in time in 

those patients treated with methadone was shown by the low number of gaps in EASs reported. 

Symptom frequencies and intensities were similar in the two groups. These results suggest that 

methadone may be a suitable alternative to morphine in the treatment of cancer pain. 

Parris, Johnson, Croghan, et al. (1998) aimed to compare the effectiveness and safety of 

controlled-release (CR) oxycodone tablets with immediate-release (IR) oxycodone in patients 

with chronic cancer pain, a multicenter, randomized, double-blind, parallel-group study was 

performed in 111 patients with cancer pain. Patients were treated with 6 to 12 tablets or capsules 

of fixed-combination opioid/nonopioid analgesics per day at study entry. Patients received 30 mg

of CR oxycodone tablets every 12 hr or 15 mg of IR oxycodone four times daily for 5 days. No 

titration or supplemental analgesic medications were permitted. The mean (+/- SE) baseline pain 

intensity (0 = none, 1 = slight, 2 = moderate, 3 = severe) was 1.5 +/- 0.1 for the CR oxycodonetreated group and 1.3 +/- 0.1 for the group given IR oxycodone (P > 0.05). The 5-day mean pain 

intensity was 1.4 +/- 0.1 and 1.1 +/- 0.1 for the CR and IR groups, respectively (P > 0.05). 

Discontinuation rates were equivalent (33%). There was no significant difference between 

treatment groups in the incidence of adverse events. This study demonstrates that cancer pain 

patients given 6 to 12 tablets or capsules of fixed-dose combination analgesics can be equally 

well treated with CR oxycodone administered every 12 hr or IR oxycodone four times daily at 

the same total daily dose. CR oxycodone offers the benefits of twice daily dosing. 

 

What is the relative analgesic efficacy of palliative pharmacological 

(chemotherapy, bisphosphonates or calcitonin) and non-pharmacological 

cytotoxic or -static (radiation therapy or radionuclide) therapy? (Question 4) 

What is efficacy of bisphosphonates in treating metastatic bone pain? (Question 

4.1) 

67
Table 17. Summary of the evidence from randomized controlled trials reporting on the relative

efficacy of bisphosphonates (various doses) or bisphophonates versus placebo. 

Number of 

studies

Patients enrolled/evaluated Internal Validity Applicability

5 1437/1371 (95.4% evaluable) A = 2 

B = 3 

C = 0 

I = 0 

A = 3 

B = 2 

C = 0 

I = 0 

Table 18. Grading of individual randomized controlled trials reporting on the relative efficacy of 

bisphosphonates (various doses) or bisphophonates versus placebo. 

Author/year 

Unique Identifier 

Study

Size* 

Baseline pain 

(VAS 0-10 cm) 

Effect

Size

Internal 

Validity

Applicability

Tian 1999 

99134535 

160 

(105) 

NR ++ B B

Arican 1999 

99456328 

53 

(50)

NR ++ B B

Lipton 2000 

20164356 

750 

(750) 

NR +++ A A

Hultborn 1999

20095088 

404 

(404) 

NR +++ B A

Koeberle 1999

99124160 

70 

(62)

Severe pain:67mm 

Moderate pain:36mm 

+++ A A

Bisphosphonates

In a multicenter trial organized in China, Tian, Zhang, Hou, et al. (1999) studied the efficacy 

and toxicity of single-dose samarium-153 ethylene diamine tetramethylene phosphonate 

(EDTMP) of 37 MBq/kg or 18.5 MBq/kg as a palliative treatment in 105 patients with painful 

bone metastases for 16 weeks. Fifty-eight of 70 patients in the high dose group and 30 of 35 in 

the low dose had a positive response, with SEPs of 22.29+/-14. 47 and 20.13+/-13.90 

respectively. Of 72 patients who had been receiving analgesics, 63 reduced their consumption. 

PGA showed that the Karnofsky score (KS) increased from 58.54+/-25.90 to 71.67+/-26. 53, 

indicating improved general condition, but the difference was not significant. 

Arican, Icli, Akbulut, et al. (1999) randomized 50 patients with bone pain caused by bone 

metastases into three groups: 800 mg/d oral clodronate, 1600 mg/d oral clodronate, and an 

undefined control group for 3 months. Significant decrease in the pain score of both active 

groups was noted when compared to control (P = 0.024 and P = 0.007, respectively). The 

analgesic use of 11 patients in low dose group (69%) and 8 patients in high dose group (47%) 

was decreased, but only the decrease in low dose patients was statistically significant (P = 

0.038). Pain score increased in 5 patients in controls (29%), and 3 patients in low dose (19%) 

and high dose groups (18%). 

Follow-up results from two prospective, multicenter, randomized, double-blind, placebocontrolled intervention trials were combined in Lipton, Theriault, Hortobagyi, et al. (2000) to 

provide data with which to evaluate the long term efficacy of pamidronate therapy. Women with 

Stage IV breast carcinoma and osteolytic metastases were randomized to receive either a 90-mg

intravenous pamidronate infusion (367 patients) or a placebo infusion (384 patients) every 3-4 

68
weeks. Pain and analgesic scores were significantly worse in the placebo group compared with 

those patients in the pamidronate group. 

Hultborn, Gundersen, Ryden, et al. (1999) in a randomized, placebo-controlled, multicenter 

study in Sweden and Norway evaluated the efficacy of pamidronate 60 mg i.v. q in 404 women 

with advanced breast cancer with skeletal metastases over 4 weeks. A self-estimated pain-score 

using Visual Analog Scales and analgesic consumption was recorded every third month as well. 

There was a significantly increased time to progression of pain (p < 0.01) in favor for the 

pamidronate group; this group fared better regarding performance status (p < 0.05). There was a 

statistically not significant lower consumption of opioid analgesics in the pamidronate group (p = 

0.14). 

In a double-blind, randomized study, Koeberle, Bacchus, Thuerlimann, et al. (1999) 

compared the effects of two pamidronate dosages, given as repeated infusions in patients with 

advanced malignant osteolytic bone disease and bone pain. Seventy patients were randomly 

assigned to receive pamidronate 60 mg or 90 mg i.v. every 3 weeks for a maximum of six cycles. 

Pain parameters, analgesic consumption, and performance status were assessed at baseline and 

throughout the study. Sixty percent (95%) of the patients in the 60 mg group and 63% (95%) of 

the patients in the 90-mg group had a sustained reduction of pain intensity and were classified as 

pain responders. Median duration of pain response was 15 versus 12 weeks in the 60-mg and 90-

mg groups, respectively (P = 0.32). After two infusions, significant changes in pain intensity, 

pain frequency, general well-being, and WHO pain score were observed (P<0.01). A trend 

toward improved performance status and reduced consumption of analgesics was also observed. 

Theriault, Lipton, Hortobagyi, et al. (1999) randomized 372 women with breast cancer who 

had at least one lytic bone lesion and who were receiving hormonal therapy to 90 mg of 

pamidronate or placebo as a 2-hour intravenous infusion given in double-blind fashion every 4 

weeks for 24 cycles. Bone pain, use of analgesics, quality of life, performance status, bone tumor 

response, and biochemical parameters were evaluated. There was no statistical difference in 

survival or in objective bone response rate. 

 

What is the efficacy of chemotherapeutic drugs in treating cancer pain (e.g., 

gemcitabine)? (Question 4.3) 

Table 19. Summary of the evidence from randomized controlled trials reporting on the efficacy of 

chemotherapeutic drugs in the management of cancer pain. 

Number of

studies

Patients enrolled/evaluated Internal Validity Applicability

7 1379/1334 (96.73% evaluable) A = 2 

B = 4 

C = 0 

I = 0 

A = 6 

B = 0 

C = 0 

I = 0 

Table 20. Grading of individual randomized controlled trials reporting on the efficacy of

chemotherapeutic drugs in the management of cancer pain.

Author/year 

Unique Identifier 

Study

Size* 

Baseline pain 

(VAS 0-10 cm) 

Effect

Size

Internal 

Validity

Applicability

Kantoff, 1999 

20030045 

242 

(234) 

NR + B A

Osoba, 1999 161 NR +++ B A 

69
Author/year 

Unique Identifier 

Study

Size* 

Baseline pain 

(VAS 0-10 cm) 

Effect

Size

Internal 

Validity

Applicability

20029930 (161)

Kramer, 2000

20389254 

331 

(294) 

Not VAS ++ B A 

Small, 2000 

20200496 

458 

(458) 

Suramin+HC=4.0 

Placebo+HC= 3.9 

+++ A A

Fossa, 2000 

20229671 

113 

(113) 

Not VAS + B A 

Riccardi, 2000 

20184074 

74 

(74)

NR + A A

Chemotherapeutic Agents

Kantoff, Halabi, Conaway, et al. (1999) compared the efficacy of the combination of 

mitoxantrone and hydrocortisone (M+H) versus hydrocortisone alone in 242 patients with 

hormone refractory prostate cancer. Patients were monitored for quality-of-life (QOL) 

parameters. There was some indication that QOL was better with M+H, in particular with respect 

to pain control. There was also some possible benefit of M+H with respect to pain control over 

hydrocortisone alone. 

Osoba, Tannock, Ernst, et al. (1999) compared either daily prednisone alone or mitoxantrone 

(every 3 weeks) plus prednisone. Those who received prednisone alone could have mitoxantrone 

added after 6 weeks if there was no improvement in pain. HQL was assessed before treatment 

initiation and then every 3 weeks using the European Organization for Research and Treatment 

of Cancer Quality-of-Life Questionnaire C30 (EORTC QLQ-C30) and the Quality of Life

Module-Prostate 14 (QOLM-P14). At 6 weeks, both groups showed improvement in several 

HQL domains, and only physical functioning and pain were better in the mitoxantrone-plusprednisone group than in the prednisone-alone group. After 6 weeks, patients taking prednisone 

showed no improvement in HQL scores, whereas those taking mitoxantrone plus prednisone 

showed significant improvement in global quality of life (P =.009), four functioning domains, 

and nine symptoms (.001 < P <. 01), and the improvement lasted longer than in the prednisonealone group (.004 < P <.05). The addition of mitoxantrone to prednisone after failure of

prednisone alone was associated with improvement in pain, pain impact, pain relief, and global 

quality of life (.001 < P <.003). 

Kramer, Curran, Piccart, et al. (2000) compared the quality of life (QL) of 331 advanced 

breast cancer patients with single-agent paclitaxel versus doxorubicin. Patients completed both 

the EORTC QLQ-C30 questionnaire and the Rotterdam Symptom Checklist (RSCL) with six 

additional items, at baseline and after the third, fifth and seventh cycles of chemotherapy. 

Doxorubicin was associated with significantly less bone pain (P=0.042) than paclitaxel. Both 

treatments were associated with improved emotional function and reduction in psychological 

distress at cycle 3. Longitudinal data suggested that doxorubicin was associated with less pain, 

specifically bone pain. 

Small, Meyer, Marshall, et al. (2000) compared suramin plus hydrocortisone therapy versus 

placebo plus hydrocortisone for patients with symptomatic hormone-refractory prostate cancer. 

Placebo patients were allowed to cross-over to open-label suramin plus HC. In addition to pain 

and opioid analgesic intake, quality of life, performance status, and survival were compared. 

Overall mean reductions in combined pain and opioid analgesic intake were greater for suramin 

plus HC (rank sum P =.0001). Pain response was achieved in a higher proportion of patients 

70
receiving suramin than placebo (43% v 28%; P =.001), and duration of response was longer for 

suramin responders (median, 240 v 69 days; P =.0027). Neither quality of life nor performance 

status was decreased by suramin treatment. 

Fossa, Curran, Aaronson, et al. (2000) compared the quality of life (QL) of patients with poor 

prognosis M1 prostate cancer treated with orchiectomy alone (ORCH) or orchiectomy combined 

with adjuvant mitomycin C. Patients completed a truncated version of the EORTC QLQ-C30 (V 

1.0) at randomization (baseline) and every 6-12 weeks thereafter. In both arms, pain improved 

during treatment. Compared with patients from the ORCH arm, the use of adjuvant MMC was 

associated with a significant reduction in global health status/QL and with impairment in 7 of 11 

QL dimensions covered by the questionnaire. Some improvement in QL was observed after 

discontinuation of MMC. 

In 74 consecutive patients with advanced breast cancer, Riccardi et al. (2000) tested the 

doubling of the epirubicin dosage within the 5-fluorouracil, epirubicin and cyclo-phosphamide 

regimen for quality of life. The QoL was assessed over and after treatment by the EORTC QLQC30 (VER 2.0) and QLQ-BR23 questionnaires, and the Spitzer's QL-index. There was no 

statistically significant difference in RR or in improvement of baseline overall QoL. Over 

baseline, the 120- but not the 60FEC patients had significantly greater pain decrease. Over 

baseline, pain decrease was also greater in these patients. 

 

What is the efficacy of external-beam radiation and radionuclides in treating 

cancer pain? (Question 4.4) 

Table 21. Summary of the evidence from randomized controlled trials reporting on the efficacy of 

external-beam radiation in the management of cancer pain. 

Number of

studies Patients enrolled/evaluated Internal Validity Applicability

4 2859/2770(96.8% evaluable) A = 0 

B = 4 

C = 0 

I = 0 

A = 1 

B = 8 

C = 8 

I = 0 

Table 22. Grading of individual randomized controlled trials reporting on the efficacy of externalbeam radiation in the management of cancer pain.

Author/year 

Unique Identifier 

Study Size Baseline pain 

(VAS 0-10 cm) 

Effect Size Internal 

Validity

Applicability

"The bone pain trial 

working party," 

1999 

20043645 

761(761) None: 32 (4%) 

Mild: 211 (29%) 

Moderate: 325 (44%) 

Severe: 168 (23%) 

Pain score on a 4-

point graded scale 

(none, mild, 

moderate, severe) 

± B A

Roos, 2000 

20171357 

90(90) Mild: 16% 

Moderate: 42% 

Severe: 38% 

Unknown: 3% 

Pain score on a 4-

point graded scale 

(none, mild, 

moderate, severe) 

+ B B

71
Author/year 

Unique Identifier 

Study Size Baseline pain 

(VAS 0-10 cm) 

Effect Size Internal 

Validity

Applicability

Steenland, 1999 

20043644 

1171(1157) Mean = 6.30 ± B A 

Whelan, 1999 

20283039 

837(762) Not stated + B A

Individual Summaries on External-beam Radiation Therapy for Cancer Pain 

The Bone Pain Trial Working Party (1999) aimed to compare a single fraction of 8 Gy with a 

course of multifraction radiotherapy in terms of long-term benefits and short-term side effects in 

patients with painful skeletal metastases. Seven hundred and sixty-five patients with painful 

skeletal metastases requiring palliative radiotherapy were entered into a prospective randomized 

clinical trial comparing 8 Gy single fraction with a multifraction regimen (20 Gy/5 fractions or 

30 Gy/10 fractions). Patients recorded pain severity and analgesic requirements on selfassessment questionnaires before treatment, at 2 weeks and at 1, 2, 3, 4, 5, 6, 8, 10 and 12 

months after radiotherapy. Pain relief was the primary endpoint of treatment benefit. Short-term

side effects were compared in a subset of 133 consecutive patients who graded nausea, vomiting 

and antiemetic usage prior to treatment and at daily intervals from days I to 14. Overall survival 

at 12 months was 44%, with no statistically significant difference apparent between randomized 

groups. There were no differences in the time to first improvement in pain, time to complete pain 

relief or in time to first increase in pain at any time up to 12 months from randomization, nor in 

the class of analgesic used. Re-treatment was twice as common after 8 Gy than after 

multifraction radiotherapy, although re-treatment for residual or recurrent pain did not reflect a 

difference between randomised groups in the probability of pain relief. The difference in the rate 

of retreatment is thought to reflect a greater readiness to prescribe radiotherapy after a single 

fraction, not a greater need. There were no significant differences in the incidence of nausea, 

vomiting, spinal cord compression, or pathological fracture between the two groups. 

Roos, O'Brien, Smith, et al. (2000) initiated a multicenter randomized trial comparing a 

single 8 Gy fraction with 20 Gy in 5 fractions for neuropathic bone pain (NBP) with an accrual 

target of 270. Formal interim analyses were planned at 90 and 180 patients. The 90th patient was 

accrued in June 1998, and data from the first interim analysis with both arms combined form the 

basis of this preliminary report. Forty-four patients were randomized to a single 8 Gy, 46 to 20 

Gy in 5 fractions. The commonest primary sites were prostate (34%), lung (28%) and breast 

(10%). Median age was 68 years (range 37-89). The index site was spine (86%), rib (13%), base 

of skull (1%). On an intention-to-treat basis, the overall RR was 53/90 = 59% (95% CI = 48-

69%), with 27% achieving a complete response and 32% a partial response. The overall 

Response Rate for eligible patients was 49/81 = 60% (95% CI = 49-71%) with 27% and 33% 

achieving complete and partial responses respectively. Estimated median time to treatment 

failure was 3.2 months (95% CI = 2.1-5.1 months), with estimated median survival of 5.1 

months (95% CI = 4.2-7.2 months). During the study, six spinal cord/cauda equina compressions 

and four new or progressive pathological fractures were detected at the index site after 

randomization, although one cord compression occurred before radiotherapy was planned to 

commence. These results are preliminary and indicate and suggest a role for RT in the treatment 

of NBP. 

Steenland, Leer, van Houwelingen, et al. (1999) aimed to address the question whether a 

single fraction of radiotherapy that is considered more convenient to the patient is as effective as 

72
a dose of multiple fractions for palliation of painful bone metastases. 1171 patients were 

randomized to receive either 8 Gy x 1 (n = 585) or 4 Gy x 6 (n = 586). The primary tumor was in 

the breast in 39% of the patients, in the prostate in 23%, in the lung in 25% and in other locations 

in 13%. Bone metastases were located in the spine (30%), pelvis (36%), femur (10%), ribs (8%), 

humerus (6%) and other sites (10%). Questionnaires were mailed to collect information on pain, 

analgesics consumption, quality of life and side effects during treatment. The main endpoint was 

pain measured on a pain scale from 0 (no pain at all) to 10 (worst imaginable pain). Costs per 

treatment schedule were estimated. On average, patients participated in the study for 4 months. 

Median survival was 7 months. Response was defined as a decrease of at least two points as 

compared to the initial pain score. The difference in response between the two treatment groups 

proved not significant and stayed well within the margin of 10%. Overall, 71% experienced a 

response at some time during the first year. An analysis of repeated measures confirmed that the 

two treatment schedules were equivalent in terms of palliation. With regard to pain medication, 

quality of life and side effects no differences between the two treatment groups were found. The 

total number of retreatments was 188 (16%). This number was 147 (25%) in the 8 Gy x 1 

irradiation group and 41 (7%) in the 4 Gy x 6 group. It was shown that the level of pain was an 

important reason to retreat. In a cost-analysis, the costs of the 4 Gy x 6 and the 8 Gy x 1 

treatment schedules were calculated at 2305 and 1734 Euro respectively. Including the costs of 

retreatment reduced this 25% cost difference to only 8%. The saving of radiotherapy capacity, 

however, was considered the major economic advantage of the single dose schedule. A more 

detailed analysis of the study is in progress 

Whelan, Levine, Julian, et al. (2000) aimed to evaluate the effect of breast irradiation on 

quality of life, including cosmetic outcome, for patients enrolled in a clinical trial. Between 1984 

and 1989, a randomized trial was conducted in Ontario, Canada, in which women with lymph 

node negative breast carcinoma who had undergone lumpectomy and axillary lymph node 

dissection were randomized to either breast irradiation or no further treatment. A modified 

version of the Breast Cancer Chemotherapy Questionnaire (BCQ) was administered to women at 

baseline, 1 month (4 weeks), and 2 months (8 weeks) after randomization. Irritation of the skin 

of the breast, breast pain, and appearance of the breast to the patient were also assessed every 3 

months for the first 2 years of the study. Of 837 patients, 416 were randomly allocated to 

radiation therapy and 421 to no further treatment. The mean change in quality of life from

baseline to 2 months was -0.05 for the radiation group and +0.30 for the control group. The 

difference between groups was statistically significant (P = 0.0001). Longer-term radiation 

therapy increased the proportion of patients who were troubled by irritation of the skin of the 

breast and breast pain. Radiation therapy did not increase the proportion of patients at 2 years 

who were troubled by the appearance of the treated breast; 4.8% in irradiated and nonirradiated 

patients (P = 0.62). Breast irradiation therapy had an effect on quality of life during treatment. 

After treatment, irradiated patients reported increased breast symptoms compared with controls. 

However, no difference was detected between groups at 2 years in the rates of skin irritation, 

breast pain, and being upset by the appearance of the breast.

What is the relative efficacy of current adjuvant (non-pharmacological/non 

invasive) physical or psychological treatments (relaxation, massage, heat and 

cold, music, exercise, and so on) in the management of cancer-related pain? 

(Question 5) 

73
Table 23. Grading of individual randomized controlled trials reporting on the efficacy of various 

physical treatments (reflexology and acupuncture) in the management of cancer pain. 

Author/year 

Unique Identifier 

Study

Size* 

Baseline pain 

(VAS 0-10 cm) 

Effect

Size

Internal 

Validity

Applicability

Stephenson, 2000 23 20 (mean) ± B B

Wen, 1998 48 NR ± I B

Reflexology 

Stephenson, Weinrich, and Tavakoli (2000) studied foot reflexology and its effects on pain 

and anxiety in 23 patients with breast or lung cancer. This crossover study randomized patients 

to receive either a half hour of reflexology, with at least 48 hours in between, and then a control 

time period during which no intervention occurred, or to begin with the control period. The 

Short-Form McGill Pain Questionnaire and Visual Analogue Scale for anxiety were used. Only 

56% (13/23) of the patients had pain at the study start. This is a small study already and thus the 

numbers for studying pain shrink even further. In patients with breast cancer who had pain, 

which is 11 people, a statistically significant (p <.05) reduction in pain was found with 

reflexology. The initial mean pain scores on the 0-100 VAS measurements recorded as part of 

the SF-MPQ was only 20. The limitations of this study as to utility of foot reflexology for pain 

include: small sample size; use of patients who began the study pain-free; lack of clarity as to 

how the control period was identified, as the maximum interval was 7 days; the intervention was 

solely one reflexology session; lack of specifics as to whether data collector was blinded. 

Acupuncture 

Wen and Jiebin (1998) studied pain in people with stomach cancer. For measuring pain, they 

had 16 patients in a group that got filiform needle acupuncture; 16 had filiform needle 

(presumably filiform needle acupuncture) and injection of certain points with human transfer 

factor twice a week. The Western medicine group of 16 got graded medications using the World 

Health Organization guidelines; by the list printed this did not include antidepressants or 

antiepileptic agents. For certain blood tests they used also a group of 16 normal controls. The 

authors state "all groups received analgesic therapy on the basis of routine chemotherapy"; it is 

unclear to this reader as to exactly what this comprised. Analgesic effects were measured as 

markedly effective, improved, or ineffective. Patients were needled one a day for 10 days. 

Results were recorded in the needled groups 30 minutes after treatment and 12 hours afterwards. 

It is not stated when they were recorded in the Western medicine group. When analgesic effects

was assessed over 10 days at the end of the 2-month study period, the markedly effective groups 

for filiform needle and point injection were higher than for Western medicine. From looking at 

the table, the numbers of patients rating their treatment as ineffective was essentially equivalent

in all three groups. Source of pain is not specified, i.e., neuropathic versus direct tumor invasion, 

nor is there a way to track if pain stayed the same or in fact worsened during the study period. 

 

74
What is the efficacy of cognitive behavioral interventions in treating cancer 

pain?(Question 5.1) 

Table 24. Summary of the evidence from randomized controlled trials reporting on the efficacy of 

cognitive behavioral interventions in the management of cancer pain. 

Number of

studies

Patients enrolled/evaluated Internal Validity Applicability

4 390/350 (89.74% evaluable) A = 1 

B = 3 

C = 0 

I = 0 

A = 0 

B = 3 

C = 0 

I = 1 

Table 25. Grading of individual randomized controlled trials reporting on the efficacy of cognitive

behavioral interventions in the management of cancer pain. 

Author/year 

Unique Identifier 

Study

Size* 

Baseline pain 

(VAS 0-10 cm) 

Effect

Size

Internal 

Validity

Applicability

Clotfelder, 1999 

99120134 

60(53) 14.2 experimental

17.5 control 

++ B B

De Wit, 1999 

20029919 

159 2.4 average pain -* B I 

Du Pen, 1999

99385437 

96 

(81)

3.5 baseline, 6.1 

worst (experimental 

group) 

3.5 baseline, 6.0 

worst (control group) 

+ A B

Ward, 2000 

20505578 

43 

(25)

3.33 experimental 

group 

4.56 control 

± B B

*Not enough information in the article to assign a score for effect size 

Individual Summaries 

Clotfelter (1999) looked at an educational intervention in patients with cancer, viewing a 

video and receiving a booklet on the management of cancer pain. 18 were in the experimental 

group and 18 in the usual care group. Pain intensity scores were assessed at two weeks after the 

intervention. There was a statistically significant difference in favor of the experimental group 

when compared to the control group. The pain in both groups at both times of measurement 

averaged 29 on a 0-100 scale. The control patients had a pretest mean of 17 compared with 14 in 

the experimental group, so had started out with slightly more pain. This study specifically looked 

at patients 65 years and older. Patients were invited to participate in the study based on their 

stability at an office visit. Co-morbidity was not noted, and the source of the pain being studied 

was not captured in the data. 

De Wit, van Dam, Hannement et al. (1999) looked at the use of a pain diary in patients with 

cancer pain; 159 were in the experimental group, using the diary to record pain twice a day, and 

154 were control patients. The article reports only on the experimental group, unfortunately. 

Exclusion criteria included life expectancy less than 3 months, living in a nursing or retirement 

home, and lack of phone. Study duration was 8 weeks. Pain intensity scores were assessed at 2, 

4, and 8 weeks. The authors recommend use of Present Pain intensity scores, rather than Average 

75
Pain Intensity scores, as being less affected in accuracy by the stability of the pain. They note 

86% compliance with use of the pain diary. The lack of any report on the control group does 

limit the utility of this study. 

Du Pen, Du Pen, Polissar et al. (1999) conducted a prospective, randomized, controlled study 

in which use of the algorithm for cancer pain management put for by the Agency for Health Care 

Policy and Research was contrasted with standard practice management. Patients had pain rated 

at minimum 3 on 0-10 scale to enter the study. In the intervention group, pain management was 

done by the study team with the referring oncologists blinded to the specifics of analgesic 

therapy. The Brief Pain Inventory 0 - 10 scale, Memorial Symptom Assessment Scale, 

Functional Assessment of Cancer Therapy Scale - Quality of Life, and Pain Treatment 

Acceptability Scale, were used for assessment. For "usual pain" the algorithm group fared better 

than the standard treatment group, with p < .02. There was no difference between the two groups 

as to reduction of the "worst" pain, pain character, or adherence to prescribed treatment 

regimens. The algorithm group used more adjuvants, such as non-steroidal anti-inflammatory 

drugs and antidepressants, but this did not cause opioid dosing to decrease compared with 

controls. The authors note that in this study, compliance correlated with outcomes as far as pain, 

yet patients often chose not to comply with the recommendations. 

Ward, Donovan, Owen et al. (2000) studied women with gynecologic cancer to determine if 

an educational intervention consisting of a face-to-face educational session with a nurse and 

written information would result in better control of pain, better management of analgesic side 

effects, and less pain interference with daily life. Twenty-one women were in the intervention 

group, which included two follow-up clarification phone calls in addition to the education 

session. There were 22 control patients, who received usual care, which did include resource 

material available on request. Duration of study was 2 months. Data obtained included the 

presence of patient-related barrier to pain management, adequacy of analgesia, analgesic side 

effects, pain intensity, pain interference, and overall quality of life. Exclusion criteria included 

no pain within two weeks prior to the commencement of the study. The groups did not differ on 

outcomes measured. Shortcomings of the study included that there was only one face-to-face 

session, the small number of participants, and that the women who elected to enter the study had 

mild to moderate pain, as opposed to severe. The authors note that all women had a decrease in 

barriers between baseline and 2-month follow-up and decrease in pain interference with life 

scores, and wondered if the act of completing baseline measures sensitized the women to issues 

of pain control. 

Oral Mucositis-Related Pain

Oral mucositis or stomatitis is a significant side effect of the treatment of cancer. The 

incidence of oral mucositis ranges from 40% in patient populations undergoing chemotherapy 

treatment to approximately 80% in patient populations receiving radiation treatment (Carl and 

Havens, 2000). It is manifested as a diffuse inflammatory process affecting the mucous 

membranes lining the mouth and is characterized by erythema, ulceration and hemorrhage 

resulting in pain and dysphagia and secondary malnutrition and dehydration (Twycross and 

Wilcock, 2001). Although not definitively associated with oral mucositis, a variety of risk factors 

have been implicated and are being investigated (Dodd, Miaskowski, Shiba, et al., 1999). Oral 

mucositis is produced as a direct toxic effect on the oral mucosal cell lining owing to the rapid 

turnover rate of these cells. Anti-cancer treatments reduce the rate of basal cell renewal leading 

to thinning of the oral mucosal thickness and increased susceptibility to infection by 

76
microorganisms making up the normal flora of the oral cavity and ultimately leading to ulcer 

formation (Carl and Havens, 2000). Prevention measures aim to decrease the likelihood of 

infection and ulceration, to relieve pain, and maintain hydration and nutrition. Numerous 

mechanism-based treatment modalities have been employed clinically to prevent oral mucositis. 

These measures fall into a broad range of different categories according to the biologic 

mechanism of prevention. They include agents that form a local barrier on the oral mucosa such 

as sucralfate, agents that stimulate the response to epithelial cell damage and desquamation such 

as prostaglandins, antioxidants and thiols, astringents, amino acids (e.g., glutamine) and nonpharmacological measures such as low-energy helion laser beam. Also used are indirect 

cytoprotectant agents such as stimulants of the hematopoietic system (e.g., G-CSF, GM-CSF), 

anti-inflammatory agents (e.g., indomethacin and benzydamine), immunoglobulins and 

antimicrobial agents such as broad-spectrum antimicrobials (e.g., chlorhexidine and providoneioidine) or narrow-spectrum antimicrobials (e.g., specific antibiotic/ antifungal combinations) 

(Sutherland and Browman, 2001). Other non-specific measures are used, some with significant 

effectiveness, such as ice chips or chamomile mouth- rinses (Clarkson, Worthington, and Eden, 

2000). These preventive measures have been evaluated in clinical investigations in the form of 

randomized clinical trials. In the present report we aimed to synthesize and summarize data from

the best available evidence. 

The majority of randomized controlled trials identified by our search was included in two 

recently published complementary systematic reviews on the prevention of oral mucositis 

(Clarkson, Worthington, and Eden, 2000; Sutherland and Browman, 2001). Thus we present here 

the findings of these reports. 

Clarkson, Worthington, and Eden, (1999, 2001-last update) performed a systematic review to 

evaluate the effectiveness of oral (and topical) prophylactic agents for oral mucositis and oral 

candidiasis in patients with cancer (excluding head and neck cancer), compared with placebo or

no treatment. This summary focuses only in findings of this review regarding prevention of oral 

stomatitis. Thus, findings on oral candidiasis are not included here. The background, 

methodology and main findings on the prevention of oral mucositis are summarized below. 

Treatment of solid malignant tumors and the leukemias with cytotoxic chemotherapy is 

becoming increasingly more effective but it is associated with short and long-term side effects. 

Among the clinically important acute side effects is the disruption in the function and integrity of 

the mouth. The consequences of this include severe ulceration (mucositis) and fungal infection of 

the mouth (oral candidiasis, thrush). These disease and treatment induced complications may 

also produce oral discomfort and pain, poor nutrition, delays in drug administration, increased 

hospital stays and costs and in some patients life threatening infection (septicemia). Oral 

complications remain a major source of illness despite the use of a variety of agents to prevent 

them. There are variations in usage between cancer centers in terms of the mouth care regimen 

used. There have been several traditional reviews published and most of these present a general 

discussion for both chemotherapy and radiotherapy-induced oral side effects (De Pauw, 1997; 

Denning, Donnelly, Hellreigel, et al., 1992; Lortholary and Dupont, 1997; Stevens, Dibble, and 

Miaskowski, 1995; Symonds, McIlroy, Khorrami, et al., 1996; Verdi, 1993; White, 1993). The 

conclusions drawn and recommendations made vary from advocating a particular therapy to 

recommending oral care procedures which have not been systematically investigated. 

The authors in this systematic review carried out a search strategy using the computerized 

MEDLINE®, EMBASE, CINAHL®, CANCERLIT®, the Cochrane Controlled Trials Register 

and the Cochrane Oral Health Group Specialist Register search up to July 1999. The search 

77
terms for oral mucositis were: (stomatitis or (oral and cand*) or (oral and mucos*) or (oral and 

fung*) ) and ((bone and marrow and transplant*) or (chemo*)) and (rand*). Reference lists from

relevant articles were scanned and the authors of eligible studies were contacted to identify trials 

and obtain additional information. Studies for consideration in this review were selected if they 

met the following criteria: design-random or quasi-random allocation of participants; participants 

- anyone with cancer receiving chemotherapy (excluding head and neck cancer); interventions - 

prophylactic agents prescribed to reduce oral conditions arising from cancer or its treatment; 

outcomes - mucositis and oral candidiasis. Data regarding methods, participants, interventions, 

outcome measures and results were independently extracted, in duplicate, by two reviewers. 

Specialist advice was sought to categorize interventions. A quality assessment was carried out 

using the Jadad criteria (Jadad, Moore, Carroll et al. 1996). The adequacy of the randomization 

concealment is also indictated in the "Characteristics of included studies" table, where 

A=adequate, B=inadequate, C=unclear and D=not used. The Cochrane Oral Health Group 

statistical guidelines were followed and relative risk values calculated using random effects 

models where significant heterogeneity was detected (P < 0.1). 

Thirty-eight reports of trials were initially included. Two were duplicate reports and nine 

were excluded as there was no useable information. Of the 27 useable studies 14 had data for 

mucositis comprising 945 randomized. Of the 27 included trials, 15 (56%) were conducted in 

USA, nine (33%) in Europe, two (7%) in Canada and one (4%) in Mexico. The majority of trials 

received external funding, 11 (41%) trials obtained government funding and 10 (37%) 

acknowledged assistance from the pharmaceutical industry, all but two of the latter being 

conducted in the United States. The providers and assessors of the prophylactic oral care were 

mainly medical staff though six (22%) of the trials involved a dentist and in five trials the patient 

was involved in the clinical outcome measure. The population in these studies included anyone 

with cancer (excluding head and neck cancer) receiving chemotherapy. Patients with head and 

neck cancer were excluded from this review because of specific oral complications they 

experience during treatment such as xerostomia (dry mouth). Nineteen (70%) of included trials 

recruited only adult patients with cancer, six included both adults and children with a difference 

in age as large as 1 to 70 years and only two of the trials were conducted solely on pediatric 

patients. The type of cancer for which patients were being treated with chemotherapy was 

exclusively leukemia in 13 trials, solid tumors in nine and a combination of hematological and 

solid tumors in five. The chemotherapy regimen was described in most of the trials though the 

chemotherapeutic agents were not always described in full detail. Of the 13 trials involving 

patients treated for leukemia, four were studies involving patients receiving a bone marrow 

transplant, five included patients undergoing remission induction therapy and in two trials 

patients were included when their granulocyte count was less than 1x109/L (1000/ml). The 

chemotherapy regime included 5-FU in six of the nine trials for patients with solid tumors. The 

types of interventions included active agents (i.e. any oral (and topical) agent prescribed 

prophylactically for mucositis) in comparison to placebo or no treatment. 

Mucositis was the outcome considered in this review. The interventions for the 14 studies 

assessing oral mucositis were: 

chlorhexidine (Dodd 1996; Ferretti 1988; Ferretti 1990; Wahlin 1989), 

ice chips (Cascinu 1994; Mahood 1991), 

prostaglandin (Duenas 1996; Labar 1993), 

glutamine (Anderson 1998; Jebb 1994), 

sucralfate (Shenep 1988), 

78
CM-CSF (molgramostim) (Cartee 1995), 

chamomile (Fidler 1996), 

allupurinol mouthrinse (Loprinzi 1990). 

For the studies reporting the prophylactic treatment for mucositis most described the index 

used. It was administered frequently on similar five point scales ranging from 0 (normal) to 4 

(severe). Eleven studies provided information for an absent versus present dichotomy and nine 

studies provided information for dichotomies of mucositis at other levels. The duration of the 

mucositis studies varied from 8 to 90 days with two studies reporting outcomes at multiple time

intervals. For these studies data from the nearest assessment to the median for the other studies 

(28 days) was used. 

The incidence of mucositis in the placebo/no treatment control group ranged from 25 to 

100%. There were three treatment subgroups that included more than one study: chlorhexidine, 

ice chips and prostaglandin. Of the eight prophylactic agents used for mucositis only one, ice 

chips, was effective (Relative risk 0.57, 95% CI 0.43 to 0.77, chi-square for heterogeneity = 0.26 

(df = 1), p = 0.61). The NNT to prevent one extra case of mucositis over the baseline incidence 

using ice chips was 4 (95%CI: 3 to 7). 

The NNT for when the baseline incidence of mucositis in the population ranges from 50% to 

80% are 5 to 4 respectively. This result should be viewed with caution as it is based on only two 

trials with a total of 177 subjects who were not blind to the treatment (Cascinu, Fedeli, Fedeli, et 

al., 1994; Mahood, Dose, Loprinzi, et al., 1991). The general reporting of RCTs was poor 

however the median Jadad score was acceptable and improved further when the authors provided 

additional information. Results on comparisons of prophylactic measures for oral mucositis are 

presented in Tables 1 (for dichotomous data, mucositis absent versus present) and 2 (for graded 

data, mucositis grade 0-3 versus 3+).

The authors conclude that there is some evidence that ice chips may have a beneficial effect 

for the prevention of mucositis. However this conclusion is based on two studies involving only 

117 subjects who were not blind to treatment. None of the other prophylactic agents included in 

this review prevented mucositis. Future trials in this area should address the link between oral 

and general health including outcomes relevant to the patient. There is a need for a well designed 

and conducted trial with sufficient numbers of participants to perform subgroup analyses by type 

of disease and chemotherapeutic agent to investigate prophylaxis for oral problems in patients 

with cancer. The authors indicate that the appearance of the mucositis and oral candidiasis can be 

similar; therefore if the assessor is neither trained nor experienced in the diagnosis of these oral 

lesions, the validity might be affected. Scores of mucositis were not always defined although 

there was consistency in the number of categories of the indices used, with the lowest indicating 

no mucositis. There should be continued evaluation of agents for mucositis. More work is needed 

to determine the most effective antifungal agent. Outcome measures of any future trial should 

address the link between oral and general health including the outcomes relevant to the patient. 

Collaboration between medical and dental teams is indicated. 

79
Table 26. Comparisons of active treatment versus placebo/no treatment for treatment of mucositis 

(absent vs present).

Treatment/studies Relative Risk [95% CI] 

Chlorhexidine 

 Dodd 1996

 Ferreti 1988 

 Ferreti 1990 

 Wahlin 1989 

Subtotal 

0.91 [0.57, 1.45] 

0.26 [0.06, 1.09] 

0.10 [0.01, 0.73] 

1.14 [0.57, 2.29] 

0.70 [0.49, 1.01] 

Ice chips 

 Cascinu 1994 

 Mahood 1991 

Subtotal 

0.64 [0.37, 1.08] 

0.54 [0.38, 0.76] 

0.57 [0.43, 0.77] 

Prostaglandin 

 Duenas 1996 

 Labar 1993

Subtotal 

3.11 [0.94, 10.27] 

0.94 [0.84, 1.05] 

1.09 [0.92, 1.29] 

Glutamine 

 Jebb 1994

Subtotal 

0.82 [0.46, 1.45] 

0.82 [0.46, 1.45] 

Chamomile

 Fidler 1996

Subtotal 

0.79 [0.58, 1.07] 

0.79 [0.58, 1.07] 

Allopurinol mouthrinse

 Loprinzi 1990 

Subtotal 

1.49 [1.10, 2.03] 

1.49 [1.10, 2.03] 

Table 27. Comparisons of active treatment versus placebo/no treatment for treatment of mucositis 

(grade 0-2 versus 3+).

Treatment/studies Relative Risk [95% CI] 

Ice chips 

 Cascinu 1994 

 Mahood 1991 

Subtotal 

0.36 [0.12, 1.07] 

0.43 [0.19, 0.97] 

0.40 [0.21, 0.77] 

Prostaglandin 

 Labar 1993

Subtotal 

1.06 [0.66, 1.70] 

1.06 [0.66, 1.70] 

Glutamine 

 Jebb 1994

Subtotal 

1.25 [0.40, 3.87] 

1.25 [0.40, 3.87] 

Sucralfate 

 Shenep 1988 

Subtotal 

0.33 [0.10, 1.08] 

0.33 [0.10, 1.08] 

CM-CSF (molgramostrim)

 Cartee 1995 

Subtotal 

1.88 [0.52, 6.76] 

1.88 [0.52, 6.76] 

Chamomile

 Fidler 1996

Subtotal 

1.49 [0.51, 4.31] 

1.49 [0.51, 4.31] 

Allopurinol mouthrinse

 Loprinzi 1990 

Subtotal 

1.13 [0.54, 2.34] 

1.13 [0.54, 2.34] 

80
Sutherland and Browman (2001) performed a systematic review and meta-analysis to 

identify, classify, and evaluate agents used in the prophylaxis of oral mucositis in irradiated head 

and neck cancer patients. This systematic review is complementary to the Cochrane review by 

Clarkson, Worthington and Eden (1999, 2001). The target population in this systematic review is 

that of patients with head and neck cancer. Head and neck cancer patients were excluded in the 

review summarized above by Clarkson, Worthington and Eden (1999, 2001). Sutherland and 

Browman (2001) proposed a classification scheme to categorize the findings of forty-two 

radnomized controlled trials, of which 15 were combined in a meta-analysis. The classification 

was based on the biologic mechanism of the preventive measures investigated. The authors 

found that the interventions reduced the odds of developing severe oral mucositis, when assessed 

by clinicians, by 36% (OR: 0.64; 95% CI: 0.46, 0.88). In a subgroup analysis they found that 

only the narrow-spectrum antibacterial lozenges were effective (OR: 0.45; 95% CI: 0.23, 0.86); 

however, they comment that the power of the aggregated data in the other classes may have been 

insufficient to detect differences. In addition, when the outcome is assessed by patients, there is 

no significant difference treatment and the control groups (OR: 0.79; 95% CI: 0.56-1.12). The 

background, methodology and main findings on the prevention of oral mucositis are summarized 

below. 

Oral mucositis is the major dose-limiting side effect in patients receiving radiotherapy for 

head and neck malignancies. It has the potential to cause significant treatment interruptions or 

premature termination of therapy (Parsons, 1994). The authors report that an estimate of 

approximately 60% of patients receiving standard radiotherapy and more than 90% of patients 

receiving experimental modalities (i.e., combined chemotherapy and radiation, altered 

fractionation) will develop severe oral mucositis (Browman, Cripps, Hodson, et al., 1994; Horiot, 

Le Fur, N'Guyen, et al., 1992; Merlano, Corvo, Margarino, et al., 1991; Pinto, Canary, Araujo, et 

al., 1991). The underlying physiologic mechanisms and symptoms of chemotherapy-induced and 

radiation-induced oral mucositis are similar. However, differences exist related particularly to 

the systemic effects and resultant myelosuppression of chemotherapy, the direct and inevitable 

stomatotoxicity of radiotherapy, and the impact of the disease itself on the symptoms

experienced by patients with head and neck cancer. This review focuses on studies of

interventions used to prevent oral mucositis in irradiated head and neck cancer patients and, 

given the trend to use combined chemotherapy and radiotherapy in advanced disease, includes 

studies using combined therapy. 

The authors’ objectives for this review is to determine the effectiveness of interventions used 

in the prophylaxis of oral mucositis in patients undergoing radiotherapy to the head and neck 

region for malignant disease and focuses on agents that have been used to prevent the 

development or progression of oral mucositis. Also, as discussed earlier, the authors propose a 

classification scheme based on the hypothesized biologic basis for the condition and the most 

plausible mechanism(s) of action of the agent used for prevention of oral mucositis in this patient

population. 

The authors applied a search strategy to MEDLINE®, EMBASE, CINAHL®, and 

CANCERLIT® databases from 1966 to June 2000, using the following sensitive search strategy 

terms: [head and neck neoplasms] AND [(radiotherapy/or drug therapy/) AND stomatitis] OR 

[exp.stomatitis/rt,dt] AND [limit to clinical trial]. They limited their search strategy to "nonMEDLINE®" to the CANCERLIT® database to identify non-overlapping reports published in 

this database. Broad screening criteria were applied in the citation lists by three reviewers to 

include patients receiving radiotherapy to the head and neck in whom any intervention to prevent 

81
oral mucositis appeared to have been used. Finally the authors identified all agents included in 

identified reports and classified these according to their possible mechanism of action. A hand 

search of all reference lists of articles, review papers, and relevant book chapters was also 

performed. Only the full text of English language papers was obtained. 

The authors applied the following criteria were used to determine eligibility of studies for 

inclusion in the review: 

Target population. Studies with patients undergoing radiation treatment to the head and 

neck area were eligible. Reports where head and neck cancer patients received neoadjuvant or 

concurrent chemotherapy were included, whereas trials that evaluated patients with other 

malignancies receiving systemic therapy were considered ineligible. Similarly, studies where 

patients were treated with radiation therapy alone, but which included patients with disease at 

sites other than the head and neck region (for example, head and neck plus lung or esophagus 

cancers), were also deemed ineligible. 

Intervention. Studies were eligible if they compared any intervention to a control group that 

included no active treatment for oral mucositis, where the intent was to prevent the development 

or progression of oral mucositis. Studies of agents that were clearly used for palliation, such as 

analgesics and anesthetic agents, were excluded.

Outcome measures. Studies that reported clinician-assessed oral mucositis scores, proxy 

measures of oral mucositis such as radiotherapy interruptions or G-tube placements, or patientassessed ratings of oral mucositis or other symptoms were included. 

Type of study. All studies, including Phase II and observational studies, that met the 

eligibility criteria were included for the purpose of developing the classification scheme, 

assessing trends in, and possible future directions for, research. However, only randomized trials 

were included in the analysis from which inferences on effectiveness were drawn. 

The authors selected the validated assessment tool developed by Jadad, Moore, Carroll et al. 

(1996) to assess the quality of the selected studies. 

Data processing and transformation. In studies where dichotomous outcome measures 

were not reported, the data were derived in one of two ways. If individual patient information 

was available in the report, this was simply abstracted in a dichotomous format. For continuous 

data, when means were provided but where different scales were used by different researchers, 

the data were transformed to a common percentage scale, using the method described by 

Eisenberg, Berkey, Carr et al. (1994). The data were then dichotomized using the technique of 

Moore, McQuay and Gavaghan (1996), that was tested and found to be robust in the oral 

mucositis model. 

The outcomes of interest were severe oral mucositis as assessed by clinicians and as

rated by patients. These are summarized for all studies for which they were available, using 

individual odds ratio (OR) of response to treatment (test vs. placebo) and associated 95% 

confidence intervals, for each trial. For this analysis, an OR > 1 favors control, while an OR = 1 

indicates exact equivalence between the two groups. 

A pooled interval estimate of the population OR was calculated. A test for heterogeneity was 

done, using the Chi-square test. Significance for this test was set liberally at p 0.1, since in 

practice the test often lacks the power to detect inter study differences of the treatment effect 

(Lau, Ioannidis, and Schmid, 1997). The DerSimonian and Laird Random Effects Model of 

pooling (DerSimonian and Laird, 1986) was used, based on the assumption of the presence of 

interstudy variability, to provide a more conservative estimate of the true effect. 

82
Subgroup analysis. Several sources of heterogeneity were anticipated. To explore the 

relationship between treatment effect and study features, several a priori hypotheses regarding 

heterogeneity were developed and subgroup analyses planned. For each of the outcome

measures, an analysis was done for each of the classifications: direct cytoprotectants, indirect 

cytoprotectants, and antibacterials. Based on the a priori hypothesis that sucralfate, which forms 

a mechanical barrier, in addition to its other properties as a direct cytoprotectant, might be more 

effective than the other direct cytoprotectants, a subgroup analysis was planned to assess this. 

Similarly, it was postulated that antibiotic lozenges, which are thought to selectively eliminate 

the aerobic Gram-negative flora associated with acute oral mucositis, might be more effective 

than the broad-spectrum rinses, and so a further analysis was undertaken of these two groups. 

The impact of radiotherapy dose (50 Gy vs. <50 Gy) and the influence of methodologic quality 

(score 3 vs. score <3) were analyzed. 

Results 

Fifty-nine English language studies were retrieved and reviewed. Eight non-English language 

reports were identified, studying amifostine (Altmann and Hoffmanns, 1999; Buntzel, Glatzel, 

Schuth, et al., 1999), sucralfate (Scherlacher and Beaufort-Spontin, 1990), sodium alginate 

(Oshitani, Okada, Kushima, et al., 1990), Ancer-20 (Okutomi, Kato, Ichihara, et al., 2000), 

prostaglandin (Raletic-Savic, Zivanovic, and Savic, 1991), and povidone-iodine (Adamietz, 

Rahn, Bottcher, et al., 1998). Two of these (Adamietz, Rahn, Bottcher, et al., 1998; Buntzel, 

Glatzel, Schuth, et al., 1999) were duplicates of reports published in English. Agreement on 

eligible studies between the two reviewers was high (Kappa = 0.83). 

Initially, 17 papers were eliminated for the following reasons: trials included patients who 

received chemotherapy for systemic malignancies or solid tumors outside the head and neck site 

(Ferretti, Raybould, Brown, et al., 1990; Lever, Dupuis, and Chan, 1987; Prada and Chiesa, 

1987; Prada, Lozza, Moglia, et al., 1985; Schubert and Newton, 1987); trials included patients 

who received radiotherapy to sites other than the head and neck region (Allison, Vongtama, 

Vaughan, et al., 1995; Meredith, Salter, Kim, et al., 1997); interventions were aimed at palliation 

rather than prophylaxis (Carnel, Blakeslee, Oswald, et al., 1990; Kim, Chu, Lakshmi, et al., 

1985); reports were not studies of therapy (Matejka, Nell, Kment, et al., 1990; Tanner, Stamford, 

and Bennett, 1981; Wagner, Radmard, and Schonekaes, 1999); or papers were duplicate reports 

of included trials (Epstein, 1986; Epstein and Stevenson-Moore, 1986; Hanson, Marks, Reddy, et 

al., 1995; McIlroy, 1996; Wagner, Prott, and Schonekas, 1998). 

Forty-two studies were included in the classification of agents used to prevent oral mucositis, 

according to the postulated mechanism of action. These data are shown in Table 2 of the original 

report (Sutherland and Browman, 2001). 

Of the 42 reports, 25 were subsequently excluded from the analysis on the basis of study 

design. One excluded report was a retrospective chart review (Matthews and Ercal, 1996). 

Twelve of the excluded studies were Phase I/II investigations or historical control. Ten of the 

excluded studies had concurrent controls. Of these, six were not, three compared two different 

agents with no placebo control, and one was an interim analysis. Two more reports, although 

described as randomized trials, received a quality score of 0 and were therefore excluded. In 

addition, two reports did not report outcome data for severe mucositis in a manner that could be 

abstracted using the planned techniques. 

83
Trial characteristics. Fifteen randomized, controlled trials were included in the analysis. 

One study in progress, a multicenter trial of an antibiotic lozenge currently under way in Canada 

(NCIC, 1997) was identified. 

A total of 1022 patients were included in the 15 studies. Nine studies assessed direct 

cytoprotectants. Of these, five evaluated the barrier sucralfate, and four evaluated protectants that 

are thought to stimulate epithelial response (one each of prostaglandin, beta-carotene, hydrogen 

peroxide, and laser therapy). One assessed indirect cytoprotectants (benzydamine), and five trials 

considered antibacterials. Of those, three studied broad-spectrum antibacterials, while two 

evaluated narrow-spectrum antibiotic lozenges. 

In nine studies, it was clear that the radiation field covered the oral cavity/oropharynx in all 

patients, whereas in six reports other head and neck sites such as larynx were also included, or 

the field was unspecified. Seven of the studies excluded patients who had received prior 

chemotherapy or radiotherapy. 

The radiotherapy dose was at least 50 Gy in 10 trials, while five trials included some patients 

who had received a total dose of 45 Gy or less. In two studies (Foote, Loprinzi, Frank, et al., 

1994; Okuno, Foote, Loprinzi, et al., 1997) with sample sizes of 52 and 112, respectively, the 

radiotherapy dose ranged from 30-45 Gy. In 13 of the studies, radiotherapy was delivered in a 

conventional fractionation scheme, while two trials (Carter, Hebert, Smink, et al., 1999; 

Symonds, McIlroy, Khorrami, et al., 1996) included a hyperfractionation schedule in one 

stratum. Three trials (Carter, Hebert, Smink, et al., 1999; Mills, 1988; Rahn, Adamietz, 

Boettcher, et al., 1997) used concurrent chemotherapy as part of the planned treatment. 

Methodologic quality. The authors found a median quality score of 3 of a maximum 

possible score of 5 (range 1-5); the scores for each study can be obtained from the original 

report. Although all studies stated that they were randomized, only three described the method of 

randomization. Twelve of the studies were described as double-blind, and the method of doubleblinding was clearly appropriate in 11 of these. Eight of the 15 provided a statement on 

withdrawals and dropouts. Agreement for the quality of studies was modest (Kappa = 0.43). 

Meta-analysis 

Outcome: severe oral mucositis, clinician assessments. Thirteen of the 15 trials supplied 

information on the proportion of patients who developed severe oral mucositis, as assessed by 

clinicians (Bensadoun, Franquin, Ciais, et al., 1999; Carter, Hebert, Smink, et al., 1999; Cengiz, 

Ozyar, Ozturk, et al., 1999; Feber, 1996; Foote, Loprinzi, Frank, et al., 1994; Hanson, Marks, 

Reddy, et al., 1997; Lievens, Haustermans, Van den, et al., 1998; Makkonen, Bostrom, Vilja, et 

al., 1994; Mills, 1988; Okuno, Foote, Loprinzi, et al., 1997; Rahn, Adamietz, Boettcher, et al., 

1997; Spijkervet, van Saene, Panders, et al., 1989; Symonds, McIlroy, Khorrami, et al., 1996). 

Two trials did not report the data in a manner that could be abstracted (Epstein, StevensonMoore, Jackson, et al., 1989; Epstein and Wong, 1994) for this outcome. The use of all 

interventions together had a significant impact on mucositis, reducing the odds of developing 

severe oral mucositis by 36% (OR 0.64; 95% CI: 0.46, 0.88). 

The baseline risk for developing severe oral mucositis in the control groups of the combined 

studies was 43%, while the overall absolute risk reduction when prophylactic interventions were 

used was 9%. 

The odds ratio favors antibacterial agents over placebo (OR 0.47; 95% CI: 0.25, 0.92), and 

within this grouping, the only significant effect is for the narrow-spectrum antibacterials (OR 

0.45; 95% CI: 0.23, 0.86). Studies of higher quality (validity score 3) tended to support the use of 

treatment across all studies (OR 0.68; 95% CI: 0.48, 0.96). An overall treatment effect of the 

84
interventions was seen when all patients received a radiotherapy dose of at least 50 Gy; no 

difference was demonstrated when studies included some patients receiving less than 50 Gy. 

Outcome: Severe Oral Mucositis, Patient Assessments 

Data for severe oral mucositis, as assessed by patients, were available for 10 of the trials. The 

combined results of these studies suggest only a trend for a difference in prophylaxis of oral 

mucositis between the treatment and the control groups (OR 0.79; 95% CI: 0.56-1.12). No 

significant heterogeneity was detected. The only study of broad-spectrum antibacterial agents 

reporting patient measures (Foote, Loprinzi, Frank, et al., 1994) showed a strong trend favoring 

the control group. In this trial of chlorhexidine (n = 52), no significant clinical benefit of the 

treatment rinse vs. placebo rinse was demonstrated, and a significant proportion of patients on 

the treatment arm reported moderate to severe mouthwash-induced discomfort and taste 

alteration. 

Discussion

In this systematic review the authors propose a classification system that groups the 

preventive interventions into three broad categories: direct cytoprotectants, indirect 

cytoprotectants, and antibacterials. They note that the modes of action for each agent are 

postulated mechanisms based on the literature and are presented to enable a preliminary 

classification scheme to be developed. They suggest that changes to the classification system

may be warranted as mechanisms of the various interventions become better understood, 

particularly in the setting of radiated tissues. 

This review shows that there has been a significant amount of preliminary research in the 

prevention of oral mucositis in irradiated head and neck cancer patients. Many of the studies that 

were excluded from this systematic review on the basis of trial design report promising results, 

warranting further research, but, in some areas, randomized trials have not been forthcoming. 

The authors discuss the various challenges in executing high-quality clinical trials on prevention 

of oral mucositis. They suggest that the low incidence rates of head and neck cancer and the 

variety of histologic diagnoses and subsequent variety in radiation treatment field and dose may 

yield small numbers of patients that can be included in a trial. This was apparent in the trials in 

this systematic review, where several studies included significant numbers of larynx patients; a 

number delivered radiotherapy to some patients at doses of less than 50 Gy. Other difficulties in 

prevention of oral mucositis studies arise from the fact that most of the commonly used oral 

mucositis scoring systems have not been validated (Parulekar, Mackenzie, Bjarnason et al., 

1998), and there appears to be lack of agreement on which tools to use and which endpoints are 

most relevant. 

The authors also discuss the quality of and deficiencies of the studies included in their 

systematic review. They note that the overall quality of the trials was sub-optimal. Deficiencies 

related to description of appropriate methods of randomization, where only 3 of the 15 included 

studies reported this clearly. 

The authors according to their findings suggest that in aggregate the interventions chosen on 

a sound biologic basis to prevent severe oral mucositis are effective. When oral mucositis is 

assessed by clinicians, narrow-spectrum antibiotic lozenges may be beneficial. When patients 

evaluate the symptoms of oral mucositis, none of the interventions appear to be effective, and, in 

fact, chlorhexidine may be poorly tolerated by patients. 

85
With regards to sub group analyses, they note that statistical significance was not attained for 

most subgroups, although all interventions, with the exception of broad-spectrum antibacterials, 

showed a trend toward effectiveness underlining the need for more and larger well-designed 

randomized trials to strengthen the evidence in this area. 

Finally the authors conclude that at the present time, there is not a strong body of evidence to 

support the development of specific recommendations for the prevention of oral mucositis in 

clinical practice. However, narrow-spectrum antibacterials appear to be advantageous. 

Future research. The authors suggest that in other promising areas, where the research has 

been of an exploratory nature, randomized controlled trials are needed. If such trials demonstrate 

a benefit from individual agents, comparison studies and studies of combinations of agents from

different classes will be beneficial. In addition, the difference between clinician-rated and 

patient-rated measures needs to be acknowledged. In studying patient-assessed outcomes in head 

and neck radiotherapy, it seems that symptom-specific scales need to be complemented or 

replaced with the use of multidimensional quality of life measures. In planning future research 

strategies, the choice of clinically relevant primary outcome measures using validated 

measurement tools, in larger, methodologically sound trials, is essential. 

Acute Herpes Zoster and Postherpetic Neuralgia (PHN) in Cancer 

Patients

Postherpetic neuralgia (PHN) is the most common complication of herpes zoster, and as such 

has been an area of extensive medical research for the past three decades. PHN is uncommon in 

patients under 40 years of age. A recent prospective study on the epidemiological characteristics 

of PHN in 421 patients with long term follow up (Helgason, Petursson, Gudmundsson, et al., 

2000) demonstrated that among patients younger than 60 years, the risk of PHN three months 

after the start of zoster was 1.8% (0.59% to 4.18%, 95% confidence interval) with mild pain. The 

same study showed that the risk of PHN is increased in patients 60 years or older but the pain is 

usually mild to moderate. Earlier reports suggest that the incidence of PHN does not increase in 

immunocompromised patients that in their majority are cancer patients (Rusthoven, Ahlgren, 

Elhakim et al., 1988). Among patients with cancer, those with leukemia and lymphomas have the 

highest risk for herpes zoster; 20% to 50% of patients with Hodgkin's lymphoma develop herpes 

Zoster (Schrimoff, Serpick, Stoler et al., 1972; Sokal and Firat, 1965). Evidence from non-cancer 

patients suggests that early treatment of acute herpes zoster with antiviral agents may prevent 

and shorten the duration of PHN but with marginal effectiveness. A meta-analysis of randomized 

controlled trials in immunocompetent patients demonstrated that treatment with oral acyclovir—

the most commonly used antiviral agent—within 72 hours of rash onset may reduce the 

incidence of residual pain by 46% at six months (Jackson, Gibbons, Meyer, et al., 1997). A 

recent systematic review provided marginal evidence that oral acyclovir prophylaxis reduces 

pain at 1 and 3 months following zoster, while famcyclovir and valacyclovir reduced the 

duration but not the incidence of PHN (Alper and Lewis, 2000). The same systematic review 

provided evidence from a single trial showing that some reduction in the incidence of PHN can 

be achieved with early amitriptyline treatment for 90 days or early use of transcutaneous 

electrical nerve stimulation (TENS). None of the above reports included data from cancer patient 

populations. When PHN is established treatment is difficult and frustrating for both the 

healthcare provider and the patient (Lojeski and Stevens, 1997). A few studies have 

demonstrated efficacy of tricyclic antidepressant medications such as amitryptyline (Lojeski and 

Stevens, 1997) in immunocompetent patients with PHN. Anticonvulsant medications have also 

86
been shown to be effective in the management of PHN (McQuay, Carroll, Jadad et al., 1995). A 

large scale multicenter randomized placebo-controlled trial in 229 patients demonstrated a 

significant reduction in pain intensity in those receiving gabapentin versus placebo for 8 weeks 

(Rowbotham, Harden, Stacey, et al., 1998). 

This strategy yielded 23 reports of which only 15 satisfied our inclusion criteria. Six of these 

reports studied neuropathic pain in cancer patients and included a mixed patient population and 

have been included in a previous extensive synthesis of the literature on the management of 

cancer pain (Goudas, Carr, Bloch, et al., 2001). 

Table 28. Grading of individual randomized controlled trials reporting on the effects of 

prophylactic antiviral treatments against zoster pain and PHN. 

Author/year 

Unique Identifier 

Study

Size* 

Baseline pain 

(VAS 0-10 cm) 

Effect

Size

Internal 

Validity

Applicability

Betts/1975 

75181958 

60 NA − B B

Ch'ien/1976 

76216149 

87 NA None C C

Merigan/1978

78156258 

90 NA + B B

Stevens/1980

80108369 

97 NA ± B B

Merigan/1981 

81230966 

32 NA ± B B

Whitley/1982 

82272286 

121 NA + B B

Balfour/1983 

84032170 

20 NA + C I 

Shepp/1986 

86092132 

22 NA + B B

Leyland-Jones/1986 

86279775 

34 NA + B B 

Table 29. Summary of randomized controlled trials comparing various treatments of herpes with 

respect to zoster pain and Postherpetic Neuralgia (PHN) in cancer patients. 

Author 

Year 

UI Treatments compared 

Conclusion based 

on any pain outcomes 

Betts/1975 

75181958 

Cytarabine versus placebo Cytarabine was worse compared to 

placebo 

Ch'ien/1976 

76216149 

Adenine arabinoside (ara-A) versus

placebo 

No conclusion can be drawn by this 

study. 

Merigan/1978

78156258 

Interferon (three doses) versus placebo 

(Three studies) 

Interferon beneficial compared to 

placebo. 

Stevens/1980

80108369 

Pooled gamma-globulin [NSG] versus 

zoster immune globulin [ZIG] 

There was no difference between the 

two active treatments

Merigan/1981 

81230966 

Interferon versus placebo (albumin) Interferon treatment marginally 

beneficial compared to placebo 

87
Author 

Year 

UI Treatments compared 

Conclusion based 

on any pain outcomes 

Whitley/1982 

82272286 

Vidarabine versus placebo Vidarabine beneficial compared to 

placebo 

Shepp/1986 

86092132 

Acyclovir versus vidarabine Acyclovir superior to vidarabine 

LeylandJones/1986 

86279775 

2'-Fluoro-5-iodoarabinosylcytosine (FIAC) 

versus adenine arabinoside ara-A) 

FIAC superior to ara-A 

All identified reports investigated the effect of antiviral treatments on the recovery from 

acute herpes zoster and on the reduction of acute zoster pain and PHN. No trial was identified on 

the effectiveness of treatments in established PHN in cancer patients underlining the paucity of 

evidence in this area. Pain characteristics as well as pain intensity were generally poorly 

reported. Seven reports compared specific or nonspecific antiviral treatments with placebo. None 

of these reports demonstrated a strong effect in reducing pain during the acute phase (48 hours to 

a week) or at follow up assessments up to 6 months. 

Treatment of Cancer-Related Depression 

What are the effects of medications on depression in cancer patients?

Only eleven controlled studies of the effects of medications on depressive symptoms in

cancer patients exist. Nine of them are primarily treatment studies on depressive symptoms. 

One is a pain study that also assessed depressive symptoms and one is a depression prevention 

study. 

Table 30. Psychopharmacologic Studies of Treatment of Depression in Cancer 

Double-blind randomized control trialsa

Author 

Year 

UI N Medication Results

Methodological 

Quality Applicability

Johnston

1972 

50 Thioridazine Better than placebo for 

depressed mood at 1 

week, but not week 3 

and 6. Helpful for 

insomnia and crying 

spells at all time points 

(p<.05) 

B A

 a The Holland, 1991 study is not double-blinded.

88
Author 

Year 

UI N Medication Results

Methodological 

Quality Applicability

Purohit 

1978 

39 Imipramine 80% imipramine 

patients Improved, 

42% of controls 

B B

Bruera 

1985 

40 Methylprednisol

one 

Day 13 MP patients 

had improved

depression (p<.05), 

day 33 no significant 

difference with placebo

A B

Costa 

1895 

73 Mianserin Exp. group greater 

improvement in HDRS 

(p<.01) and ZSDRS 

(p<.05) at 4 weeks; 

significantly more 

responders on CGI in 

exp. Group (p<.025) 

A A

Bruera 

1986 

26 Mazindol No significant

difference with placebo

A B

Holland 

1991 

147 Alprazolam vs.

progressive 

muscle 

relaxation 

Both groups improve, 

alprazolam group 

significantly more 

improvement with ABS 

(p=.04) and HDRS 

(p=.08) 

B A

Van 

Heerigen

1996 

55 Mianserin HDRS scores lower 

than placebo at 2 

weeks (p=.056), 4 

weeks (p=.004), and 6 

weeks (p=.004), 

number of responders 

significantly greater

than placebo (p<.05) at 

4 and 6 weeks 

A B

Eija 

1996 

15 Amitriptyline No significant

differences

C C

Razavi

1996 

115 Fluoxetine Both groups improved, 

no significant 

difference with placebo

A I 

Razavi

1996 

91 

rando

mized 

Fluoxetine No significant

difference in change in 

depression scores or

percentage of

responders (HADS <8)

B B

89
Author 

Year 

UI N Medication Results

Methodological 

Quality Applicability

Holland 

1998 

37 Fluoxetine vs.

Desipramine

Both groups improved

significantly by both 

scales, no significant 

differences between

drugs 

A A

Razavi

1999 

27 Trazodone vs.

Clorazepate 

By CGI, 91% T group 

responders, 57% C 

group, but no

significant differences; 

by HADS scores 

decreased in both but 

no significant 

differences

B B

Musselman 

2001 

20 per 

group 

Paroxetine Patoxetine significantly

reduced the incidence 

of depression (p=.04), 

11% in paroxetine vs. 

45% in control; 

paroxetine had 

significant effect on 

severity of depressive 

symptoms (p<.001) 

A C

These studies reflect the history of psychopharmacology. Antipsychotics became available 

first and then tricyclic antidepressants. Later selective serotonin reuptake inhibitors appeared. 

The first study took place in 1972 and was a 6-week placebo controlled trial of thioridazine 

25 mg tid for depression in a hetergeneous sample of 50 cancer patients. Thioridazine is an 

antipsychotic medication that is now not usually used for the clinical treatment of depression. 

The study included inpatient, outpatient, and terminal patients with various cancers. Depression 

was assessed by physician ratings of depressive symptoms. Although it appeared better than 

placebo for depressive symptoms at the end of the first week, this difference was not statistically 

significant at weeks three and six. However, at all time points, it was significantly better than 

placebo for insomnia and crying spells. The authors reported that no side effects were observed. 

Because this study did not clearly chose participants with a diagnosis of major depressive 

disorder and did not use standardized rating instruments, it is difficult to fully interpret this data 

(Johnston, 1972). 

Purohit and colleagues conducted a 4-week placebo controlled trial of imipramine in 39 

hospitalized cancer patients receiving radiation therapy (Purohit, Navlakha, Modi, et al., 1978). 

All patients staerted with a physician diagnosis of major depressive disorder. The imipramine 

was dosed between 25 and 50 mg a day. The doses were adjusted for tolerability. Although they 

demonstrated that 80% of the imipramine group improved compared to 42% of the controls 

using the Hamilton Depression Scale, they did not analyze their data for statistical significance 

of these differences. 

The effects of a glucocorticoid were studied by Bruera and colleagues (Bruera et al., 1985). 

This 33 day randomized, placebo-controlled trial used methylprednisolone 16 mg bid in 40 

90
terminal oncology patients with various cancers. Although at day 13, the methylprednisolone 

showed greater improvement in the Hamilton Depression Scale than placebo (p<0.05), there was 

no significant difference at day 33. Side effects included 5% of patients reporting increased 

anxiety and 5% of patients developed Cushingoid features. 

Costa and colleagues conducted a 4-week randomized controlled trial of mianserin in 73 

women with cancer (Costa, Mogos, and Toma, 1985). Women required significant depressive 

symptoms as measured by the Hamilton depression Scale to enter the study. Mianserin was 

dosed between 30-60 mg per day. At four weeks, there were more responders in the miasnserin 

group assessed by changes in CGI (p<0.25) and the mianserin group had a greater improvement 

in the Hamilton Depression Scale (p<0.01). There were no significant differences in side effects. 

Bruera and colleagues studied the effects of another medication, mazindol, in cancer patients 

(Bruera, Carraro, Roca, et al., 1986). Twenty-six terminal patients with various cancers 

participated in this 12-day randomized placebo-controlled trial. The mazindol was dosed at 1 mg

tid. At 12 days, there was no significant difference in changes in the Hamilton Depression Scale 

between groups, but the mazindol group experienced “serious toxicity.” These side effects 

included nervousness, sweating, delirium, and weakness. 

Holland and colleagues, comparing alprazolam with progressive muscle relaxation (Holland, 

Morrow, Schmale, et al., 1991), did the only non-blind trial included in this series. One hundred 

forty-seven people with various cancers participated in this 10-day trial. Patients were included 

if they met criteria for depression or anxiety. Both groups showed improvement in the Hamilton 

Depression Scale and the Affects Balance Scale. However, the alprazolam group had greater 

improvement in the Affects Balance Scale (p<0.04) and an improvement trend with the Hamilton 

Depression Scale (p<0.08). There were more drop outs in the alprazolam arm and side effects 

reported were drowsiness, sedation, and lightheadedness. 

Mianserin was also studied by Van Heeringen and colleagues (van Heeringen and Zivkov, 

1996). In this 6-week randomized, placebo-controlled trial in fifty-five women with breast 

cancer receiving radiation, depression was diagnosed with a DSM-III interview. Mianserin was 

dosed at 60 mg per day. Hamilton Depression scale scores were significantly lower in the 

mianserin group compared to placebo at week 2 (p<0.056), week 4 (p<0.004), and week 6 

(p<0.004). The number of responders was greater in the mianserin group compared to placebo at 

weeks 4 and 6 (p<0.05). Although placebo participants tended to terminate the study earlier, the 

some of the mianserin group reported postural symptoms and sedation. 

Although depression was not the primary endpoint, Eija and colleagues assessed depression 

in their 4-week, randomized placebo-controlled trial of amitriptyline for neuropathic pain in 

fifteen breast cancer patients (Eija, Tiina, and Pertti, 1996). Amitriptyline was dosed at 25-100 

mg per day. No significant differences were noted in depression between groups, but depression 

was not assessed in a standardized way. Patients were asked two questions regarding depression 

with a four-point scale. Side effects reported from amitriptyline included sedation, dry mouth, 

constipation, and sweating. 

Razavi and colleagues conducted a 4-week randomized, placebo-controlled study of 

fluoxetine after one week of placebo in both groups (Razavi, Allilaire, Smith, et al., 1996). 

Ninety-one people with various cancers and DSM-III diagnoses of major depressive disorder 

participated. Fluoxetine was dosed at 20 mg per day. No significant differences in the numbers 

of responders as defined by HADS < 8 or changes in depression scores with the HADS and 

MADRS were found between groups. There were also no significant differences in side effects 

between groups. 

91
Fluoxetine was also studied by Holland and colleagues in a 6-week comparison study with 

desipramine, after one week of both groups receiving placebo (Holland et al., 1998). Thirtyseven women with cancer diagnosed with depression by DSM-II-R interview participated. 

Although doses were variable with responses, fluoxetine was dose at 20 mg per day and 

desipramine was dose at 100 mg per day. Both groups improved significantly by both the 

Hamilton Depression scale and the CGI. However, there were no significant differences 

between groups. Both groups reported side effects that included nausea, dry mouth, insomnia, 

and dyspepsia. 

Although major depressive disorder was not the focus, Razavi and colleagues studied the 

effects of trazodone and clorazepate on depressive symptoms in a 4-week comparison trial 

(Razavi, Kormoss, Collard, et al., 1999). Twenty-seven breast cancer patients diagnosed with 

adjustment disorder with depressed mood by DSM-II-R criteria participated. Trazodone was 

dosed between 50-150 mg per day and clorazepate was dosed between 10-30 mg per day. 

Although there were a greater number of responders by CGI in the trazodone group, this 

difference was not statistically significant. There were also no significant differences in change 

in depression scores with the HADS. 

The last study was not a depression treatment study. Musselman and colleagues studied 

paroxetine in preventing depression in melanoma patients receiving interferon (Musselman, 

Lawson, Gumnick, et al., 2001). This 14-week trial had 40 participants. Paroxetine was initially 

dosed at 10 mg per day and increased up to 40 mg per day. Paroxetine significantly reduced the 

incidence of depression (p=0.04) and the severity of depressive symptoms (p<0.001) as 

measured by the Hamilton depression Scale. Adverse events did not differ significantly between 

groups. 

With the exception of two studies, all medications classified as antidepressants showed

benefit. The two studies that did not show benefit studied the medications for not more than four 

weeks. This is not surprising because antidepressants can typically take between four to six 

weeks to take effect. Medications other than antidepressants did not appear to be effective. 

Are psychosocial interventions effective in treating depressive symptoms in 

cancer patients? 

There have been hundreds of studies on the effectiveness of psychosocial interventions on 

depressive symptoms in cancer patients. Because of the large number of studies, we limited our 

review to published meta-analyses of these studies. 

Although these meta-analyses were not done necessarily on patients with significant 

depressive symptoms, there does appear to be a small to moderate effect size from these 

treatments. Though one of these meta-analyses did not note a significant difference in effect size 

among different types of treatments, the limitations of that study make interpretations of that 

observation difficult. 

Despite its title as a meta-analysis of psychoeducational care, Devine and Westlake, (1995) is 

actually a meta-analysis of psychosocial interventions in adult cancer patients. It included 98 

studies with 5,326 subjects published from 1976 to 1993; 47% were published in a journal or 

book, 45% doctoral dissertations, and 6% theses published in a journal. Inclusion criteria were 

provision of a psychosocial intervention to adults with cancer; use of an experimental, 

quasiexperimental, or pre-post single test design; and outcome measures of physical and 

emotional well being. Exclusion criteria were studies that had comparison arms to other 

92
treatments (such as medications); studies with less than five subjects, and all treatment groups 

not being from the same setting. Interventions included educational, behavioral/cognitive 

counseling, non-behavioral/cognitive counseling. The most prevalent intervention was 

behavioral/cognitive counseling. It is not noted whether both individual and group interventions 

were included. Although the studies were not necessarily on patients with depression, a positive 

effect was present in 92% of the studies with the average effect size being medium. 

Meyer and Mark (1995) is a meta-analysis of psychosocial interventions in adult cancer 

patients. It included 45 studies with 2,840 subjects. Its inclusion criteria were published 

randomized experiments; psychosocial intervention compared to control or minimal intervention; 

and the inclusion of behavioral and emotional outcome measures. The only exclusion criterion 

was hospice or terminal care studies. Interventions included educational, behavioral, nonbehavioral counseling, social support or other interventions (music therapy, for example). It is 

not noted if both individual and group interventions were noted. Although this meta-analysis 

showed a small effect size, it was not as stringent in evaluating depressive symptoms. Measures 

of emotional adjustment were included rather than measures of depression. This meta-analysis 

also did not show a significant difference in effect size according to type of intervention. 

Sheard and Maguire (1999) is a meta-analsis of psychological interventions for anxiety and 

depression in cancer patients. It included 20 studies with 1,101 subjects. Inclusion criteria were 

studies of psychosocial interventions for psychodistress in cancer patients; a control condition;

and published in English in a journal or indexed as a dissertation. The one exclusion criterion 

was a single group design without a control. In the evidence-based table, only the effects of 

studies that assessed for depressive symptoms were included. Both individual and group data are 

included in the analysis. The interventions included individual therapy, relaxation, group 

therapy, group therapy excluding psychoeducation, and group psychoeducation. Although these 

studies were not specifically done on patients who were depressed, a small to medium effect size 

was seen, but the effect size decreased with the authors' assessment of the quality of the study. 

Are alternative treatments effective for the treatment of depressive symptoms in 

cancer patients? 

Although there have been descriptive reports of alternative or complementary treatments for 

depression in people with cancer, there have been no controlled trials. 

Treatment of Cancer-related Fatigue 

Our search strategy identified ten randomized controlled trials assessing the efficacy of 

various interventions for the treatment of cancer-related fatigue (Table 32). Some of the 

methodologic issues affecting the interpretation of these trials will be addressed, and then the 

major findings will be reviewed. The majority of these trials were small; only two included 

more than 100 subjects. Six trials were conducted in single institutions and three in multiple 

institutions. In one trial (Spiegel, Bloom, and Yalom, 1981) the number of institutions could not 

be determined. 

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Table 31. RCTs of Treatment of Fatigue in Cancer Patients 

Author 

Year 

UI N Treatment Effect

Methodological 

Quality Applicability

Spiegel 

1981 

81206415 

86 weekly support

group for one year 

Declines in vigor and increasing

fatigue were seen in control group 

but not in the treatment group 

(p<.01). Those who participated in 

weekly group session for one year 

had significantly lower scores on 

POMS fatigue subscale. 

C B

Forester

1985 

85094657 

100 Psychotherapy SADS administered at baseline, 

near midpoint of RT, at end of RT 

and 4 weeks and 8 weeks postRT. Only at 4 weeks post RT was 

there a significantly greater 

change from baseline fatigue 

scores in the therapy group 

compared with control group. 

C I

Decker 

1992 

92291348 

82 Relaxation

therapy 

Treatment group had a 

nonsignificant change in fatigue 

score over the course of 

treatment, whereas in controls, 

fatigue increased significantly. 

C I

Mock 

1997 

97387565 

46 Exercise Exercise group scored significantly 

higher than usual care group on 

physical functioning (p=0.003) and 

symptom intensity, especially 

fatigue. 

B B

Ahles

1999 

99446233 

34 Massage vs. quiet 

time 

Borderline significant results for 

fatigue (p=0.06). Most robust 

effects at Day –7 assessment (first 

week of treatment). 

C B

Dimeo 

1999 

99256640 

59 Aerobic exercise

(biking) vs. control 

No significant differences were 

present at baseline; control group 

had significantly more fatigue at 

discharge compared with baseline 

(p<0.02), exercise group did not. 

B B

GastonJohansson

2000 

20395088 

110 Comprehensive

Coping Strategy 

Program vs. no 

treatment 

Fatigue significantly less in

treatment group compared with 

control at day 7. Significance 

disappears in multivariate analysis

when controlled for demographic 

variables and fatigue at day –2. 

B B

94
Author 

Year 

UI N Treatment Effect

Methodological 

Quality Applicability

Oyama 

2000 

20440886 

30 Bedside Wellness

System using

virtual reality 

technology vs. 

chemo as usual 

There was a statistically significant 

difference between level of fatigue 

in treatment and control groups 

after 2 treatments, but not after 1. 

C A

Mock 

2001 

11879296 

PMID 

48 walking program

vs. usual care 

Fatigue scores did not differ 

significantly between exercise and 

usual care groups at end of

treatment. 

C B

Littlewood 

2001 

21281037 

251 Epoetin alfa vs. 

placebo 

There was a strong statistically 

significant correlation between 

hemoglobin levels and QOL. The 

mean increase in hemoglobin level 

from baseline to last value was

significantly greater in the epoetin 

alfa group than the placebo group 

(2.2 g/dL v. 0.5 g/dL, P<0.001). 

Significant differences observed 

for epoetin for all 5 cancer and 

anemia-specific primary QOL 

measures (P≤.0048) 

A A

Reporting of elements of the study design such as primary and secondary endpoints, sample 

size calculation, eligibility criteria and procedures for randomization and stratification is usually 

inconsistent. A significant and recurrent issue in the design and reporting of these trials is the 

absence of prospectively defined quantitative primary and secondary endpoints. Among the ten 

trials, only one provided a clear definition of endpoints Littlewood, Bajetta, Nortier et al., (2001) 

in a study of epoetin alfa in patients receiving chemotherapy. 

The absence of prospectively defined endpoints is problematic in studies such as those that 

measure and report numerous outcome variables. For example, Ahles, Tope, Pinkson et al., 

(1999) examined the effects of massage therapy on anxiety, depression and mood in bone 

marrow transplantation (BMT) patients using the State-Trait Anxiety Inventory (STAI), Beck 

Depression Inventory (BDI), and Brief Profile of Mood States (POMS). They also assessed 

emotional distress, fatigue, nausea and pain using a numerical (0-10) scale, systolic and diastolic 

blood pressure, pulse and respiratory rate, and the STAI-state score. All measurements were 

done at three timepoints. No differences were seen between the massage and control groups in 

the overall scores on the STAI, BDI or POMS. Fatigue was found to be significantly lower in 

the massage group at two of the three time points (p=.02 at day -7, and .03 pre-discharge). 

However these fatigue scores were only two of 36 dependent variables (12 variables at three 

timepoints) each of which was assessed for significant differences between the treatment and 

control group. Among so many potential outcomes, the post-hoc selection of the few variables 

with p values less than .05 is of uncertain significance. 

Similar problems arise in interpreting the results of a study by Gaston-Johansson, FallDickson, Nanda et al., (2000) evaluating a Comprehensive Coping Strategy Program (CCSP) in 

patients undergoing autologous BMT for breast cancer. They studied the effects of this program

95
on pain, fatigue, psychological distress and nausea using a number of questionnaires and visual 

analogue scales at three time points. This generated 24 outcome variables. Of these, only the 

measurements of nausea at day +7 and fatigue at day +7 correlated significantly with the CCSP. 

It is difficult to interpret the few outcomes that correlate significantly with CCSP in light of the 

large number of outcomes reported, the absence of a prospective definition for which these 

outcomes was of primary interest, and an estimation of the effect size that would be considered 

clinically important. 

Since endpoints were not defined prospectively in the large majority of these trials, 

calculations of the sample size required for detection of significant outcome differences could 

not be performed. With a few exceptions, the sample sizes appear to have been chosen 

arbitrarily. It is therefore possible that some of the reported negative outcomes are due to 

underpowering of the studies. Underpowering is certainly a concern in small studies of 

heterogeneous populations examining a symptom such as fatigue, which is highly multifactorial. 

The patient populations in several of these trials were quite heterogeneous. Six of the ten trials 

enrolled patients with multiple types of cancer. For example, Decker, Cline-Elsen, and 

Gallagher (1992) studied the effects of relaxation therapy in 82 patients with 15 different types 

of cancer undergoing palliative or curative radiation therapy. Patient factors such as functional 

status, disease factors such as stage, and treatment factors such as dose and anatomic sites of 

radiation therapy were probably highly variable in this group. These factors may have accounted 

for much of the variance of fatigue. Stratification to assure balance of such factors between the 

arms of a study would have been a reasonable approach in many of these trials, but only two of 

the more recent studies stratified patients (Littlewood, Bajetta, Nortier, et al., 2001; Mock, 

Pickett, Ropka, et al., 2001). Particularly in earlier trials, minimal demographic, disease and 

treatment information is provided. In the last of these studies, significant baseline differences in 

scores on the Profile of Mood States (POMS) between the treatment and control groups were 

found. Differences in scores on the Profile of Mood States (POMS) between the treatment and 

control groups were found, suggesting that an imbalance in important risk factors for fatigue was 

in fact present. 

Several trials evaluated the effect of psychosocial interventions on fatigue. Spiegel, Bloom, 

and Yalom (1981) randomized 86 women with metastatic breast cancer to either usual care plus 

weekly support group meeting for one year or usual care alone. Despite a high drop out rate 

(only 30 subjects remained at the end of the year), the support group arm had significantly better 

scores on multiple dimensions of the POMS, including less fatigue and more vigor. Over the 

course of the year, controls showed increasing fatigue and declining vigor, but this result did not 

occur in the treatment group. Despite flaws in this study, the consistent benefit associated with 

support group attendance across multiple dimensions of the POMS is striking and certainly 

consistent with more recent data on the benefits of support groups. 

Forester, Kornfeld, and Fleiss (1985) examined the effect of psychotherapy on emotional and 

physical distress in patients receiving radiotherapy. Forty-eight patients were randomized to 

weekly psychotherapy for 10 weeks during and after radiation, and 52 to radiation alone. The 

groups were reasonably well balanced according to basic demographics and type of cancer. 

Subjects were administered the SADS (Schedule of Affective Disorders and Schizophrenia) at 5 

time points from baseline to 14 weeks. Psychotherapy patients had a significantly greater 

decline in emotional symptoms than controls from the end of radiation to the final timepoint. 

Physical symptoms, and fatigue in particular, declined more in the treatment group, but only 

reached statistical significance at one timepoint. While this study is by no means definitive, it is 

96
consistent with other data that suggest a strong influence of psychological state (and possibly 

psychological intervention) on physical symptoms such as fatigue. 

Some of the problematic features of the trial of relaxation therapy during radiation therapy 

(Decker, Cline-Elsen, and Gallagher, 1992) have been discussed above. The sample was highly 

heterogeneous, and only rudimentary patient information was provided. Significant baseline 

differences in all subscales of the POMS suggest that the arms were poorly balanced for factors 

associated with mood states and fatigue. While fatigue remained stable in the relaxation therapy 

group and increased significantly in the control group, the validity of these results are 

questionable. 

Gaston-Johansson, Fall-Dickson, Nanda, et al. (2000) randomized 110 patients undergoing 

autologous BMT to a Comprehensive Coping Strategy Program vs. usual care. The CCSP 

consists of counseling, education, written materials and an audiotape providing information on 

pain control and its importance, mechanisms of pain, strategies for reducing pain and emotional 

distress, coping skills, cognitive restructuring to avoid catastrophizing, demonstration and 

instruction in guided imagery and relaxation. Patients undertook this program before hospital 

admission. The groups were well balanced for demographic and disease variables. As noted 

above, several instruments were used to assess psychological distress, fatigue, nausea and pain. 

Although a few statistically significant correlations were found between participation in the 

CCSP and reduced symptoms at certain time points, the evidence for a clinically meaningful 

benefit from this approach is preliminary. 

Three studies examined the effects of exercise on fatigue in breast cancer patients. Mock, 

Dow, Meares, et al. (1997) randomized 46 women undergoing radiation therapy for early stage 

breast cancer to an individualized, home-based walking exercise program or usual care. The 

outcomes were physical functioning (measured by a 12-minute walking test), and scores on the 

Symptom Assessment Scale and Piper Fatigue Scale, administered at the midpoint and end of 

radiation therapy. The patient sample was relatively small but homogeneous, and they 

underwent a fairly uniform treatment (radiation therapy for localized breast cancer). The groups 

were well balanced demographically and by disease factors, and there were no significant 

differences in the baseline levels of fatigue or other symptoms. All patients experienced fatigue. 

There were highly significant differences in the pre- to post-test values in physical functioning, 

exercise level, fatigue, difficulty sleeping and anxiety, all favoring of the treatment group. At the 

end of radiation treatment, when fatigue is typically most intense, the exercise group was 

significantly less fatigued. A similar study by Mock, Pickett, Ropka, et al. (2001) assessing 

exercise in both chemotherapy and radiation patients, was confounded by the fact that a high 

percentage of the control group participated in exercise, while compliance in the treatment group 

was low. Dimeo, Stieglitz, Novelli-Fischer, et al. (1999) found that in patients undergoing 

autologous peripheral blood stem cell transplantation, daily biking on an ergometer in the supine 

position was associated with stable levels of fatigue at discharge compared to admission, while 

in a control group, fatigue levels rose significantly. The levels of fatigue (or changes in these 

levels) in the treatment and control groups do not appear to have been directly compared, 

Several non-randomized studies have also provided evidence for a beneficial effect of 

exercise on cancer-related fatigue (Dimeo, Bertz, Finke, et al., 1996; Dimeo, Rumberger, Keul, 

1998; Schwartz, 2000; Porock, Kristjanson, Tinnelly, et al., 2000; Schwartz, Mori, Gao, et al., 

2001). The studies, in addition to the positive result of the randomized trial by Mock, Dow, 

Meares, et al. (1997) should provide a stimulus to further investigation in this area. 

97
Littlewood, Bajetta, Nortier, et al. (2001) have performed the only randomized, controlled 

trial showing a benefit for a pharmacological intervention in cancer-related fatigue. They 

randomized patients receiving non-platinum chemotherapy to thrice-weekly subcutaneous 

epoetin alfa (n=251) or placebo (n=124) in double-blind fashion. Patients had hemoglobin levels 

of < 10.5 g/dL, or 10.5-<12 g/dL with a decline of > 1.5 g/dL per cycle of chemotherapy. 

Patients were stratified according to solid vs. hematologic malignancies and hemoglobin level. 

This study was appropriately powered to detect the primary endpoint (the proportion of patients 

transfused after four weeks). Secondary endpoints were change in hemoglobin level, percentage 

of patients with an increase in hemoglobin of > 2 gm/dL, and change in quality of life scores 

from baseline to last value. Quality of life measure were the FACT-An, which contains a fatigue 

subscale, the Linear Analog Scale Assessment (LASA), and the Medical Outcomes Study Short 

Form-36 (SF-36). 

Transfusion requirements were significantly lower and hemoglobin levels significantly 

higher on the epoetin alfa arm. All quality of life measures also showed a benefit. There was a 

highly significant difference in the mean of the change in fatigue subscale scores on the FACTAn favoring epoetin alfa (p=.0040). Changes in hemoglobin levels strongly correlated with 

quality of life. There was a trend towards an improvement in overall survival in the epoetin 

group. These results are consistent with two large open-label non-randomized studies of epoetin 

alfa that also demonstrated benefits in terms of hematologic parameters, quality of life, and 

measurements of energy and fatigue (Demetri, Kris, Wade, et al., 1998; Glaspy, Bukowski, 

Steinberg, et al., 1997). Additional non-randomized studies have indicated that there is an 

equivalent benefit with once-weekly dosing (Gabrilove, Cleeland, Livingston, et al., 2001), and 

that anemic patients not currently receiving chemotherapy also benefit from epoetin alfa in terms 

of amelioration of anemia and improvement in quality of life (Ludwig, Sundal, Pecherstorfer, et 

al., 1995).

98
Chapter 4. Conclusions 

Prevalence 

Cancer-related Pain 

Pain is an important component of the already considerable disease burden of cancer. 

Minorities, women, and the elderly are particularly at risk for cancer-related pain, and this 

observation possibly reflects both underassessment and undertreatment. Nearly all 

epidemiological studies that contain population-based estimates of the prevalence and severity of 

cancer pain report few details concerning specific mechanisms of cancer pain, nor do they track 

pain and other symptoms longitudinally across time; however, credible survey information is 

emerging that suggests the prevalence of pain and other symptoms is related to the type of cancer 

(though not related to information such as grade or stage). The total number of patients surveyed 

in published reports of the prevalence and severity of cancer-related pain, as well as in 

methodologically sound trials of cancer pain relief, is a minor fraction of those receiving care— 

much lower than for nearly all other high-impact, costly conditions. There remains an incomplete 

picture of variations in cancer pain prevalence, severity, and course with respect to: patient

factors (age, gender, ethnicity, race, culture); disease characteristics (type, grade, stage as well as

other features such as genotypic or phenotypic classification); the setting in which care is 

provided (provider attributes and professional qualifications, location and nature of healthcare 

practice); and specific treatments directed toward the underlying disease and its associated pain. 

Cancer-related Depression 

Major depressive disorder and depressive symptoms occur frequently in patients with cancer. 

Despite using standardized measures, there is a wide range of reported incidence and prevalence. 

From our review of the literature, the prevalence rates appear to be between 10 to 25 percent for 

major depressive disorder and a similar range for clinically significant depressive symptoms

regardless of psychiatric diagnosis. Given that the estimated point prevalence of major 

depressive disorder is 2.2 percent in the general population, these rates in cancer patients may be 

at least four times greater. 

Despite using standardized measures, there is a wide range of reported incidence and 

prevalence. This range may be the result of several factors that include the timing of the 

assessment, concurrent treatment, medical morbidity and pain, and age. Cancer patients are a 

heterogeneous population with different sociodemographics, cancer types, treatments, and 

responses to treatment. More accurate estimates might be obtained in studying the rates in more 

homogeneous sub-groups. 

Reports on the incidence of depressive symptoms are limited to prospective studies of 

patients receiving certain cancer treatments. Reports of incidence range widely from about 2 to 

17 percent during the time frame of the studies. Although it is difficult to generalize these results 

to all cancer patients, the incidence appears to be somewhere between 2 and 7 percent per year. 

However, these studies, like the prevalence studies, face the same difficulties of heterogeneous 

populations, and there are too few naturalistic studies that follow patients from the time of 

diagnosis conducting serial depressive assessments. Despite the lack of high quality data, it 

appears that the incidence of depression in cancer patients is much higher than the general 

population’s yearly aggregate incidences: 0.25 to 0.6 percent for women and 0.08 to 0.2 percent 

for men. 

99
Cancer-related Fatigue 

Estimations of fatigue prevalence have been performed in many settings but the data is by no 

means comprehensive. Our search identified 27 reports on fatigue prevalence. Thirteen studies 

included patients with a variety of cancers, five studies addressed breast cancer at various stages 

and during various treatments, and four focused on lung cancer and two on prostate cancer. 

Many types of cancer were not specifically addressed. A more complete picture of cancer-related 

fatigue could be obtained by extracting fatigue prevalence data from HQL and general symptom

studies, and from clinical trials in which fatigue is reported as a side effect of treatment. 

A very broad range of prevalence rates has been reported. Prevalence rates ranged from 4 

percent in breast cancer prior to starting chemotherapy and 8 percent in prostate cancer prior to 

radiation therapy (Jacobsen, Hann, Azzarello, et al., 1999; Monga, Kerrigan, Thornby, et al., 

1999), to 91 percent in breast cancer patients after surgery and chemotherapy and before bone 

marrow transplantation (Gaston-Johansson, Fall-Dickson, Bakos, et al., 1999). Findings of 

significant concern were the prevalence rates of fatigue in cancer survivors: 26 percent in 

Hodgkin's disease survivors (Loge, Abrahamsen, Ekeberg, et al., 1999); 35 to 56 percent in 

breast cancer survivors (Bower, Ganz, Desmond, et al., 2000; Okuyama, Akechi, Kugaya, et al, 

2000); and 48 percent in a cohort treated for cancers (Servaes, van der Werf, Prins, et al., 2000). 

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. A 

few studies used criteria for fatigue that were based on normative data from control populations 

(Stone, Hardy, Broadley, et al., 1999; Bower, Ganz, Desmond, et al., 2000). In many studies, 

however, the criteria for fatigue were arbitrary. 

Population-based surveys of fatigue prevalence (Vogelzang, Breitbart, Cella, et al., 1997; 

Cella, Davis, Breitbart, et al., 2000) represent an advance since they potentially avoid the 

selection bias inherent in small cohort studies, although other bias may be introduced by the fact 

that only a minority of potential subjects were contacted. The primary purpose of the study by 

Cella, Davis, Breitbart, et al. (2001) was to evaluate proposed ICD-10 criteria for cancer-related 

fatigue, which, if adopted, would allow comparison of data from a wide range of sources. 

The period over which the prevalence of fatigue was assessed in any group of patients was 

short, generally confined to the period of treatment and immediately after, or one time point in 

studies of survivors. No studies used a uniform methodology to track the time course of fatigue 

longitudinally. Few studies on the prevalence of fatigue included data on factors that might 

contribute to fatigue (such as anemia, infections, etc.), or attempted to determine to what extent 

fatigue was due to treatment, disease, or other factors. 

Assessment 

Cancer-related Pain 

One hundred eighty-four unique trials were retrieved for the prior evidence report, plus an 

additional 34 in the updated search, for a total of 218 trials. In these trials, a total of 125 different 

outcome measures were employed. Many were similar to each other but not directly combinable, 

e.g., four-point and five-point pain intensity scales. The most frequently employed scales were of 

pain intensity: the 0-100 VAS (58 uses), a 10 cm VAS (44 uses), and five-point (26 uses) or 

four-point (24 uses) pain intensity scales. Of the 21 instruments that were employed five or more 

times in the pooled retrieved studies, four were numerical measurements of pain intensity and 

one was an integrated pain intensity score, three were pain relief scales, two were peak or 

summed pain intensity differences between treatments, two were global evaluations or global 

100
efficacy of intervention scales, and one was the McGill-Melzack pain questionnaire. Only one of 

the 21 most frequently applied instruments (a four-point scale) appraised side effects (5 uses); 

analgesic consumption was assessed 21 times. 

The need for detailed assessment conducted within a psychosocial framework is addressed in 

virtually all guidelines or monographs on cancer pain management. A voluminous literature 

exists that describes the multidimensional, experiential nature of cancer pain and links poor 

control of cancer pain to impaired quality of life, including functionality. Expectations for 

detailed, multidimensional assessment of cancer pain, including quality of life assessment, 

during cancer care contrast with minimalist assessments of pain intensity presented during 

relatively brief observation intervals reported in nearly all of the retrieved 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 addresses the issue of side effects; that one is a 

coarse, four-point measure. 

Cancer-related Depression 

The clinical interview, using DSM criteria, is the standard of care for diagnosing major 

depressive disorder and other depressive syndromes in people with cancer. 

Because depression may go undetected and untreated in oncology practices, the importance 

of screening tools and rapid assessments has been emphasized. Many self-report assessments are 

available that could be completed by patients before visits in clinic waiting rooms. These 

assessments range from circling answers to series of questions to The Distress Thermometer, a 

modified visual analogue scale that is presented in the NCCN guidelines for the treatment of 

psychosocial distress. Available data on the sensitivity, specificity, predictive values, and crosscorrelations are presented in the evidence-based table. 

Although these assessment tools may have been validated in studies, there is currently no 

evidence on how widely they are used clinically or to suggest that they affect clinical care and 

outcomes. 

Cancer-related Fatigue 

The literature on fatigue assessment focuses on tools that are used in research studies, and to 

a much lesser extent on methods of assessment for clinical use. The NCCN practice guidelines 

on cancer-related fatigue recommended the use of simple 0-10 numerical self-report scales or 

verbal scales (e.g., mild, moderate or severe) to assess the severity of fatigue in practice settings. 

This recommendation is based on a study by Piper, Dodd, Ream, et al. (1999) correlating selfreport scores on a 0-10 scale of fatigue with the Physical Functioning Subscale of the Medical 

Outcomes Study Short Form 36 (SF-36). They found a significant impairment in physical 

function on the SF-36 when fatigue scores were >7. If moderate or severe fatigue is reported, the 

NCCN panel then recommended a focused history and physical examination and evaluation of 

the pattern of fatigue, associated symptoms, and interference with normal functioning. Five 

potential causes should be addressed because they are common and potentially reversible: pain, 

emotional distress, sleep disturbance, anemia, and hypothyroidism. A review of medications was 

not included in this initial evaluation although in practice this is certainly done. If no etiology of 

fatigue is identified, the NCCN panel recommended a more comprehensive evaluation, education 

and counseling, and consideration of a variety of strategies to reduce fatigue. Although this 

approach is not based on controlled clinical trials validating its effectiveness, it is intuitively 

101
reasonable. It would be useful to know the extent to which causes of fatigue can be identified and 

reversed using this algorithm.

In the context of clinical research, assessment of fatigue involves the use of patient selfassessment tools of varying levels of complexity. 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. 

Treatment 

Cancer-related Pain 

As reported in the prior evidence report, the number of randomized controlled trials to 

evaluate analgesic interventions for cancer pain is approximately one percent of the total of

initial titles retrieved. The heterogeneity of existing trials precludes meta-analysis to answer most 

clinically relevant questions. For example, the trials do not disclose differences between the 

relative efficacy of opioids and nonsteroidal antiinflammatory drugs (NSAIDs) administered by 

various routes to patients with mild, moderate or severe cancer pain. There is evidence of an 

opioid dose-sparing effect from co-administration of an NSAID but no consistent reduction in 

side effects from doing so. There is little evidence for significant differences in analgesic 

efficacy between NSAIDs (only one trial out of 18 reported this outcome). The studies 

comparing different NSAIDs could not be combined in a meta-analysis due to between-study 

heterogeneity in the outcomes assessed, drug doses and schedules compared, and study duration. 

Trials that compare the efficacy of NSAIDs versus “weak” opioids (i.e., opioids commonly 

prescribed for mild to moderate pain) reveal no difference in analgesic efficacy between these 

two classes of agents, even when the latter are co-administered with the same NSAID tested in 

the other study arm. These trials enroll relatively small numbers of patients and are of relatively 

short duration. A single randomized controlled trial of breakthrough pain treatment demonstrated 

the superiority of oral transmucosal fentanyl citrate to placebo. We found no randomized 

controlled trials addressing analgesic efficacy and safety of NSAIDs selective for the 

cyclooxygenase-2 isoenzyme in treating cancer pain. 

Published trials exploring different routes of administration for NSAID or opioid drug classes 

show no difference in analgesic efficacy between oral or rectal routes of delivery of each class of 

drug. Limited data from trials show no benefit from a purely analgesic standpoint of parenteral 

(intramuscular or intravenous) administration over enteral administration. Failure to prove 

overall superiority of one route over another does not diminish the value of a particular route in a 

specific clinical situation (for example, the use of suppositories or transdermal administration in 

the presence of dysphagia). Insufficient information exists to permit comment upon differences 

in patient preference for specific routes and administration, or acceptability of side effects. There 

was no evidence to indicate improved analgesia with controlled-release oral formulations versus 

immediate-release formulations or transdermal delivery. The benefit of less frequent doses upon 

patient compliance is a possible advantage of controlled-release formulations. 

Trials of biphosphonate therapy are heterogeneous with respect to inclusion criteria, 

concomitant medical and radiotherapeutic treatments, disease categories, dosage regimens, 

choice of agent, and duration of follow-up. Differences in pain assessment methods are also 

considerable, ranging from analgesic consumption to a “requirement” for palliative radiation 

therapy. However, many studies showed a positive effect, some showed no effect, and no study 

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showed a detrimental effect of biphosphonate therapy on skeletal symptoms of metastatic disease 

or myeloma. Positive effects were less evident in patients who received concurrent hormones or 

chemotherapy that might by themselves have a favorable effect on bone symptoms. The evidence 

in aggregate suggests that biphosphonates are effective in reducing bone pain in patients with 

cancer, although this benefit may be less marked when such therapy is combined with other 

tumor-directed therapy. The radionuclide strontium-89 was more effective than placebo (inactive 

strontium), and equally effective as external radiation. 

The literature on the effects of various chemotherapeutic and hormone therapy regimens on 

pain is also quite heterogeneous, with differing inclusion criteria and therapeutic regimens. 

Analgesic consumption is reported in a minority of these studies. In only one chemotherapy trial, 

and in no hormonal therapy trial, did pain outcomes differ significantly between treatment arms. 

Eighteen trials compared fractional dosing schedules of external radiotherapy for pain from

bony metastases. No trial found more than a transient difference in pain between fractionation 

schedules, although external radiation as a whole is effective in decreasing pain. Meta-analysis 

was precluded by heterogeneity of the dosing schedules, variability in the anatomic sites and 

fields treated, and outcomes assessed. Short courses (even single doses) of palliative treatment 

with higher doses appear to produce results similar to those of longer courses that deliver a lower 

dose per treatment. The minimal total dose of radiation to provide pain relief has not yet been 

determined. A possible detrimental effect upon quality of life due to transient skin irritation and 

discoloration at the site of post-mastectomy chest radiation was reported in one study (Whelan, 

Levine, Julian, et al., 2000). 

The number of studies of physical or psychological treatments to decrease cancer-related 

pain is small, and variability of the specific intervention and type of pain addressed precludes 

any broad conclusions. Studies of education evaluated different interventions in patients, medical 

staff, and the community at large. Studies of hypnosis in the pediatric and adult age groups 

indicate benefit for procedural and mucositis-related pain. Cognitive behavioral treatments may 

also be helpful. More studies are needed, with larger numbers of patients and control groups. 

Sufficient randomized controlled trials on neurolytic celiac plexus block (NCPB) for pain 

relief in pancreatic and other visceral cancers were identified to indicate the efficacy of this 

modality. NCPB lowered pain scores or produced a prolonged dosage-sparing effect upon 

analgesic drug requirement. The scarcity of randomized or controlled trials on the efficacy of 

spinally administered opioids or other agents led us to retrieve nonrandomized reports in an 

effort to estimate the efficacy of this modality. These additional reports, although positive, were 

case series without control groups and hence yielded no data on relative efficacy of the spinal 

versus systemic route of drug administration. Similarly, the efficacies of ablative neurosurgical 

interventions such as cordotomy or rhizotomy were addressed only in case series. There were no 

trials that addressed the efficacy of acupuncture.

Cancer-related Depression 

The current evidence shows that interventions are beneficial for depressive symptoms in 

cancer patients. There appears to be a clear benefit of psychosocial interventions, although the 

magnitude of the effect size seems to be in the mild to moderate range. Because of the hundreds 

of studies on psychosocial interventions in cancer patients, we limited our review to published 

meta-analyses of these studies. However, in limiting our review in this way, the contribution of 

effects from preventive studies and depression treatment studies could not be separated. The 

effects of psychosocial interventions may vary in these two different kinds of studies. 

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Although not all pharmacologic studies showed benefit for depression in cancer patients, all 

studies that used antidepressants and conformed to usual practices for antidepressant trials did 

show benefit. Since antidepressants typically can take four to six weeks for their full effect, 

studies of antidepressants under five weeks tended to show less benefit. Currently, there is 

efficacy data for selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants. 

Another antidepressant that showed benefit, mianserin, is an atypical antidepressant not available 

in the United States. Although trazodone, an atypical antidepressant, showed some benefit in 

treating depressive symptoms, it is not commonly used as an antidepressant because it often 

causes sedation at therapeutic doses.

No controlled studies on alternative treatments for depression in cancer patients were 

identified. 

Cancer-related Fatigue 

Ten randomized, controlled trials were identified that assess interventions for cancer-related 

fatigue. Four involved psychosocial interventions (support groups, psychotherapy, relaxation 

therapy, and a comprehensive coping strategy program). Three clinical trials evaluated the 

impact of exercise on fatigue. One trial involved massage therapy and one evaluated a "bedside 

wellness system" using virtual reality technology. There was only one trial of pharmacotherapy 

(epoetin alfa for fatigue related to anemia in patients receiving chemotherapy). Some of the 

concerns regarding the methodology of these studies are addressed in the results section. 

Endpoints were often poorly defined and sample size calculations absent. It is probable that 

many of these studies were underpowered to detect the outcome of interest. Although several 

studies reported statistically significant associations between the intervention being tested and 

various outcomes, the absence of prospectively defined endpoints renders these results difficult

to interpret.

The studies by Mock, Hassey Dow, Meares, et al. (1997) provides evidence that exercise 

may be helpful in reducing or preventing fatigue in patients receiving radiation therapy for early 

stage breast cancer. The beneficial effects of exercise are less clear in other contexts such as 

peripheral blood stem cell transplantation (Dimeo, Stieglitz, Novelli-Fischer, et al., 1999). 

Nonetheless, this is certainly an approach that warrants further investigation. 

The randomized, placebo-controlled, double-blind trial by Littlewood, Bajetta, Nortier, et al. 

(2001) suggests a substantial benefit associated with epoetin alfa in terms of quality of life, 

fatigue, and hematologic parameters in anemic patients undergoing chemotherapy. The findings 

of this study are supported by large, non-randomized trials. 

104
Chapter 5. Future Research 

Prevalence

Cancer-related Pain 

Comprehensive, credible surveillance data describe the incidence and prevalence of cancer in 

the United States and survival rates for each major neoplastic disorder. The evidence that 

undertreated pain adds substantially to the disease burden of cancer is equally credible but less 

extensive and detailed. Limited cross-sectional data link tumor type and stage with pain quality 

or intensity (Caraceni, Portenoy, and the IASP Working Group, 1999), and there is no 

corresponding longitudinal, tumor-specific data on individual pain trajectories during treatment 

of cancer and cancer-related pain. Tumor- and population-specific data of this nature are needed 

if the natural history of cancer pain and its relief are to be understood with sufficient precision to 

advise individual patients and their families on the selection of pain control options. Data of this 

sort is available, for example, to facilitate informed choices by patients, families, and their care

providers as to the likely progression, appearance of complications of, and risks and benefits of 

therapies for many prevalent conditions such as hypertension, heart disease, diabetes mellitus, 

infectious disease, and (as mentioned above) cancer itself. 

Cancer-related Depression 

There is much variance in the literature on reports of rates of both major depressive disorder 

and depressive symptoms in cancer patients. Even when standardized instruments are used, wide 

variance is seen. One recommendation would be to conduct prevalence studies that examine 

reasons for such variance and contributing factors for such differing rates. The timing of 

measurements of depressive symptoms appears to be important and may contribute to the 

variance. Since depression is more common in women in the general population, the effect of 

gender on depression in cancer patients needs to be more carefully studies. One goal may be to 

develop a statistical model that could predict the rate of depressive symptoms given the cancer, 

treatment, and demographics of the population. 

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 studies start at the time of diagnosis, 

or even before if possible, to get better estimates of the incidence of depression once people are 

diagnosed with cancer. Both studies of incidence and prevalence should assess past histories of 

depression. 

Research on the prevalence and incidence of depression in children with cancer is scarce and 

must be enlarged. 

Cancer-related Fatigue 

Studies of the prevalence of cancer-related fatigue are by no means comprehensive. 

Additional studies of fatigue prevalence in many types of cancer and many different clinical 

contexts are needed. 

Data on fatigue prevalence are reported in studies on health-related quality of life, general 

studies of symptom prevalence, and from treatment trials in which fatigue is reported as a side 

effect. Extracting fatigue prevalence data from these sources could potentially provide a much 

more detailed and complete picture of the scope and impact of cancer-related fatigue. Methods 

105
for comparing prevalence rates obtained using different assessment tools would need to be 

devised. 

We were unable to identify studies that provided a longitudinal assessment of fatigue 

prevalence. All existing studies were confined to a brief period associated with treatment or a 

limited number of time points during the palliative phase or in cancer survivors. Thus, while data 

exists, for example, on the prevalence of fatigue in women with breast cancer during 

chemotherapy, radiation therapy, and in long-term follow-up, these studies use heterogeneous 

assessment techniques and do not provide insight into the time course of fatigue. There is a need 

for studies of the prevalence of fatigue over the entire course of treatment and follow up using 

uniform methods of assessment. 

 

Assessment 

Cancer-related Pain 

The present sophistication of quality-of-life assessment, and documentation of relationships 

between pain, disability, and impairment, mandate that clinical trials of cancer pain control 

incorporate outcomes measures beyond mere pain intensity. Textbooks, guidelines and review 

articles on cancer pain all describe the need to perform a detailed history so as to assess the 

psychosocial and cultural frameworks and individual factors underlying pain experience and 

complaint. Such monographs further recount the importance of formulating whenever possible a 

mechanism-based pain diagnosis so as to guide therapy, the quantification of pain intensity as 

well as distress and impairment of quality of life and function associated with pain, and the 

reassessment of pain and distress across the continuum of care. Indeed, assessment of pain 

intensity and appropriate treatment are already clinical standards of the Joint Commission on 

Accreditation of Healthcare Organizations. To accomplish pain assessment and treatment related

to clinical trials as well as clinical care in an increasingly diverse society creates a need for 

developmentally, culturally, and gender-appropriate instruments that are sensitive, reliable, and 

easy to administer. Instruments to assess health-related quality of life, particularly functional 

status, have been applied in recent years during cancer treatment trials. Analgesic trials for the 

most part have omitted such instruments, and those that incorporated them did so in a 

heterogeneous fashion. Because breakthrough pain contributes to overall pain morbidity in many 

patients, pain intensity itself is normally assessed in clinical practice not only at a single time but 

also across the course of illness and most importantly, during activity that includes movement. 

Uni-dimensional, “dip-stick” measures of pain intensity at rest, repeated a few times during a 

short observation interval and often after only a single dose of medication, must be supplanted by 

more clinically relevant and comprehensive pain assessment during clinical trials. 

Important information to strengthen interpretation of the results of clinical trials is at present 

mostly lacking. Such information, to permit responder or non-responder subgroup analyses, 

includes genetic and genders characteristics, medical comorbidity and concurrent treatments, as 

well as other individual features such as ethnicity and culture. 

Because side effects of therapy often limit doses of analgesic agents employed, and 

contribute to global morbidity associated with cancer pain, the prospective assessment of side 

effects should be accomplished with the same care as has been bestowed upon assessment of 

analgesia. To do so will require development and validation of age and culture-appropriate scales 

for individual side effects that may appear during therapy. 

106
Cancer-related Depression 

There are many screening and assessment instruments currently available for depression in 

cancer patients. Researchers can choose instruments based on ease of use versus the instrument 

performance. The performance of brief instruments that appear to have promising predictive 

value, such as the one-item, “Are you depressed?,” require further study and replication. The 

development of short instruments that assess all three symptoms (depression, pain, and fatigue) 

could be one possible area of future research. 

Although some of these instruments are currently being used in clinical practices, there are 

currently no published studies of their effect on outcome. Outcome research, both psychological 

and medial, needs to be done using the instruments as “lab tests.” 

More research needs to be done on the assessment of depression in children with cancer.

Cancer-related Fatigue 

Further research is needed on methods for the clinical evaluation of fatigue. A useful strategy 

would involve studies to validate the screening and assessment algorithms recommended in the 

NCCN practice guidelines on cancer-related fatigue. These would include studies on the utility 

of brief fatigue screening tools such as visual or verbal analogue scales in different clinical 

settings, and on the clinical application of more elaborate assessment instruments. Further 

research is also needed on the prevalence of treatable factors contributing to fatigue, and the 

reversibility of fatigue based on the treatment of these underlying factors. 

In the research context, there should be a continued reliance on assessment instruments that 

are well characterized in terms of their validity, consistency and reliability. Clinical

interpretation of the outcomes of these measures still remains problematic. Further comparisons 

are needed between data on fatigue in cancer patients and normative data from control groups. 

Given the large number of instruments used to assess fatigue, methods to compare results 

from studies using different instruments are needed. Researchers in this field should consider 

developing consensus criteria for the assessment of fatigue for use in future studies. 

Treatment 

Cancer-related Pain 

This is an exciting time in translational research on cancer-related pain, because preclinical 

research has generated novel insights into distinctive mechanisms through which tumors produce 

pain. Increased understanding of the pathogenesis of cancer-related pain (as well as other 

symptoms such as depression and fatigue) may foster therapies that are increasingly targeted, 

i.e., mechanism-based. At present, however, in nearly every respect (number of trials, sample 

size, representative study populations, and study design), the quality of the scientific evidence on 

cancer pain treatment compares unfavorably with that for cancer treatment. Cancer treatment 

trials for the most part exemplify mechanism-based clinical research. Leading investigators in 

the area of cancer pain relief trials have repeatedly called for improving the quality of trials in 

this area. This goal cannot be achieved merely by incorporating standardized pain assessment 

and health-related quality-of-life measurements into cancer treatment trials. Although such a 

strategy is laudable, data so gathered cannot be generalized to the treatment of pain during 

intervals of stable disease, or to patients who are in remission but who continue to experience 

residual pain. Carefully designed trials with pain or pain relief as a primary outcome are required 

in diverse populations with well-defined disease. These groups include patients with stable 

107
disease, others with treatment-induced, incident, or breakthrough pain, and those with specific 

pain syndromes (such as postmastectomy syndrome) during disease remission. 

Standards for cancer pain treatment trials must adhere to those for clinical trials in general, as 

expected by editors of most leading medical journals. Trials of cancer pain relief should enroll 

more patients and follow them longer than has generally been customary 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. To these criteria must be added the need to study gender, race, 

age, ethnicity and culture with greater precision than in the past, to avoid overgeneralization of 

results. Categorizing patients by tumor type and stage, and by mechanism of pain, with inclusion 

criteria that yield homogeneous groups within individual studies, appears to offer the best chance 

of translating preclinical advances into improved clinical analgesia. Pilot studies that indicate 

gender and ethnic differences in analgesic pharmacokinetics and pharmacodynamics merit larger 

scale follow-up. Small-scale, short-term randomized controlled trials that establish treatment 

efficacy for purposes of Food and Drug Administration approval are not designed to prove 

effectiveness in larger scale, long-term applications in the treatment of cancer pain relief. To 

meet this need, outcomes research can provide valuable data that are not feasible to acquire 

through controlled trials. 

Just as combination chemotherapy is employed to treat many forms of malignancy, the 

practice of analgesia commonly involves drug co-administration. Methods are needed to 

synthesize published evidence on drug interactions and to apply and extend existing methods 

(now employed in acute pain studies) to characterize such interactions during long-term cancer 

pain treatment. Related to this area is the important issue of developing clinical evidence on 

optimal strategies for the sequence of drug therapies employed for cancer pain control (that is, 

the WHO model or other treatment algorithms), and the optimal means to combine drug and nondrug therapies. Trials to address these issues, like those to evaluate one component of a 

multidrug antitumor regimen, are effort intensive and may require large numbers of subjects per 

treatment arm. 

Data on individual variation in preferences for, responses to, and costs of drug and non-drug 

interventions are limited. 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 the selection of initial or secondary 

agents or combinations. Drug interactions during long-term cancer pain treatment require 

clarification. A host of complementary therapies are now employed, but with little rigorous 

testing of their efficacy. 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. 

Cancer-related Depression 

Psychopharmacologic, psychosocial, and alternative interventions offer some benefit on 

treatment for depressive symptoms with cancer patients. Research needs to be done to support 

current clinical practices in the prescribing of medications for depression in cancer patients. 

108
Because antidepressant medications have been shown to be effective, the newer antidepressants, 

especially the atypical ones, should be studied in this population. There should also be more 

trials of 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 specifically of treatment studies on depressed patients remains to be done. 

This will probably change the effect sizes estimated in the meta-analyses that included large 

numbers of prevention trials and may better differentiate between the effectiveness of types of 

psychosocial interventions. 

To evaluate their efficacy, controlled trials on alternative therapies for depression in cancer 

patients should be done. Studies on the treatment of depression in children with cancer are 

needed. 

 

Cancer-related Fatigue

The absence of treatment options for cancer-related fatigue reflects a lack of understanding 

of its fundamental physiology and the very small number of controlled clinical trials that have 

addressed this problem. Further basic research is needed, including the development of animal 

models to study the role of cytokines, nutritional factors, muscle wasting, and other potential 

contributors to fatigue. Studies correlating such factors with fatigue in cancer patients are also 

needed in order to develop rational hypotheses for treatment trials. 

Several promising strategies for treatment of fatigue have been identified based on 

preliminary clinical trials or clinical experience. These strategies require further investigation in 

randomized controlled trials. Among the more promising treatment approaches are exercise 

programs, psychosocial interventions (with a particular focus on the detection and treatment of 

depressive symptoms), and stimulant medications. Research on fatigue in other contexts may 

provide leads for effective therapies in cancer patients. For example, Breitbart, Rosenfeld, Kaim, 

et al. (2001) recently reported improvement in fatigue associated with the psychostimulants 

methylphenidate and pemoline in a randomized, placebo-controlled trial in patients with HIV 

disease. 

Other potential treatment approaches that warrant preliminary laboratory investigations 

and/or pilot trials include hormonal treatments such as human growth hormone, melatonin, and 

androgens, as well as anti-inflammatory medications, and dietary interventions. 

Future clinical trials for cancer-related fatigue should use appropriate study designs, 

including prospectively defined endpoints. They should be appropriately powered to detect 

differences in the endpoints of interest. Strategies are needed to identify and eliminate barriers to 

effective diagnosis and treatment of fatigue and other cancer symptoms, and to enhance accrual 

to studies of these symptoms. 

Concurrency and Interactions between Pain, Depression, and 

Fatigue 

Clinical impressions and a small amount of observational data suggest that the three cancerrelated comorbidities of pain, depression and fatigue are often concurrent and reinforce each 

other in their corrosive effect upon quality of life. For example, immobility due to movementrelated pain may result in deconditioning as well as poor sleep, that in turn augments depression 

and fatigue; or, depression and fatigue may render a patient less compliant with an analgesic 

109
regimen that requires remembering multiple medications to be taken at different times, and kept 

in a site in the patient’s home different from where the patient spends most time (e.g., the 

bedroom). The organization of the present State-of-the-Science Conference that focuses upon 

this symptom triad reflects widespread opinion that each of these elements often co-exists and 

interacts with the other. Definition of the concurrency of these interactions within distinct 

subjects and contexts, the assessment and quantification of such interactions, and analysis of how 

treatment of one or more elements influences the others are all potentially important topics for 

future research. Such research, conducted in patients who may be very ill, have fluctuating 

physical function, mental status and mood, and shifting patterns of pain is often challenging. 

Nonetheless, the clinical research community concerned with improving symptom control in 

patients with cancer has already shown itself capable of surmounting these and other challenges 

in providing a strong evidentiary base upon which to base further research and daily clinical care. 

110
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133 
Evidence Table 1 – Epidemiology of Cancer Pain - A Literature Update 1998- May 

135 

Author, Year Identifier1 Setting Population Aim of the study Type of cancer 

Incidence or petiology, characteristics 

Petzke 1999 99314299 

Part I Country: Germany Setting: 1 Outpatient Clinic Specialty: Anesthesiology 

N=243 (39% of 613 consecutive cancer pts with pain; 270M, 361F) Age: 59.2+/- 13.8 yrs (16-97) Symptoms: Transitory exacerbations of pain Duration: Within past week Source of data: Patient Interview 

To identify and evaluate the incidence of transitory pain in cancer pain patients 

GI 26%, GU 17%, Head/Neck 16%, Breast 12%, Other 29% 

Location of canpresence’absentype of therapy different in patietransitory pain. baseline pain wwithout transitosevere-maximaHowever, the in

transitory pain wmaximal in 92% 

Part II Country:Germany Setting: Clinic as above Specialty: Anesthesiology 

N=55 (68% of 81 pts, 33M, 22F) reported transitory pain on admission. Age: 59+/- 12.1 yrs  (30-85) Symptoms:Pain similar in frequency, duration and intensity to those in Part I.

To further describe and quantify transitory pain experienced by these patients. 

Comparable to those in Part I. 

Transitory pain rapid onset (wit58% of these pless than 15 mieither neuropatnociceptive paipatients identifievent, while moanalgesic regimknown triggers Additional or reeffective in relie75%of patient. with novel delivoral transmucosfound effective 
Evidence Table 1 – Epidemiology of Cancer Pain - A Literature Update 1998- May 

136 

Author, Year Identifier1 Setting Population Aim of the study Type of cancer 

Incidence or petiology, characteristics 

Chang 2000 20164366 

Country: US 

Setting: VA Medical Center, NJ Specialty: Medical Oncology

N=240: (232M, 8 F) 100 consecutive outpatients, 140 consecutive inpatients who reported pain symptoms. Age: Median 68 (27-89); Symptoms: 

median of 8 

To assess symptom prevalence, symptom intensity and their relationship to QOL in this population. 

Solid tumors: 201 (139 metastatic); Hematologic disease: 39 

Symptom assesmedian numbe8. Fatigue/ lack were most prevand 52% respesymptoms, inteof distress were of disease. Lowindicated a likedistressing symthat pain was nsymptom, and smarker for pressymptoms. 

Zepetella 2000 20445999 

Country:UK Setting: Hospice Specialty: Palliative Medicine

N= 245 (59%of 414 consecutive cancer admissions; 185M, 229F) Age: 71( 33-

100) 

Symptoms: Chronic pain of variable duration 

To examine the preva-lence and characteristics of breakthrough pain in terminally ill pts admitted to hospice. Satisfaction with treatment was also assessed. 

Lung 27%, Breast, Prostate and Unknown Primary 9% each. Most breakthrough pain was tumor-related; 38% rated as severeexcruciating, and related to patient dissatisfaction, underlining the value of ongoing assessment. 

Of the 245 partbreakthrough pfrequent and shthat effective tremedications thareadily and quic
Evidence Table 1 – Epidemiology of Cancer Pain - A Literature Update 1998- May 

137 

Author, Year Identifier1 Setting Population Aim of the study Type of cancer 

Incidence or petiology, characteristics 

Meuser 2001 21406100 

Country: Germany Setting: Academic Medical Center Specialty: Anesthesiology Pain service

N= 593 (All patients treated by the service between August 1992 and July 1994; 46.8%M, 43.2%F).) Age: 59 (+/- 14) Symptoms: Pain + at least one other symptom

To survey symptom prevalence, etiology and severity, taking all possibilities of symptom relief into consideration. 

Percentages: GI 24.6, Respiratory 19.8, GU 18.9, Head/neck 16.9 most prevalent. 98.3% of patients referred suffered pain and at least one other symptom. 

Non-opioid anafrequently- initiafinally by 78.3%were used thropalliative treatmchemo, hormonand surgery in and 8/9% respegood in 70%, saand inadequate a significant redsymptoms, demrelief can be acincreasing mos
Evidence Table 1 – Epidemiology of Cancer Pain - A Literature Update 1998- May 

138 

Author, Year Identifier1 Setting Population Aim of the study Type of cancer 

Incidence or petiology, characteristics 

Beck 2001 21461209 

Country: South Africa Setting: Inpatient and outpatient areas of two healthcare facilities in Pretoria: a 120 bed private hospital, a 1000 bed public hospital Specialty: Medical oncology

Phase I: N=263 (98.5% of 267pts seen during study period; 103M,160 F; 75% white) Age: m 55(18-87) Symptoms: Pain Sx Duration: Not stated Source of Data: Survey of Cancer Pain in South Africa (BPI translated into 5 local languages)

To document the prevalence of pain among cancer patients in inpatient and outpatient settings 

All types represented in patients of the two participating facilities 

Cancer type andetermined. Of top distribution lymphoma 14, heach 11, lung acolorectal 9. In distribution wasuterus 13, lynphlung 3. 

Phase II: N= 479 

were eligible;. 426 

completed the questionnaire.(163 M, 251F) 46% white, 42% black, 12% colored or Asian 

Age: m 56.7 (18-90) Symptoms:Pain

To describe patterns of cancer pain and pain management in South Africa 

In male pts, prostate, lung, head/neck and esophagus accounted for 50.5%, in females breast and cervix alone accounted for 53.3%; lymphoma, colorectal and esophageal afflicted most of the rest in both. 

57.4% of pts ex23.6% were in of ‘worst pain’ wcommunity-basin hospices (23many pts were ‘pain now’ in pu(20%) settings. (black/colored/Aexperienced ‘wsevere intensity (P<0.0001). 
 Evidence Table 2. Cross-Sectional Studies on Prevalence of

 Major Depressive Disorders (MDD) Using DSM Criteria

Author

Year

UI N Population/Setting

Mean Age 

(Range) % Male Cancer Type

Derogatis

1983

83112345

215 Multicenter, new 

inpatients and 

outpatients

50.3±15.5 49% All: 20% lung; 18% breast; 

11% lymphoma

Bukberg

1984

84248575

62 Oncology inpatients 51 (23-70) 53% All: 38% leukemia/ 

lymphoma; 21% GU, 13% 

lung 

Morton

1984

85025487

48 Patients treated in last 3 

yrs., no evidence of 

disease

>60 100% Head and neck

Evans

1986

86156362

83 Oncology inpatients 53.1±15.6

(20-86)

0% Gynecological

Grandi

1987

Med Sci Res

18 Consecutive surgical 

oncology inpatients

(29-75) 0% Breast

Colon

1991

92073507

100 Routine evals of 

hospitalized BMT pts

30 65% Acute leukemia, BMT

Golden

1991

91293995

65 Oncology inpatients 54.2±2.0

(20-86)

0% Gynecological

Alexander

1993

94083044

60 Oncology inpatients 55.0±13.3 60% Various, not specified

Sneeuw

1993

Qual Life 

Res

1112 Early stage, patient 

status not noted

ND 0% Breast

139
 Evidence Table 2. Cross-Sectional Studies on Prevalence of

 Major Depressive Disorders (MDD) Using DSM Criteria

Author

Year

UI Treatment Criteria Prevalence Comments

Derogatis

1983

83112345

ND DSM III interview 13% class;

5.5% MDD

Karnofsky at least 50; 

different rates at sites

Bukberg

1984

84248575

90% receiving 

treatment

Mod. DSM III 42%; 24% severe Excluded patients may 

underbias; cognitive 

impairment common; did 

not distinguish somatic 

symptoms

Morton

1984

85025487

No, post-treatment DSM III interview 39.6% No data on recruitment

Evans

1986

86156362

No, 7% had surgery in 

month prior to study

DSM III interview 23% MDD; 24% nonmajor depression27% refusal rate; study 

part of neuro-endocrine 

tests

Grandi

1987

Med Sci Res

Post surgical treatment DSM III interview 22.2%

Colon

1991

92073507

Pre-treatment DSM III interview 1%; 6% Adj. D. with 

depressed mood

Pre-treatment

Golden

1991

91293995

No DSM III interview 23% No data on physical 

debilitation

Alexander

1993

94083044

Not noted, most likely 

receiving treatment

DSM III-R interview 13%; adj. D w 

depressed mood 

10%

33% unaware of cancer 

diagnosis; level of physical 

debility not noted

Sneeuw

1993

Qual Life 

Res

DIS, based on DSM 

III

5.4% No recruitment data

140
 Evidence Table 2. Cross-Sectional Studies on Prevalence of

 Major Depressive Disorders (MDD) Using DSM Criteria

Author

Year

UI N Population/Setting

Mean Age 

(Range) % Male Cancer Type

Berard

1998

98251414

100 Oncology outpatients 51.8±13.3 16% 55% breast; 43% lymphoma

Breitbart

2000

21023505

92 Hospitalized palliative 

care oncology patients

65.9±15.6 40% Various, not specified

Pirl

2002

Psychooncology

45 Ambulatory prostate 

cancer patients receiving 

androgen deprivation 

therapy

69.4±7.4 100% 100% prostate

141
 Evidence Table 2. Cross-Sectional Studies on Prevalence of

 Major Depressive Disorders (MDD) Using DSM Criteria

Author

Year

UI Treatment Criteria Prevalence Comments

Berard

1998

98251414

46% receiving 

treatment

DSM-IV interview 19% Possible bias towards 

healthier patients

Breitbart

2000

21023505

Palliative treatment SCID, DSM-IV 16% Less than 6 months to live

Pirl

2002

Psychooncology

yes SCID, DSM-IV 12.8% All receiving androgen 

deprivation therapy; strong 

assoc. to past history of 

MDD

142
 Evidence Table 3. Cross-sectional Studies on Prevalence of Significant

 Depressive Symptoms in Adults Using the HADS

Author

Year

UI N

Population/ 

Setting

Cancer 

Type

Mean Age

(range) % Male Treated?

Espie

1989

90011914

41 Outpatient follow-up 

at least 6 months 

after treatment

Head and 

neck

64 (43-78) 66% No

Razavi

1990

90123787

210 Inpatients Various 55.3±14.5 32.9% ND, but in hospital

Hopwood

1991

91369830

204 Consecutive 

ambulatory patients

Breast ND 0% 78% receiving 

treatment, 20% not 

receiving treatment

Hopwood

1991

91369831

81 Ambulatory patients Advanced 

breast, no 

brain 

metastases

ND 0% 13% not receiving 

treatment

Maraste

1992

93103705

133 Ambulatory patients Breast 61 (32-84) 0% Yes

Pinder

1993

93168443

139 Inpatients and 

outpatients

Advanced 

breast 

cancer

60.5 (27-90) 0% Not all receiving 

treatment

Chaturvedi

1996

96322574

50 New patients 

undergoing 

treatment, hospital 

status not known

Head and 

neck 

cancers

ND 80% Beginning treatment

143
 Evidence Table 3. Cross-sectional Studies on Prevalence of Significant

 Depressive Symptoms in Adults Using the HADS

Author

Year

UI Instrument Prevalence Comments Associated Factors

Espie

1989

90011914

HADS (≥9), GHQ 17% 33% of M subjects felt to 

be “heavy drinkers:” 70% 

participation rate

No significant 

associations

Razavi

1990

90123787

HADS, MADRAS, 

DSM-III interview

7.8% random, 

25.5% referred

43% of potential subjects 

referred to psych 

services, 57% random

Greater prevalence in 

terminal patients

Hopwood

1991

91369830

HADS (≥11), RSCL 9%, 1% 

borderline, and 

9% mixed 

depression and 

anxiety

No data on functional 

status of sample

Not associated with 

response to 

treatment; impaired 

functional status and 

SOB associated with 

depression

Hopwood

1991

91369831

HADS (≥11), RSCL, 

DSM-III interview

34.60% 25% of subjects had 

mood or anxiety disorder 

diagnosed from interview, 

no data on functional 

status of sample

Maraste

1992

93103705

HADS (≥10r) 1.5%, 3.75% 

borderline

Prevalence too low for 

power for associations

Not associated with 

masectomy

Pinder

1993

93168443

HADS (≥11) 12%, 62% inpatients Associated with 

inpatient status, poor 

performance status, 

social class; not 

marriage, disease 

stage, or previous 

psychological history

Chaturvedi

1996

96322574

HADS (≥8) 62% probable 

cases not noted 

% of depressive

Depressive symptoms not 

separated out

144
 Evidence Table 3. Cross-sectional Studies on Prevalence of Significant

 Depressive Symptoms in Adults Using the HADS

Author

Year

UI N

Population/ 

Setting

Cancer 

Type

Mean Age

(range) % Male Treated?

Grassi

1996

97097507

86 Home care patients Various 66.8±11.6 58% Palliative care

Roth

1998

98246550

113 Outpatients Prostate ND 100% ND

Groenveld

1999

99314675

538 Ambulatory 

survivors

Breast 55 0% Post-treatment

Newell

1999

99404992

195 Outpatients Various 50-69: 50% 41% 50% receiving 

treatment

Chen

2000

20544343

203 Inpatients Various ND 49.8% ND

Cliff

2000

20522093

164 Outpatients Prostate 73.9 100% Most receiving 

treatment

145
 Evidence Table 3. Cross-sectional Studies on Prevalence of Significant

 Depressive Symptoms in Adults Using the HADS

Author

Year

UI Instrument Prevalence Comments Associated Factors

Grassi

1996

97097507

HADS (≥11), EROTC 

QLQ-C30

45% 27% non-completers, 

mean KPS 54.65

Associated with most 

EROTC QLQ items, 

not with KPS, cancer 

type, or gender

Roth

1998

98246550

HADS 15.2%

Groenveld

1999

99314675

HADS (≥11) 3.5%, 6.5% 

borderline

67.4% participated, HADS 

scores from general 

population may not be 

directly comparable

Compared sample to 

a population sample 

and found that when 

controlling for age 

mean HADS score 

greater in survivors 

but % of “cases” no

Newell

1999

99404992

HADS (cut off not 

specified), CNQ

8%, 15% 

borderline

9% of potential subjects 

excluded because too 

physically or mentally ill to 

participate; HADS cut off 

not specified

Associated with high 

levels of home 

support

Chen

2000

20544343

HADS (≥11) 20.2%, 23.7% 

borderline

Convenience sample, 

Taiwanese population, 

KPS 79.41±12.85

Associated with pain, 

disease status, 

perception of 

treatment response

Cliff

2000

20522093

HADS (cut off not 

specified)

8.1% HADS cut off not 

specified

146
 Evidence Table 3. Cross-sectional Studies on Prevalence of Significant

 Depressive Symptoms in Adults Using the HADS

Author

Year

UI N

Population/ 

Setting

Cancer 

Type

Mean Age

(range) % Male Treated?

Hopwood

2000

20139496

987 Data from 3 

multicenter 

treatment studies

Lung ND ND Treatment trials

Pascoe

2000

20488835

504 Outpatients Various 62 median

(20-93)

45% At least 41% in 

treatment

147
 Evidence Table 3. Cross-sectional Studies on Prevalence of Significant

 Depressive Symptoms in Adults Using the HADS

Author

Year

UI Instrument Prevalence Comments Associated Factors

Hopwood

2000

20139496

HADS 17%, 16% 

borderline

64-79% completed pretreatment and 1st follow 

up, no change in 

depression rates with 

treatment but >50% of 

baseline depressed still 

depressed and 17% of 

baseline normal 

depressed or borderline 

depressed

Associated with 

female 

gender,fdecreased 

functional impairment, 

increased symptom 

burden, not age

Pascoe

2000

20488835

HADS (≥10) 7.1%, 11.0% 

borderline

Participation rate in 

recruitment not noted

Advanced disease, 

functional impairment, 

and English as 2nd 

languade associated 

with depressiom; 

treatment not 

associated

148
 Evidence Table 4. Depressive Symptoms in Children with Cancer

Author

Year

UI N

Population/

Setting Cancer Type

Mean Age

(range) % Male Treated?

Multhern

1994

Child Health 

Care

99 Consecutive hospitalized 

children with cancer in 

remission

Various, 

41.4% 

leukemia

12.9 median

(8-16)

60.6% Yes

Suris

1996

97016462

3139 - 162 

chronic 

illness, 39 

cancer

Random sample of 

Spanish high school 

students, 14-19 years old, 

data analyzed as chronic 

illness (including cancer) 

vs. control, no sig. 

difference found between 

cancer and other chronic 

illnesses

ND (14-19) ND ND

von Essen

2000

20173130

Group 1: 16

Group 2: 35

2 groups of hospitalized 

children with cancer 

diagnosed no later than 1 

month pre-study ages 8-

18 yrs. old 

Various Group 1: 

13.3±3.3

Group 2: 

12.6±3.3

69%

51%

Yes

No

149
 Evidence Table 4. Depressive Symptoms in Children with Cancer

Author

Year

UI Instrument Prevalence Associations Comments

Multhern

1994

Child Health 

Care

CDI (>11), 

CBCL (>64)

Specifics not noted, <10% Associated with 

severity of physical 

symptoms (p<.01)

Majority of children with 

depressive symptoms 

did not have resolution 

of depression with 

improving physical 

symptoms

Suris

1996

97016462

Questionnaire 

including 

questions 

about emotion 

problems

Significantly higher report of 

depressive symptoms, 30.0% 

of females reported 

“emotional problems” with 

23.5% reporting SI, 16.1% 

males reported “emotional” 

problems with 16.1% 

reporting SI

Illnesses twice as 

likely to have 

“emotional 

problems”

Non-standardized 

measures, no 

confirmed medical 

diagnoses, no data on 

physical morbidity

von Essen

2000

20173130

CDI (≥13), 

ITIA, RCMAS

14% of all subjects, 6.3% on 

treatment, 17.1% off 

treatment

Associated with 

higher reports of 

anxiety and lower 

self esteem; no 

differences between 

group receiving 

treatment and 

group not receiving 

treatment

Higher CDI cut-off, no 

data on physical 

morbidity

150
 Evidence Table 5. Incidence of Depressive Symptoms in Adult Cancer 

 Patients - HADS

Author

Year

UI N Population/ Setting % Male Treatment

Time 

Course Instruments

Chadurvedi

1996

Psychooncology

100, 57, 21 Consecutive newly 

diagnosed patients 

starting radiation, 

various cancers (55% 

cervix), 67% under 40 

yrs. old

21% radiation 3-4 months 

posttreatment

HADS (≥8)

Nordin

1999

99149570

159, 113 Consecutive newly 

diagnosed GI cancers, 

mean age 67 years 

(range 23-89)

51% biopsy 3-6 months 

after 

diagnosis

HADS (≥8 for 

depression or 

anxiety scales), 

MAC, IES

Hjermstad

1999

20107424

130, 130, 

94

Consecutive leukemia 

patients for stem cell 

transplatation, median 

age 35 (range 17-55)

56% BMT 1 year HADS (≥8)

Hammerlid

1999

99287399

357, 345, 

215

Head and neck cancer 

patients pre-treatment, 

mean age 63 (range 18-

88)

72% Various, 

combined 

and radiation 

in majority

1 year HADS (≥11)

Hopwood

2000

20139496

987, 718 Lung cancer patients in 

clinical trails, 55% poor 

prognosis

ND 3 clinical 

trials, 3 

chemo and 1 

radiation

Time of 1st 

follow-up not 

noted

HADS (≥11), 

RSCL

151
 Evidence Table 5. Incidence of Depressive Symptoms in Adult Cancer 

 Patients - HADS

Author

Year

UI Baseline Time 1 Time 2 Comments

Chadurvedi

1996

Psychooncology

4% Finishing course 

of radiation, 44%

3-4 months post 

treatment, 48%

No data on changes in patients, Indian 

population

Nordin

1999

99149570

21.2% 3 or 6 months 

later, 12.4%

Half of subjects who initially scored in had 

now scored under cut off, only 1.8% new 

subjects met cut off, did not separate out 

anxiety and depression

Hjermstad

1999

20107424

4.6% 2 weeks, 40% 1 year, 10.6% 7.4% of non-depressed subjects scored 

>8, 50% of subjects depressed at baseline 

stayed depressed, no sig. difference 

between SCT and ASCT

Hammerlid

1999

99287399

6%, 11% 

borderline

3 month 13%, 

11% borderline

1 year, 8%, 9% 

borderline

At 3 months 20 % of all depressed new 

and 8% of depressed no longer scored in 

at 1 year 13% of all depressed new and 

10% of previous depressed no longer 

scored in, only predictor for psychiatric 

disturbance at 12 months is 

anxiety/depression at baseline

Hopwood

2000

20139496

17%, 16% 

borderline

1st follow up, 

29% depressed 

or borderline

59% of depressed remained depressed, 

17% of non-depressed became 

depressed; treatment trials with more 

advanced cancers possibly at entry with 

histories of past cancer treatment, 2 of 

trials were palliative

152
 Evidence Table 6. Prevalence of Fatigue in Cancer Patients

Author

Year

UI N Design

Mean age 

(range) % Male Cancer Type, Setting

King

1985

85242295

USA

96 prospective 

cohort

(26-83) 52% chest, head and neck, GU, 

GYN, during and post-XRT

Hurny

1993

94207627

Switzerland

127 prospective 

cohort

ND ND SCLC, chemo trial

Donnelly

1995

95271387

USA

743 prospective 

cohort

(61-70) 53% various cancers, on palliative 

care service

Hickok

1996

97089233

USA

50 retrospective 

chart review

63 (37-78) 

avg.

68% lung cancer patients receiving 

XRT

Longman

1996

97158314

USA

307 prospective 

cohort

55 (25-82) 0% breast cancer, stage I-IV, 

chemo, hormonal therapy or 

XRT

Richardson

1997

98155331

UK

129 prospective 

cohort

58 (26-82) 44% various, during chemo

Sarna

1997

97165457

USA

60 retrospective 

secondary 

analysis of 

data from 2 

clinical trials

58.3 (33-80) 0% advanced lung cancer

153
 Evidence Table 6. Prevalence of Fatigue in Cancer Patients

Author

Year

UI Scales Timepoints Outcomes Comments

King

1985

85242295

USA

Symptom Profile weekly during XRT, 

then monthly x 3

65-93% during XRT, 

14-46% @ 3 months 

(% reported for each 

anatomic site)

non-validated 

instrument, fatigue not 

quantitated

Hurny

1993

94207627

Switzerland

EORTC QL 

subscale

at baseline and 

before each of 5 

subsequent chemo 

treatments

43% moderate or 

severe at baseline, 

30-37% during 

chemo

fatigue was most 

prominent symptom 

over course of 

treatment

Donnelly

1995

95271387

USA

question-nairre one time point at 

initial referral to 

palliative care 

service

48% "clinically 

important" 

(moderate or 

severe)

Non-validated 

instrument used. 

Fatigue ranked 2nd to 

pain in prevalence and 

severity of symptoms.

Hickok

1996

97089233

USA

Symptom Control 

Checklist, progress 

notes

weekly 78% experienced 

fatigue at some 

point during XRT

Intensity of fatigue not 

measured; instrument 

not validated

Longman

1996

97158314

USA

Side Effects Burden one time point 

during treatment

83%; 60.2% 

"problematic"

fatigue was most 

common and most 

problematic symptom 

reported

Richardson

1997

98155331

UK

VAS daily for 3-4 weeks 89% at some point 

during chemo

Sarna

1997

97165457

USA

SDS one time point 56.7% had "serious" 

fatigue (>3 on 1-5 

scale)

fatigue was most 

prevalent serious 

symptom

154
 Evidence Table 6. Prevalence of Fatigue in Cancer Patients

Author

Year

UI N Design

Mean age 

(range) % Male Cancer Type, Setting

Vogelzang

1997

97397931

USA

419 retrospective 

telephone 

survey, 

cancer pts 

recruited 

from 100,000 

randomly 

selected 

households

65 33% various cancers, pts who had 

received chemo or XRT

Smets

1998

98435611

Netherlands

250 prospective 

cohort

64±13 59% ambulatory patients receiving 

XRT with curative intent for 

various cancers

Smets

1998

98435610

Netherlands

154 prospective, 

case-control

65±12 57% various cancers in remission 

after XRT

GastonJohansson

1999

20152209

USA

127 prospective, 

cohort

45±7.6 0% Stage II, III & IV breast cancer 

after surgery and chemotherapy, before autologous 

stem cell or bone marrow 

transplant

155
 Evidence Table 6. Prevalence of Fatigue in Cancer Patients

Author

Year

UI Scales Timepoints Outcomes Comments

Vogelzang

1997

97397931

USA

Fatigue Coalition 

Survey

one administration 

at variable time 

points after 

treatment 

78% reported fatigue 

during their disease 

and treatment, 32% 

on daily basis

32% rated fatigue as 

having significant 

impact on daily routine

Smets

1998

98435611

Netherlands

Multi-dimensional 

Fatigue Inventory 

(MFI-20)

2 weeks pre- and 2 

weeks post-XRT; 0-

10 scale every 2 

weeks

During XRT 40% 

were tired most of 

the time, 33% 

sometimes, 27% 

hardly ever. 44% 

were more fatigued 

after than before 

XRT, 26% were less 

fatigued, 30% no 

change

Smets

1998

98435610

Netherlands

MFI-20 and 

structured interview

9 months after XRT 51% recalled fatigue 

in first 3 months 

after XRT (19% very 

much, 32% 

moderate). No 

significant 

differences in fatigue 

scores between 

cases and controls 

at 9 months

Case and control 

groups not balanced by 

gender and age

GastonJohansson

1999

20152209

USA

VAS, PFS, GastonJohansson Painometer, BDI, 

Medical Outcomes 

Study Short-form 

General Health 

Survey

one time point 91% had fatigue on 

VAS

fatigue correlated with 

pain, depression and 

health status

156
 Evidence Table 6. Prevalence of Fatigue in Cancer Patients

Author

Year

UI N Design

Mean age 

(range) % Male Cancer Type, Setting

Jacobsen

1999

20004863

USA

54 cases

54 controls

prospective 

case-control

51±10 0% breast cancer receiving 

adjuvant chemo-therapy

Loge

1999

99385422

Norway

459 cases

2214 controls

prospective 

case-control

44±12 55% Hodgkin's Disease, after 

curative treatment: 38% XRT, 

14% chemo, 47% 

XRT+chemo

Miaskowski

1999

99283638

USA

24 prospective 

cohort

56.6±13 50% various cancers, receiving 

outpatient XRT for bone 

metastases

Monga

1999

99334561

USA

36 prospective 

cohort

66.9 (55-79) 100% localized prostate cancer 

undergoing XRT

Stone

1999

99202777

UK

95 cases

98 controls

prospective, 

case-control

67 (30-89) 43% patients with advanced 

cancer in palliative care units, 

no chemo or XRT in > 4 

weeks

157
 Evidence Table 6. Prevalence of Fatigue in Cancer Patients

Author

Year

UI Scales Timepoints Outcomes Comments

Jacobsen

1999

20004863

USA

POMS-F, FSI POMS-F, FSI: 

before chemo, 

between cycles 2 & 

3, and between 

cycles 3 & 4

MSAS: prior to 

cycles 1-4

4% of patients had 

severe fatigue 

before cycle 1, 28% 

before cycle 4 

(MSAS). Patients 

had significantly 

more fatigue than 

controls at all time 

points

Increase in fatigue was 

associated with 

chemotherapy side 

effects (nausea, mouth 

sores)

Loge

1999

99385422

Norway

Fatigue 

Questionnaire

one-time 

adminstration by 

mail at a mean of 

12 years after 

treatment 

26% of Hodgkin's 

survivors were 

fatigue cases (total 

dichotamized score 

> 4 and symptom 

duration of > 6 

months) vs. 9% of 

male and 12% of 

female controls

Hodgkin's survivors had 

higher fatigue levels 

than controls (p <.001). 

There were no 

associations between 

treatment characteristics and fatigue

Miaskowski

1999

99283638

USA

Lee Fatigue Scale at time of 

enrollment & then 

prior to bedtime and 

on awakening for 2 

consecutive days

79% had moderate 

or severe fatigue at 

bedtime and 48% on 

awakening

Monga

1999

99334561

USA

PFS, FACT-P, BDI, 

Epworth Sleepiness 

Scale

8% were fatigued 

(>6 on PFS) prior to 

XRT, 25% at 

completion of XRT

High fatigue scores on 

PFS correlated with 

poorer Physical WellBeing on FACT-P

Stone

1999

99202777

UK

FSS,EORTC QLQ 

c30, HADS, VAS 

(tiredness, 

weakness, ability to 

concentrate)

at baseline and 2 

weeks later

75% had severe 

fatigue (> 95th 

percentile of controls 

on FSS)

In multivariate analysis, 

30% of variance in 

fatigue in patients was 

due to pain and 

dyspnea. In controls, 

HADS scores 

accounted for 17% of 

variance

158
 Evidence Table 6. Prevalence of Fatigue in Cancer Patients

Author

Year

UI N Design

Mean age 

(range) % Male Cancer Type, Setting

Bower

2000

20139478

USA

1957 survey study 55 0% Breast Cancer Survivors 1-5 

years after diagnosis

Curt

2000

20497163

USA

(same as Cella 

2001)

379 populationbased survey53 21% 62% breast cancer, various 

other cancers after chemo or 

XRT

Okuyama

2000

21408236

Japan

134 prospective 

cohort

55.1±10.3 0% breast cancer patients stage 0-

III, after surgery. (77% mastectomy, 23% breastconserving) 28.1% had had 

chemo, 8.9% XRT

Servaes

2000

21023870

Netherlands

85 comparison 

group

16 chronic 

fatigue

prospective 

cohort

47.5±14 56% various cancers and 

treatments, patients diseasefree at a mean of 2.9 years 

after treatment

Stone

2000

20314191

UK

62 prospective 

cohort

69 (55-80) 100% prostate cancer, various 

stages, receiving hormonal 

therapy

Stone

2000

20363241

UK

98 prospective, 

case-control

66 (30-89) 56% early breast or prostate 

cancer, inoperable lung 

cancer, or advanced cancer 

receiving inpatient palliative 

care

159
 Evidence Table 6. Prevalence of Fatigue in Cancer Patients

Author

Year

UI Scales Timepoints Outcomes Comments

Bower

2000

20139478

USA

RAND Health 

Survey 1.0, CES-D, 

BCPT symptom 

checklist, MOS 

sleep scale

one time point 35% classified as 

fatigued (scores in 

diability/limit-ation 

range on RAND 

survey)

Breast cancer survivors 

had better 

energy/fatigue scores 

than national norms for 

age-matched women

Curt

2000

20497163

USA

(same as Cella 

2001)

25 minute 

telephone interview

76% had fatigue at 

least a few days per 

month during most 

recent chemo, 30 % 

had daily fatigue

retrospective survey of 

patients at variable time 

points after treatment

Okuyama

2000

21408236

Japan

CFS, HADS, Mental 

Adjustment to 

Cancer Scale, ad 

hoc questionnaire

one time point, 

mean of 789±463 

days after surgery

56% perceived 

themselves as 

fatigued per the 

CFS.

In multiple regression, 

fatigue correlated with 

dyspnea, insufficient 

sleep, and depression, 

but not with disease or 

treatment-related 

factors

Servaes

2000

21023870

Netherlands

Checklist Individual 

Strength (CIS), BDI, 

STAI, Nottingham 

Health Profile

29% had heightened 

and 19% severe 

fatigue (>27 or >35 

on CIS)

Fatigue correlated with 

depression and anxiety, 

not disease or 

treatment variables

Stone

2000

20314191

UK

FSS, Bidimensional 

Fatigue Scale 

(BFS), EORTC 

QLQc30 fatigue 

subscale & VAS

at start of hormone 

treatment and 3 

months later

14% had "severe 

fatigue" at baseline, 

17% at 3 months 

(NS). (severe 

fatigue defined as > 

95th percentile on 

FSS in controls 

without cancer)

fatigue increased 

significantly on 6 of 8 

scales/sub-scales. 

Other than "severe 

fatigue", clinical 

significance of scores 

not defined

Stone

2000

20363241

UK

Fatigue Severity 

Scale (FSS), 

fatigue subscale of 

EORTC QLQc30

one time point while 

not on chemo or 

XRT

48% of cases had 

"severe fatigue" 

(defined as >95th 

percentile of control 

group scores)

control group was a 

"convenience sample" 

selected to match 

anticipated age and 

gender profile of 

patients

160
 Evidence Table 6. Prevalence of Fatigue in Cancer Patients

Author

Year

UI N Design

Mean age 

(range) % Male Cancer Type, Setting

Stone

2000

20489733

UK

576 crosssectional 

survey

59 (18-89) 37% patients with various cancers 

and stages attending three 

regional cancer centers over 

a 30 day period

Cella

2001

21348064

USA

(same as Curt 

2000)

379 populationbased survey53 21% various (50% breast) after 

chemo or chemo + XRT

Given

2001

21291233

USA

841 prospective 

cohort study

(>65) 55% breast, colon, lung, prostate

Okuyama

2001

21408236

Japan

157 prospective, 

cross 

sectional

63.1 (27-80) 71% ambulatory patients with 

advanced lung cancer, no 

surgery, chemo or XRT in 

past 4 weeks

Wang

2001

21481486

USA

72 prospective 

cohort study

56±11 50% locally-advanced rectal 

cancer receiving pre-op 

chemo & XRT

161
 Evidence Table 6. Prevalence of Fatigue in Cancer Patients

Author

Year

UI Scales Timepoints Outcomes Comments

Stone

2000

20489733

UK

FACT-F, 

investigatordesigned 

questionnaire

58% reported being 

"somewhat" or "very 

much" fatigued

fatigue was most 

common symptom. 

52% of fatigued 

patients did not report 

fatigue to their doctor. 

14% were advised 

about or treated for 

fatigue 

Cella

2001

21348064

USA

(same as Curt 

2000)

telephone 

questionnaire 

based on proposed 

ICD-10 criteria for 

cancer-related 

fatigue 

17% met proposed 

criteria for cancerrelated fatigue; 37% 

reported > 2 weeks 

of fatigue in 

preceeding month

70% of eligible patients 

never contacted; 

clinical signficance of 

proposed criteria for 

cancer-related fatigue 

is unknown

Given

2001

21291233

USA

single question 6-8, 12-16, 24-30 

and 52 weeks

26-33% had fatigue 

at 4 time points over 

1 year

non-validated 

instrument

Okuyama

2001

21408236

Japan

Cancer Fatigue 

Scale, Fatigue 

Numerical Scale, 

Questionnaire on 

"interference"

one time point for 

majority (2 time 

points in 37 

subjects to assess 

reliability of 

measures) 

51.3% had clinical 

fatigue, defined as 

interfering with at 

least one domain of 

daily life

Interference questions 

adapted from Brief Pain 

Inventory; validity of 

definition of clinical 

fatigue unclear

Wang

2001

21481486

USA

Brief Fatigue 

Inventory

baseline and then 

weekly during 

treatment

At baseline 26% had 

moderate and 18% 

severe fatigue; at 

end of treatment 

28% had moderate 

& 31% severe 

fatigue

162
 Evidence Table 7. Assessment of Depression in Adults: Direct

 Comparison of Instruments to Each Other or Standardized Interviews

Author

Year

UI N Population/Setting

BDIHamiltonStructured Clinician InterviewPOMSSCL 90-RGeneral Health QuestionnaireHADSRSCLVASEORTC-QOL C33Zung Self-Rating Depression"Are you depressed?"

Hardman

1989

89258578

126 Hospitalized patients with various 

cancers

x x

Sutherland

1989

J Psychosoc 

Oncol

42 Various cancers at various stages, 

over half receiving treatment; all 

participating in psychosocial 

intervention

x* x*

Kathol

1990

90328359

152 Patients with terminal solid tumors 

reporting depressive symptoms

x x

Razavi

1990

90123787

226 Hospitalized patients with various 

cancers

x

Hopwood

1991

91369831

81 Outpatients with breast cancer x x

Ibbotson

1994

94190657

514 Outpatients with various cancers, not 

all patients completed all measures, 

stratified by disease status

xxx

163
 Evidence Table 7. Assessment of Depression in Adults: Direct

 Comparison of Instruments to Each Other or Standardized Interviews

Author

Year

UI Cutoff Sensitivity Specificity Comments

Hardman

1989

89258578

Structured Clinician Interview: Standardized 

Psychiatric Interview

General Health Questionnaire: Recognized 

79% affective disorders; 34% false positive 

rate

Sutherland

1989

J Psychosoc 

Oncol

* Correlation = 0.77

Kathol

1990

90328359

BDI: <11 BDI: 93% chance not depressed. PPV = 

94% If prevalence 15%, NPV = 99%

Hamilton: PPV = 95%

Razavi

1990

90123787

HADS:

13

11

75%

54%

HADS: With optimal cutoff of 13, 25% false 

positives with DSM criteria. With cutoff of 

11, 25% false positives.

Hopwood

1991

91369831

HADS: 11

RSCL: 11

75%

75%

75%

80%

HADS: 24.7% misclassification rate with 

DSM criteria

RSCL: 21% misclassification rate with DSM 

criteria

Ibbotson

1994

94190657

GHQ: >8

HADS: >14

RSCL: >17

75%

80%

83%

92%

80%

71%

General Health Questionnaire: PPV = 69%

HADS: PPV = 41% compared to DSM 

criteria; affected by disease and treatment 

status

RSCL: PPV = 37% compared to DSM 

criteria; affected by disease and treatment 

status

164
 Evidence Table 7. Assessment of Depression in Adults: Direct

 Comparison of Instruments to Each Other or Standardized Interviews

Author

Year

UI N Population/Setting

BDIHamiltonStructured Clinician InterviewPOMSSCL 90-RGeneral Health QuestionnaireHADSRSCLVASEORTC-QOL C33Zung Self-Rating Depression"Are you depressed?"

Chochinov

1997

97282990

197 Patients receiving palliative care for 

advanced cancer

xx x x

Hall

1999

99227538

269 Women with early breast cancer x x

Lees

1999

20348060

25 Hospice patients with cancer x* x*

Skarstein

2000

21062004

568 Inpatients and outpatients with 

cancer

x* x*

Passik

2001

21211519

60 Outpatients with various cancers x* x*

165
 Evidence Table 7. Assessment of Depression in Adults: Direct

 Comparison of Instruments to Each Other or Standardized Interviews

Author

Year

UI Cutoff Sensitivity Specificity Comments

Chochinov

1997

97282990

BDI: ≥8

VAS: ≤55

Are you 

depressed?

0.79

0.72

1.0

0.71

0.50

1.0

BDI: PPV = 0.27; NPV = 0.96; 29% false 

positives

Structured Clinician Interview: SADS

VAS: PPV = 0.17; NPV = 0.92; false positive 

= 50%

"Are you depressed?": PPV = 1.0; NPV = 

1.0; false positives = 0%

Hall

1999

99227538

HADS: ≥11

RSCL: ≥11

14.1%

30.6%

98.2%

95.9%

HADS: PPV = 82% compared to PSE 

interview

RSCL: PPV = 90% compared to PSE 

interview

Lees

1999

20348060

*Correlation = 0.82

Skarstein

2000

21062004

*Correlation = 0.41

Passik

2001

21211519

Structured Clinician Interview: MINI

*Correlation = -.066

166
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

KobashiSchoot

1985

87002037

Holland

91 Cancer clinic (37-64) 41.8%

Knobf

1986

86198830

USA

78 Oncology clinic/ 

hospital

51 0%

Fawzy

1990

90334494

USA

38 Cancer clinic 42 47%

Butow

1991

92172785

Australia

103 Oncology 

outpatient/ 

radiotherapy clinics

55 (18-75) 29.5%

Bjordal

1992

92322269

Norway

126 Hospital/Outpatient 

clinic

67 (20-99) 77%

167
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

33% breast, 33% bladder, 

15% lymphoma, 23% uterine

KobashiSchoot

1985

87002037

Holland

Subjective Symptom Test 

of Fatigue

Checklist for Cancer 

Patients

6 times over 

three weeks

P

Breast Knobf

1986

86198830

USA

Symptom Distress Scale After treatment R

Malignant melanoma Fawzy

1990

90334494

USA

POMS

Dealing with Illness-Coping 

Inventory

POMS 

measured at 3 

time points: 

Baseline, 6 

weeks, and 6 

months after 

treatment

P

48% breast, 18% reproductive, 

12% lung, 10% lymphoma

Butow

1991

92172785

Australia

GLQ-8 After treatment P

33% oral, 13% pharynx, 19% 

larynx. 18% skin, 18% salivary

Bjordal

1992

92322269

Norway

EORTC QLQ-C30 5 separate 

groups 

responded at 

various time 

points during 

their treatment 

– not the same 

for all

R

168
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

Complaints about malaise 

increased within a few weeks of 

RT. For patients with lymphoma 

and uterine cancer, malaise 

scores decreased during 

weekends.

Women receiving adjuvant 

treatment for breast cancer 

experienced mild physical 

distress, mild to moderate 

psychologic distress that 

persists after treatment. 

Patients who completed 

chemotherapy reported 

significantly less distress 

(p<0.01) due to fatigue than a 

comparison group still on 

chemotherapy.

Lack of vigor decreased 

significantly at 3 time points, 

15.21±7.83, 11.05±0.09, 

10.39±0.73 (p<.001) and 

Fatigue decreased significantly, 

9.38±7.89, 4.31±0.75, 4.88±0.77 

(p<0.05).

High correlation of GLQ-8 with 

PACIS, FLIC, and Psychological 

Adjustment (PAC).

22-27% reported 3-4 on scales. 

Mean score for fatigue = 1.99.

169
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

Greenberg

1992

92166464

USA

15 Hospital 45.1 0%

Chalder

1993

93217894

UK

374 General practice (14-45) ND

Glaus

1993

94207626

Switzerland

20 Hospital 54.4

(31-85)

30%

170
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

Breast/RT Greenberg

1992

92166464

USA

POMS

VAS

Pearson-Byars Fatigue 

Feeling Checklist

Daily ratings 

during 

treatment

P

Not primarily cancer patients Chalder

1993

93217894

UK

Self-rating scale ND P

Lymphoma, myeloma, breast, 

lung

Glaus

1993

94207626

Switzerland

VAFS

Fatigue Body Chart

Yoshitake Symptom List

Symptom Distress Scale

Questionnaire on Personal 

Coping with Fatigue

During 

treatment

P, L

171
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

Fatigue decreased in first 2 

weeks, increased as treatment 

progressed, plateaued with 

maximum intensity at week 4, 

recovered three weeks after 

treatment. POMS: 3.76±3.3, 

4.30±3.7, 3.04±4.8. VAS: 

2.60±1.1, 3.74±1.4, 2.15±1.3. 

Pearson-Byars: 35.17±3.1, 

33.8±3.6, 51.5±5.2

New scale found reliable and 

valid.

VAFS mean sum of fatigue 

scores for cancer patients 

35±19, noncancer 29±17, 

healthy 30±14. Statistically 

significant difference at 21 

hours. Healthy patients 53±26, 

cancer 41±19, noncancer 

30±18. Morning levels of 

hospitalized patients highest. 

With Yoshitake Symptom List, a 

significant difference between 

subsamples are found in 

Category B (decline of working 

motivation) (p=0.029) and 

Category C (projection of fatigue 

into body) (p=0.002). No 

correlation found between 

fatigue and hemoglobin.

172
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

Dean

1995

95323020

USA

30 Cancer hospital 

and outpatient care 

facility

53 (20-85) 67%

Hjermstad

1995

95256950

Norway

270 Hospital 54 (16-87) 62%

Kaasa

1995

96262863

Norway

247 Hospital 64 (27-90) ND

Smets

1995

94363733

Holland

109 Clinic 61 avg. 53%

Joly

1996

96420624

France

93 Hospital 42 (23-85) 59%

Cella

1997

97397932

USA

(same patients 

as Yellen 1997)

50 Clinic 56 (19-83) 46%

173
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

Malignant melanoma Dean

1995

95323020

USA

Piper Fatigue Scale

Symptom Distress Scale

5 time points: 

before, 2 

weeks, 4 

weeks, 6 

weeks, 8 

weeks, and 

end of 

treatment

NRCT

30% breast, 11% testicular, 

9% lymphoma, 9% cervical

Hjermstad

1995

95256950

Norway

EORTC QLQ-C30 ≥3 months posttreatment

TestRetest

32% lung, 13% prostate, 23% 

breast, 4% myeloma, 5% GI, 

4% rectal

Kaasa

1995

96262863

Norway

EORTC QLQ-C30

VAS

Before RT, 

after RT

P

ND Smets

1995

94363733

Holland

MFI-20

VAS

Questionnaire R, C

Hodgkin’s disease Joly

1996

96420624

France

EORTC QLQ-C30 Questionnaire R, C

24% breast; 22% colorectal; 

16% lung; 10% lymphoma; 6% 

leukemia and ovarian

Cella

1997

97397932

USA

(same patients 

as Yellen 1997)

FACT-An Post-treatment P

174
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

The most extreme fatigue 

scores were in the affective 

domain (emotional).

The EORTC QLQ-C30 yields 

high test/retest reliability in 

patients whose condition is not 

expected to change during time 

of measurement.

Scale was found useful in 

detecting effect of palliative RT 

over time.

All correlations between VAS 

and MFI-20 subscales were 

significant.

Significant difference between 

patients and controls observed 

for fatigue (p=0.025).

High correlation between Piper 

Fatigue Scale and Fatigue 

Subscale, between Piper and 

FACT-F, between Piper and 

FACT-An. Hemoglobin levels 

were associated with QOL 

measured by FACT-An 

(p=0.013). Patients with 

hemoglobin levels <12g/dL 

reported significantly less 

fatigue.

175
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

Yellen

1997

97249700

USA

(same patients 

as Cella 1997)

50 Hospital 56 (19-83) 46%

Broeckel

1998

98246292

USA

61 Clinic 51.6 0%

Hann

1998

98273134

USA

230 Cancer center 52.5 0%

Irvine

1998

98217687

Canada

76 Cancer centers 60 (33-81) 0%

176
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

24% breast, 16% lung, 22% 

colorectal, 10% lymphoma, 

6% leukemia, 6% ovarian

Yellen

1997

97249700

USA

(same patients 

as Cella 1997)

FACT-F

FACT-An

Questionnaire 

<1 year

R, L

Breast/Chemo Broeckel

1998

98246292

USA

POMS-F

FSI

MFSI

Fatigue Catastrophizing 

Scale

Post-treatment R, Comparison 

Breast/RT Hann

1998

98273134

USA

Fatigue Symptom Inventory

Interference Subscale

3 time points: 

before 

treatment, 2-4 

weeks after, 4-

6 weeks after

P, L

Breast/RT Irvine

1998

98217687

Canada

Pearson Byars Fatigue 

Feeling Checklist

LASA: Psychologic 

Distress

Piper Fatigue Scale

4 time points: 

before 

treatment, 1 

week, 4-5 

weeks, 6 

months

P, L

177
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

FACT-F and FACT-An stable 

and consistent.

Fatigue in former chemotherapy 

patients was significantly higher 

than patients with no history of 

cancer as measured by POMSF (p<.01), on 3 items of FSI 

(p<.05) and on 2 items of MFSI 

(p<.01), and greater use of 

catastrophizing as a coping 

strategy.

Convergent validity was 

demonstrated using 

comparisons with existing 

measures of fatigue.

Fatigue increased significantly 

by 1 week after start of 

treatment, was highest at last 

week of treatment and returned 

to pre-treatment levels at 3 

months.

178
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

Mast

1998

98217688

USA

109 Cancer center 60 (20-90) 0%

Schneider

1998

98448614

USA

97 Rural oncology 

clinics

63.3 ND

Schwenk

1998

98384460

Germany

60 University 65 (40-81) 50%

Smets

1998

98447268

Holland

250 Hospital 64±13 58%

179
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

Disease-free breast cancer 

patients

Mast

1998

98217688

USA

Mishel Uncertainty in 

Illness Scale

McCorkle and Young 

Symptom Distress Scale

4 years after 

treatment

R

55% carcinoma, 7% 

lymphoma, 2% leukemia

Schneider

1998

98448614

USA

MFI-20

Rhoten Fatigue Scale

Questionnaire R, Comparison

Colorectal Schwenk

1998

98384460

Germany

VAS Post-op, day 1-

7

P

26% prostate, 19% breast, 

12% gynecological, 10% lung, 

6% head and neck, 6% GI

Smets

1998

98447268

Holland

MFI-20 Before 

treatment, 2 

weeks after, 9 

months after

P

180
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

Illness uncertainty had a positive 

relationship with fatigue. Age 

and time since treatment were 

not related with fatigue or 

uncertainty. Two-way ANOVA 

revealed significant main effects 

of both concurrent illness and 

chemotherapy (p=0.031) on 

fatigue. Those who had 

chemotherapy with or without 

radiation reported significantly 

higher fatigue than those who 

did not have chemotherapy.

Both scales demonstrated 

similar trend. General fatigue 

scale showed highest correlation 

with Rhoten Fatigue Scale.

The cumulative pain fatigue 

score for the first post-operative 

week was 322 (105-533) in the 

laparoscopic patients and 531 

(70-850) in conventional patients 

(p=0.009).

Fatigue increased over course 

of RT and decreased from posttreatment to 9 months of followup (p<0.0001). At pretreatment, physical condition 

explains fatigue, whereas at 

post-treatment, both physical 

condition and perception of 

burden contributes to fatigue. At 

follow-up, demands to do not 

add to the variance.

181
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

Stein

1998

98316061

USA

346 Cancer center ND 0%

Winstead-Fry

1998

99153154

USA

131 Cancer clinic >21 41%

Woo

1998

98308578

USA

322 Questionnaire 52.2 0%

Akechi

1999

99118517

Japan

455 Hospital 58.9 

(18-85)

53

GastonJohannson

1999

20152209

USA

127 Cancer center 45 (22-60) 0%

182
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

Breast Stein

1998

98316061

USA

MFSI Questionnaire L

14% prostate, 34% prostate, 

15% lung, 11% colorectal, 

26% other

Winstead-Fry

1998

99153154

USA

Multidimensional 

Assessment of Fatigue

Fatigue Severity Scale

VAS

Rhoten Fatigue Scale

Questionnaire P

Breast Woo

1998

98308578

USA

Piper Fatigue Scale Questionnaire P

22% head and neck; 19% 

lung; 19% breast; 13% 

stomach; 11% colorectal; 5% 

liver

Akechi

1999

99118517

Japan

POMS Questionnaire 

only

P

Breast GastonJohannson

1999

20152209

USA

Piper Fatigue Scale

Fatigue VAS

During 

treatment

C

183
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

MFSI is sensitive to fatigue, 

accurately discriminating cancer 

patients from controls.

All 4 scales are judged accurate 

with rural patients.

Women who received 

continuation therapy had 

significantly higher total fatigue 

scores (p<0.05) than women 

who had radiation.

Sex, education, employment 

status, size of household, 

performance status, depression 

all correlated with fatigue.

91% reported fatigue; 

intensity/severity and sensory 

dimensions correlated most 

highly with total health status. 

PFS total score 31.26.

184
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

Jacobsen

1999

20004863

USA

54 Outpatient clinic 51 0%

Kaasa

1999

99450576

Norway

987 Palliative care unit 64 (27-90) ND

Loge

1999

99385422

Norway

459 Hospital 44 56%

Lovely

1999

99311200

USA

60 Neuro-oncology 

clinics

56.3 65%

185
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

Breast Jacobsen

1999

20004863

USA

POMS-F

Fatigue Symptom Inventory

MSAS

Self-report form

3 time points: 

before start of 

2nd, 3rd, and 

4th cycles

P

Hodgkin’s disease Kaasa

1999

99450576

Norway

SF-36

EORTC QLQ-C30

Fatigue Questionnaire

Entry, 4 weeks, 

3 months, 6 

months

R, L

Hodgkin’s disease survivors Loge

1999

99385422

Norway

Fatigue Questionnaire Before 

diagnosis, 

during 

treatment

C

Glioblastoma multiform Lovely

1999

99311200

USA

POMS

MQOLS-CA2

Before 

diagnosis, 

during 

treatment

P

186
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

Fatigue worsened after 

treatment began. More severe 

fatigue before treatment 

associated with poorer 

performance status and 

presence of other symptoms. 

There was a significant 

difference in fatigue scores 

between cancer patients and 

controls (p<0.05).

Level of fatigue higher in 

palliative care population 

compared to normal samples. 

Fatigue was unchanged over 

time (while pain was reduced). 

In palliative care population, high 

level of fatigue and pain 

reported 0-1 month before 

death.

The correlation between anxiety 

and depression was much 

higher than the correlation 

between fatigue and 

anxiety/depression. There is a 

20% higher level of fatigue 

among Hodgkin’s disease 

survivors than the general 

population. Fatigue is of longer 

duration, and frequency is 

doubled.

Significant increases were 

observed in the fatigue subscale 

score of the POMS before 

treatment (6.44±4.08) and 

following (8.28±4.70) the 

completion of radiotherapy.

187
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

McLachlan

1999

99401383

Canada

150 Hospital 49 (29-79) 0%

Mendoza

1999

99190226

USA

305 Cancer center 55 (18-88) 51%

Molassiotis

1999

99291128

UK

164 Hospitals 37 (18-64) 65%

Monga

1999

99334561

USA

36 RT service 66.9 100%

188
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

Breast McLachlan

1999

99401383

Canada

EORTC QLQ-C30 ND RCT

43% lymphoma, 17% active 

leukemia, 16% chronic 

leukemia, 10% breast

Mendoza

1999

99190226

USA

Brief Fatigue Inventory ND R, C

36% acute leukemia, 28% 

chronic leukemia, 36% 

lymphoma

Molassiotis

1999

99291128

UK

Rotterdam Symptom 

Checklist

Psychological Adjustment 

to Illness Scale

After 

chemotherapy

R, C

Prostate Monga

1999

99334561

USA

Piper Fatigue Scale During, after 

treatment, longterm

P

189
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

The results support the validity 

of a summative “emotional 

distress” and “functional ability” 

score in this sample of patients.

BFI correlates highly with other 

instruments, such as FACT-F, 

FACT-An, POMS. BFI had a 

mean score of 4.7±2.8 on a 

scale 0-10. POMS-Fatigue had 

mean score 15.1±8.8 on a scale 

0-28. FACT-F had mean score 

23.3±15.1 on a scale 0-52. 

FACT-An had a mean score 

41.4±19.4 on a scale 0-80. 

POMS-Vigor had a mean score 

11.1±7.5 on a scale 0-32. All 

the correlations between BFI 

and hemoglobin were 

statistically significant.

Lack of energy was predicted in 

the chemotherapy patients. 

Tiredness was explained by a 

model consisting mainly of 

physical symptoms and 

cognitive symptoms.

The median scores were 

significantly higher at completion 

of radiotherapy as compared 

with preradiotherapy values. 

Three patients (8%) 

experienced fatigue according to 

the Piper Fatigue Scale as 

opposed to nine patients (25%) 

at completion of radiotherapy.

190
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

Schwartz

1999

99323085

USA

449 Hospital (19-81) 61%

Stone

1999

99202777

UK

95 Hospital 67 (30-89) 43%

Berger

2000

20512724

USA

14 Oncology clinics 52.4 

(32-69)

0%

Chan

2000

21023871

Hong Kong

37 Outpatient unit/ 

hospital

43.7

(30-64)

41%

Chang

2000

20164366

USA

240 Hospital clinics 65.4

(27-89)

99%

191
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

Various Schwartz

1999

99323085

USA

Schwartz Cancer Fatigue 

Scale

Final week of 

therapy, 2-3 

days after 

treatment

R

27% lung, 25% breast, 14% 

prostate

Stone

1999

99202777

UK

Fatigue Severity Scale

EORTC Fatigue Scale

VAS

P, C

Post-op breast Berger

2000

20512724

USA

Piper Fatigue Scale

Fatigue Intensity Item on 

PFS

3 time points: 

days 1-4, days 

5-10, and 2 

months posttreatment

P, C

32% breast; 19% colorectal; 

16% nasopharyngeal; 14% 

liver

Chan

2000

21023871

Hong Kong

5-question interview During 

treatment

R

38% GU, 21% lung, 13% 

hematologic, 13% GI

Chang

2000

20164366

USA

MSAS Questionnaire P

192
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

Testing did not support this new 

scale.

Of all symptoms, dyspnoea 

appeared to be the most 

consistently associated with 

fatigue. Fatigue severity was 

significantly associated with a 

number of the domains of the 

EORTC QLQ C-30.

PFS measured fatigue for 3 time 

points, 5.5±2.6, 5.6±2.4, 

3.6±2.5. FI item did likewise, 

6.4±2.3, 5.6±2.3, 3.9±1.9. Mean 

FI scores were 4.0 or higher at 

all phases, 3.6-3.9 following 

treatment. Mean PFS scores 

were higher than 5 during 

treatment, above 4 at midpoint, 

dropped to 3.6 at recovery.

Chemotherapy patients 

encounter severe fatigue 4-7 

days post-treatment, 

radiotherapy patients in second 

week post-treatment.

Patients with moderately intense 

fatigue had a median number of 

13 other symptoms (range 2-30) 

and 8 other moderately intense 

symptoms (range 1-21).

193
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

Collins

2000

20330188

Australia

160 Outpatient, 

inpatient

14 (10-18) 58%

Holley

2000

20512722

USA

121 Cancer center, VA 

hospital

59.6

(21-82)

45%

Jansen

2000

21131556

Holland

46 Clinic 55 (28-77) 0%

Knobel

2000

20370895

Norway

33 Hospital 39 (18-59) 55%

Loge

2000

20164767

Norway

421 Hospital 19-29: 47

30-39: 110

40-49: 158

50-59: 62

60-74: 44

56%

Meek

2000

20383514

USA

37 Outpatient 56.6 

(19-86)

42.3%

194
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

21% leukemia, 16% 

lymphoma, 34% solid tumor, 

11% CNS tumor, 18% rare 

malignancies

Collins

2000

20330188

Australia

MSAS Questionnaire P

28% breast, 18% lung, 17% 

hematologic, 13% GI

Holley

2000

20512722

USA

CRFDS Factor analysis P

Breast Jansen

2000

21131556

Holland

SF-36

Rotterdam Symptom 

Checklist

3 time points: 

pre-test, posttest, then-test

P

Malignant melanoma after 

BMT

Knobel

2000

20370895

Norway

EORTC QLQ-C30 After treatment R

Hodgkin’s disease survivors Loge

2000

20164767

Norway

Fatigue Questionnaire P, C

14% GI, 13% prostate, 7% 

lung, 6% gynecological, 11% 

lymphoma

Meek

2000

20383514

USA

POMS short form

MAF

Lee Fatigue Scale

MFI

RT Patients: 

last week of 

treatment, 1 

month posttreatment

Chemotherapy 

patients: 2 days 

in treatment, 

the day before 

next treatment

R

195
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

Older children with cancer have 

high prevalence of physical and 

psychological symptoms and a 

high level of symptom distress.

The CRFDS is a clinically useful 

and psychometrically sound tool 

for the measurement of cancerrelated fatigue.

Patients show more fatigue and 

lower QOL at the end of RT.

Correlates to fatigue, including 

endocrinological status and 

serum levels of IL-6, tumor 

necrosis factor, and soluble 

tumor necrosis factor receptors.

Fatigue correlated moderately 

with anxiety and depression. 

Twenty-six percent of the 

Hodgkin’s disease survivors had 

substantial fatigue for 6 months 

or longer.

Good data on time points. All 

four instruments had good testretest correlations, showed good 

stability for total scores; some 

subscales of LFS and MFI had 

marginal stability. Only LFS and 

POMS fully supported their 

construct validity.

196
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

Okuyama

2000

20151937

Japan

107 Hospital 61 (35-84) 35.5%

Okuyama

2000

20248825

Japan

134 Hospital 55.1

(28-86)

0%

Schwartz

2000

20166280

USA

25 Hospital 58.4

(31-90)

0%

Servaes

2000

21023870

Netherlands

101 Hospital 47.6 55%

197
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

26% lung, 19% colon Okuyama

2000

20151937

Japan

Cancer Fatigue Scale

VAS

Questionnaire R

Disease-free breast cancer Okuyama

2000

20248825

Japan

Cancer Fatigue Scale Questionnaire C, R

Gynecological Schwartz

2000

20166280

USA

POMS Before 

treatment, 

during 

treatment, one 

day after 

treatment, 1-2 

weeks after 

treatment

P

25% testicular, 23% colorectal, 

20% sarcoma

Servaes

2000

21023870

Netherlands

Checklist Individual 

Strength

Nottingham Health Profile

Minimum 6 

months after 

treatment

P

198
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

Construct validity confirmed by 

repeating factor analysis, was 

good. Convergent validity, 

confirmed by a correlation 

between CFS and a VAS for 

fatigue, was also shown to be 

good.

Total fatigue was significantly 

correlated with depression and 

vice versa. Sleep was one of 

the most effective strategies to 

combat fatigue in cancer 

patients. Fatigue is not 

completely equal to depression.

Fatigue increases over course 

of treatment with maximum 

observed 1 day after treatment 

ended (7.8±5.0). Vigor declined 

once treatment began to a mean 

low during treatment. It 

remained low 1 day, but after 1-

2 weeks rose to pretreatment 

levels.

Fatigue is not related to gender, 

type of cancer, or level of 

education. No significant 

difference with regard to mean 

time since treatment and mean 

duration of treatment.

199
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

Ahsberg

2001

21217964

Sweden

81 Hospital ≤30: 3

31-50: 17

51-70:51

>70: 10

10%

Furst

2001

21388349

Sweden

81 Oncology dept/ 

hospital

56 10%

Knobel

2001

21326207

Norway

92 Hospital 37 (23-56) 58.7%

Kyriaki

2001

21523833

Greece

121 Palliative care unit 62.6

(38-87)

38.3%

200
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

64% breast, 21% 

gynecological

Ahsberg

2001

21217964

Sweden

SOFI

CR-10

KSS

3 time points: 

last week of 

treatment, 1 

month after, 

and 3 months 

after treatment

P

64% breast, 21% 

gynecological, 10% urological, 

4% lymphoma

Furst

2001

21388349

Sweden

MFI-20

CR10

Karolinska Sleepiness 

Scale

HADS

3 time points: 

during, 1 

month, and 3 

months posttreatment

P

Hodgkin’s disease survivors Knobel

2001

21326207

Norway

Fatigue Questionnaire Questionnaire R, C

25% lung, 13.3% breast, 

13.7% pancreatic, 10% 

cervical, 8.3% ovarian

Kyriaki

2001

21523833

Greece

EORTC QLQ-C30 Before 

treatment, 

during 

treatment

P, C

201
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

3 scales measured fatigue over 

time points. Lack of energy 

during (1.74), 1 month after 

(1.41) and 3 months after (1.08) 

treatment. Highest levels of 

fatigue at the end of treatment, 

n.s. There was correlation 

between fatigue and depression.

Fatigue peaked on all scales 

during first week of treatment. 

MFI-20: 13.5±5.1, 11.1±5.2, 

11.1±5.2. CR10: 3.8±2.9, 

2.8±2.3, 2.3±2.0. KSS: 5.4±2.0, 

4.7±2.0, 4.2±2.0

Association found between 

fatigue and pulmonary 

dysfunction. The mean fatigue 

scores among the Hodgkin’s 

disease survivors were physical 

fatigue = 9.6±4.0, mental fatigue 

= 5.0±1.7, and total fatigue = 

14.6±5.2. The levels of fatigue 

did not differ among eurothyroid 

patients. Gas transfer 

impairment was the only 

significant predictor of physical 

fatigue.

The strongest correlations 

before treatment were observed 

between physical functioning, 

social functioning and fatigue, 

while on treatment it was 

observed between pain, physical 

functioning, role functioning and 

fatigue scales.

202
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Author

Year

UI N

Population/ 

Setting

Age 

(Range) % Male

Langendijk

2001

21201272

Holland

164 Hospital 68 (37-84) 84%

Williams

2001

21142464

USA

161 Clinic 57 54.4%

203
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Cancer Type

Author

Year

UI Scale

Time Points 

Measured

Prospective/ Retrospective/ Longitudinal/ Cross-sectional

NSCLC Langendijk

2001

21201272

Holland

QLQ-C30

QLQ-LC13

Before 

treatment, 

during 

treatment, 2 

weeks, 6 

weeks, 3 

months, 6 

months, 12 

months after 

treatment

P

Head and neck Williams

2001

21142464

USA

Therapy Related Symptom 

Checklist

Questionnaire R, C

204
 Evidence Table 8. Assessment of Fatigue in Cancer Patients

Comments

Fatigue increased significantly 

during radiotherapy followed by 

a decrease. Fatigue was found 

to be associated significantly 

with radiation-induced 

pulmonary changes.

Chemotherapy patients reported 

significantly greater severity of 8 

symptoms, including 

sluggishness.

205
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part I

193 

Author 

Year 

UI 

Studied treatment(s) (Rx, 

dose, route) 

N of 

study 

arms 

Study Design (cross-over, cohort, etc) 

Adequacy of concealment 

NSAIDs VS NSAID n=1

Pannuti 

1999 

99291253 

Comparison of efficacy and 

safety of: 

A) Ketorolac 10 mg po (t.I.d.) 

B) Diclofenac 50 mg po (t.I.d.)

2 Crossover 

Duration: 14 days, patients crossed over after 7 

days, single and repeated administration 

assessments 

OPIOID VS OPIOID n=6

Moolenaar 

2000 

20407008 

Comparison of efficacy and 

safety of: 

A) Morphine controlled 

release suppository (MSR) 

(30 mg) every 12 hr 

B) Morphine controlled 

release oral tablets (MSC) 

(30 mg) every 12 hr. 

2 Two-way crossover. 

Duration: 10 days, patients crossed over after 5 

days, plasma levels of morphine and its -3 and -6 

glucuronides were assessed on the 5th and 10th

day 

Heiskanen 

2000 

21075895 

Comparison of efficacy and 

pharmacokinetics of: 

A) Morphine controlled 

release oral tablets (CR 

morphine, 30 mg) 

B) Oxycodone controlled 

release oral tablets (CR 

oxycodone, 20 mg) 

2 Crossover 

Duration: 6 days, patients crossed over, after 3 to 

6 days. An open label titration phase for a 

maximum of 21 days preceded the study. Initial 

total daily opioid dose was calculated based upon 

the past three days of opioid analgesic therapy 

using standard conversion charts. Dose titration 

was continued until effective pain relief (pain 

intensity=none or slight and escape analgesic 

doses <=2 per day) with acceptable adverse 

effects was achieved for at least 48 hr. When the 

total daily opioid dose had been stable for at least 

48 hr without unacceptable adverse effects, the 

patient was re-randomized to a double-blind 

crossover sequence. The daily dose of the CR 

Oxycodone or CR morphine was known from the 

last day of the titration phase or calculated by the 

pharmacist using a ration of oxycodone: morphine 

of 2:3. 

Hunt 

1999 

99414499 

Comparison of efficacy and 

side effects of: 

A) Subcutaneous morphine 

B) Subcutaneous fentanyl 

2 Crossover 

Duration: 6 days, patients crossed over, after 3 

days. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part I

194 

Author 

Year 

UI 

Studied treatment(s) (Rx, 

dose, route) 

N of 

study 

arms 

Study Design (cross-over, cohort, etc) 

Adequacy of concealment 

Bruera 

1999 

99349918 

Comparison of safety and 

efficacy of controlled-release 

morphine sulphate 

suppositories administered: 

A) 12-hourly and 

B) once daily 

in patients with chronic cancer 

2 Crossover 

Duration: 14 days, patients crossed over, after 7 

days no washout period. 

Mercadante 

1998 

99032200 

Comparison of the analgesic 

and adverse effects and the 

doses of: 

A) Methadone 0.1% oral 

liquid preparation 

administered two or three 

times daily according to 

their needs and 

B) Morphine, commercially 

available oral sustainedrelease preparations, 10, 

30, 60 and 100 mg of 

morphine administered 

every 8 to 12 hours 

according to their needs 

2 Parallel 

Duration: until death 

Parris 

1998 

99019888 

Comparison of effectiveness 

and safety of: 

A) 30 mg controlled-release 

(CR) oxycodone tablets 

every 12 hr with 

B) 15 mg immediate-release 

(IR) oxycodone four times 

daily for five days 

The total daily dosage was 60 

mg for each treatment group 

2 Parallel 

Duration: five days 

BREAKTHROUGH PAIN, n=1

Portenoy 

1999 

99165545 

Evaluation of safety and 

efficacy of ascending doses of 

oral transmucosal fentanyl 

citrate (OTFC) to treat 

breakthrough pain. 

2 Cohort. Concealment was adequate. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part I

195 

Author 

Year 

UI 

Studied treatment(s) (Rx, 

dose, route) 

N of 

study 

arms 

Study Design (cross-over, cohort, etc) 

Adequacy of concealment 

ADJUVANTS n=5 

Dahm 

2000 

20462757 

Comparison of efficacy and 

side effects of: 

A) continuous intrathecal (IT) 

infusion of ropivacaine 

0.5% (5 mg/mL) 

B) continuous IT infusion of 

bupivacaine 0.5% (5 

mg/mL) for the 

management of refractory" 

non cancer or cancer pain.

The solutions were infused 

from external, electronic 

programmable pumps 

(Pharmacia-Deltec CADDPCA, St Paul, MN). The rate of 

the IT infusion was initially 

programmed at 0.2 mL/h, with 

optional bolus doses of 0.2 mL 

and lockout intervals of 10 

minutes. Thereafter both the 

basal rate and bolus doses 

were adjusted, with the aim of 

giving the patient satisfactory 

to excellent pain relief (60% to 

100%) with acceptable side 

effects from the infused drugs. 

2 Prospective, crossover study. Duration: 14 days. 

Patients crossed over after 7 days. No washout 

period. 

Mercadante 

2000 

99032200 

Comparison of efficacy and 

side effects of a slow 

intravenous bolus of: 

A) 0.25 mg/kg ketamine or 

B) 0.50 mg/kg ketamine or 

C) saline 

3 Prospective, crossover study 

Duration: 3 days, each at least two days apart. 

Patients crossed over two times. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part I

196 

Author 

Year 

UI 

Studied treatment(s) (Rx, 

dose, route) 

N of 

study 

arms 

Study Design (cross-over, cohort, etc) 

Adequacy of concealment 

Lauretti 

1999 

99287592 

Comparison of analgesia and 

adverse effects of combination 

epidural pain therapy 

consisting of: 

A) morphine 2 mg 

B) ketamine 0.2 mg/kg 

C) neostigmine 100 mcg 

D) midazolam 500 mcg 

All patients received 2 mg 

morphine epidurally twice daily 

to maintain pain intensity 

below 4 prior to randomization 

and continued this treatment 

after enetering the study. Also 

all patients were regularly 

taking oral amitriptyline 50 mg 

at bed time. 

4 Parallel 

Duration: twenty-five days 

Lauretti 

1999 

99287592 

Comparison of efficacy and 

side effects of: 

A) 20 mg oral morphine (10 

mg at 12 hr interval ) (CG) 

B) 5 mg nitroglycerin (1 patch 

daily) (NG) 

C) 0.5 mg/kg oral ketamine at 

12 hr intervals (KG) 

D) 500 mg dipyrone at 6 hr 

intervals (DG) 

All drugs were administered as 

co-adjuvants in 60 patients 

with cancer related pain 

receiving 80-90 mg/day oral 

morphine. The study drugs 

were administered in addition 

to their morphine dose when 

patients reported a pain score 

more than 4 on a 0 to 10 scale.

4 Parallel 

Duration: 30 days 

van Dongen 

1999 

99452099 

Comparison of continuous IT 

infusions of: 

A) Morphine in saline 0.5-

1.0mg/ml and 

B) Morphine 0.5-1.0mg/ml 

plus bupivacaine 2.25-

3mg/ml 

Doses: morphine 1.2-

7.2mg/day; bupivacaine 5-

21.6mg/day 

2 Parallel (for 15 of the 20 patients). Open label for 

5 patients. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part II

197 

Author 

Year 

UI Randomization method Blinding 

Total N 

(evaluable)

Mean age or range and 

(%) male 

NSAIDs VS NSAID n=1 

Pannuti 

1999 

99291253 

not stated All study medication 

tablets were 

identical; patient 

and investigator 

were blinded 

138(137) 63 median (30-71, range) 

47.44% male 

OPIOID VS OPIOID n=6

Moolenaar 

2000 

20407008 

not stated Double blind, 

double dummy 

25(20) 59 median (41-80, range) 

5% male 

Heiskanen 

2000 

21075895 

computer-generated Double blind, 

double dummy 

45(20) 60+/-1.8* (mean ± SEM) 

59.25% male 

*of the 27 patients who 

completed the study 

Hunt 

1999 

99414499 

Not stated Double blind. To 

ensure blinding the 

volume of fluid in 

the syringes was 

kept constant for 

each patient over 

the 6 days 

30(23) 70.5 (48-89, range) 

13/23 (52.2% males) 

Bruera 

1999 

99349918 

Not stated Double-blind. 

Blindness was 

maintained with the 

use of matching 

placebos. 

12 (6) 61 ± 8 (mean ± SD of the 6 

patients who completed the 

trial) 

50% males 

Mercadante 

1998 

99032200 

Not stated Open label 40(40) Morphine group 

65 ± 2.7 (mean ± SE) 

(37-82, range) 

50% male 

Methadone group 

61 ± 2.9 (mean ± SE) 

(35-79, range) 

45% male 

Parris 

1998 

99019888 

Not stated Double-dummy 111 (103) 

52 CR group

51 IR group

57 (range, 31-80) 

50% male 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part II

198 

Author 

Year 

UI Randomization method Blinding 

Total N 

(evaluable)

Mean age or range and 

(%) male 

BREAKTHROUGH PAIN, n=1

Portenoy 

1999 

99165545 

Randomization methods 

not stated for the two 

randomizations that were 

performed. 

Double-blind 65(48) 53±12 (26-74, range) 

43%male 

ADJUVANTS n=5

Dahm 

2000 

20462757 

A block of 4 treatment 

sequences (ABBA, ABAB, 

BABA, and BAAB where 

A=bupivacaine and 

B=ropivacaine) was used 

for randomization. Four 

slips with the four options 

were folded four times and 

thereafter enclosed in a 

sealed envelope. Six 

identical sealed envelopes 

were prepared. The order 

in which these 

combinations were 

selected was randomized 

by taking out 1 of the four 

slips placed in 1 of the 

envelopes. The chosen 

slip gave indications on 

assignment of the 

treatments in the first two 

patients. With the 3rd, the 

5th and the 7th patient, a 

new slip was taken out 

from the same, open, 

envelope until all 4 slips 

were used in the first 8 

patients. With the ninth 

patient, a new envelope 

was prepared and 

opened. An investigator 

looked up the assignment 

for he next patient. 

Double-blind 21(12) median=63 (26-27, range) 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part II

199 

Author 

Year 

UI Randomization method Blinding 

Total N 

(evaluable)

Mean age or range and 

(%) male 

Mercadante 

2000 

99032200 

Not stated The drugs were 

prepared in 

identical syringes 

by a person not 

involved in the test 

sessions. The 

drugs were 

administered in the 

same volume. 

10(10) mean = 57 

70% male 

Lauretti 

1999 

99287592 

Computer generated 

randomization 

double blind, 

method not stated 

48 Mean 54 (37-65, range) 

63% male 

Lauretti 

1999 

99287592 

Not stated Not blinded 60(60) CG: 60 ± 14, 

60% male 

DG: 53±11, 

66% male 

KG: 56±8, 

73% male 

NG: 54±13, 

46.6% male 

All values are mean±SD 

Van Dongen 

1999 

99452099 

Not stated 15 of 20 double 

blind; 5 of 20 open 

as late stage of 

illness: 5 patients 

initially treated with 

morphine alone 

inadequate relief 

with dose 

escalation, 

converted to M+B 

and analyzed as 

group B 

20 Morphine group: 

mean age 60 (40-82, range) 

77% male; 

Morphine plus bupivacaine 

group: 51 (35 -67, range) 

45% male 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part III

200 

Author 

Year 

UI Type(s) of Cancer 

Severity of pain of 

included patients 

Type of pain (neuropathic 

somatic visceral) 

NSAIDs VS NSAID n=1 

Pannuti 

1999 

99291253 

Breast 47/137 (34.3%) lung 

47/137 (34.3%) 

Colorectal 15/137 (10.9%) 

Other 52/137 (37.9%) 

2 "moderate" 

(median, VRS scale) 5.3 

cm (mean, VAS scale, 

range 1-10) 

Metastases were in soft tissues 

13/137 

bone 76/137 

visceral 17/137 

no metastases 31/137 

No other information about type 

of pain is stated 

OPIOID VS OPIOID n=6

Moolenaar 

2000 

20407008 

Lung 13/15 (86.6%) 

Colon 2/15 (13.3%) 

Larynx 2/15 (13.3%) 

Kidney 1/15 (6.6%) 

Esophagus 1/15 (6.6%) 

Prostate 1/15 (6.6%) 

not stated not stated 

Heiskanen 

2000 

21075895 

Breast 2/27 (7.4%) 

Lung 4/27 (14.8%) 

Prostate 6/27 (22.2%) 

Rectum 5/27 (18.5%) 

Pancreas 4/27 (14.8%) 

Ovary 1/27 (3.7%) 

Unknown/other 5/27 (18.5%) 

Pain intensity at baseline 

none or slight and escape 

analgesic doses <=2 per 

day. Baseline pain 

intensity was reached after 

a titration period. 

Neuropathic: 4/27 (14.8%) 

Nociceptive (bone metastases): 

14/27 (51.8%) Nociceptive 

(visceral): 8/27 (29.6%) 

Mixed: 1/27 (3.7%) 

Hunt 

1999 

99414499 

Lung 7/30 (23.3%) 

Prostate 3/30 (10%) 

Kidney/bladder 4/30 (13.3%) 

Ovary/endometrium 2/30 

(6.6%) 

Colon/rectal 3/30 (10%) 

Unknown 2/30 (6.6%) 

Other 9/30 (30%) 

not stated not stated 

Bruera 

1999 

99349918 

Breast 2/6 (33.3%) 

GI tract 2/6 (33.3%) 

Prostate 1/6 (16.6%) 

Kidney 1/6 (16.6%) 

not stated not stated 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part III

201 

Author 

Year 

UI Type(s) of Cancer 

Severity of pain of 

included patients 

Type of pain (neuropathic 

somatic visceral) 

Mercadante 

1998 

99032200 

Morphine group: 

Lung 20% 

Breast 15% 

Colon 10% 

Esophagus 0% 

Liver 10% 

Larynx 0% 

Leiomioma 0% 

Melanoma 5% 

Ovarian 5% 

Pancreas 10% 

Rectum 15% 

Stomach 5% 

Uterus 5% 

Methadone group: 

Lung 30% 

Breast 15% 

Colon 5% 

Esophagus 5% 

Liver 5% 

Larynx 5% 

Leiomioma 5% 

Melanoma 0% 

Ovarian 10% 

Pancreas 5% 

Rectum 5% 

Stomach 5% 

Uterus 5% 

"advanced cancer (that) 

required strong opioids for 

pain management" 

Morphine group: 

Somatic: 50% 

Visceral: 65% 

Neuropathic: 35% 

Incident: 25% 

Methadone group: 

Somatic: 70% 

Visceral: 60% 

Neuropathic: 25% 

Incident: 30% 

Parris 

1998 

99019888 

Breast, gastrointestinal, lung 

and gynecologic. 

Percentages are not 

reported. 

Mean±SE 

CR group: 1.5 ± 0.1 

IR group: 1.3 ± 0.1 

(0-3 categorical scale, 

0=none, 1=slight, 

2=moderate, 3 = severe) 

Bone pain: 45% 

Visceral pain: 28% 

BREAKTHROUGH PAIN, n=1

Portenoy 

1999 

99165545 

Breast: 17 (26%) 

Lung: 7 (11%) 

Colon: 6 (9%) 

Head/neck: 6 (9%) 

Other: 29 (45%) 

Mean (+/-SD) = 4.6+/-2.5 

for persistent pain. Mean 

breakthrough pain intensity 

= 6 (0-10 numeric scale) 

Inferred pathophysiology of the 

persistent pain: 

somatic: 29 (45%) 

visceral: 14 (22%) 

neuropathic: 22 (34%) 

Inferred pathophysiology of the 

breakthrough pain: 

somatic: 28 (43%) 

visceral: 14 (22%) 

neuropathic: 22 (34%) 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part III

202 

Author 

Year 

UI Type(s) of Cancer 

Severity of pain of 

included patients 

Type of pain (neuropathic 

somatic visceral) 

ADJUVANTS n=5

Dahm 

2000 

20462757 

Types of cancer not stated. 

Six patients suffered from 

non-cancer and 15 from 

cancer "refractory" pain. 

"Patients were 

consecutively included in 

the study when a) the pain 

dominated the patients' life 

totally, b) other methods to 

provide acceptable pain 

relief had failed, and c) the 

patients showed 

intolerance to and/or 

unacceptable side effects 

from opioids." "Refractory 

cancer and non-cancer 

pain" was pain resistant, 

usually over a period of 6 

months, to oral and/or 

parenteral morphine and to 

epidural infusion of opioid 

and/or local anesthetic, or 

IT administration of opioids 

and when other 

therapeutic alternatives 

were not applicable or had 

given unsatisfactory pain 

relief. 

Not stated 

Mercadante 

2000 

99032200 

Lung: 4 (40%) 

Histiocytoma: 2 (20%) 

Bladder: 1 (10%) 

Rectum: 1 (10%) 

Uterus: 1 (10%) 

Unknown: 1 (10%) 

Patients pain was 

unrelieved by their dose of 

morphine which ranged 

from 90 mg to 300 mg 

(orally). 

somatic: 6/10 (60%) 

mixed: 4 (40%) 

Lauretti 

1999 

99287592 

Oropharynx: 13 (27.08%) 

Lung: 6 (12.5%) 

Uterus: 1 (22.9%) 

Prostate: 6 (12.5%) 

Liver: 1 (2.08%) 

Digestive tract:10 (20.08%) 

Kidney: 1 (2.08%) 

Patients were suffering 

from cancer pain were 

systemic opioid/NSAID 

therapy was ineffective, or 

pain were presented with 

intolerance to systemic 

opioids. 

No other information is 

provided. 

Not stated 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part III

203 

Author 

Year 

UI Type(s) of Cancer 

Severity of pain of 

included patients 

Type of pain (neuropathic 

somatic visceral) 

Lauretti 

1999 

99287592 

Oropharynx: 18 (30%) 

Lung: 8 (13.3%) 

Uterus: 8 (13.3%) 

Prostate: 7 (11.6%) 

Digestevive tract: 14 (23.3%) 

Kidney: 1 (1.6%) 

Liver: 1 (6.6%) 

The VAS scores for pain 

before the oral morphine 

treatment were: 

CG: 7.6±1.9 

DG: 7.6±1.7 

KG: 7.4±1.5 

NG: 7.9±1.6 

Not stated 

van Dongen 

1999 

99452099 

Lung/pleura: 4 (20%) 

Prostate: 4 (20%) 

Gastrointestinal: 5 (25%) 

Geniturinary: 5 (25%) 

Other: 2 (10%) 

"refractory" non-malignant 

pain: 16/20 inadequate 

pain relief with "analgesic 

ladder"; 

4/20 unacceptable sideeffects (sedation in 3, 

nausea in 1) 

progressive cancer : mixture of 

continuous +/- intermittent, 

somatic +/- visceral +/- 

neurogenic 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part IV

204 

Author 

Year 

UI 

Chronicity of 

cancer pain 

(range or 

average) 

Source of Pain 

(cancer / sequela of 

treatment / 

procedure related) Inclusion/Exclusion criteria 

NSAIDs VS NSAID n=1 

Pannuti 

1999 

99291253 

28 had 

suffered from 

pain for less 

than 1 month, 

67 for 1-3 

months, 28 for 

4-6 months, 7 

for more than 1 

year 

Advanced cancer Inclusion: histologically confirmed diagnosis of 

cancer, with moderate to severe pain at baseline. 

Aged between 18 and 75 yrs, had a platelet count 

>=100,000, normal hepatic and renal function, 

negative history for thrombosis, hypertension, 

diabetes and cardiovascular disease. They did not 

receive concomitant chemotherapy and/or 

radiotherapy during the study or in the 10-15 days 

before the study, nor were they taking any 

concomitant medication that might have interfered 

with the results of the study. 

OPIOID VS OPIOID n=6

Moolenaar 

2000 

20407008 

not stated 

specifically, but 

all patients 

were already 

on morphine 

MSC 

Cancer Inclusion: patients already receiving chronic oral 

morphine (MSC, 30 mg every 12 hr) for cancer pain.

Exclusion: severe obstructive lung disease, 

diarrhea, concurrent use of higher doses of 

morphine or other opioid analgesics, and abnormal 

liver/kidney/thyroid gland blood values. All patients 

were treated with several other drugs, mainly 

laxatives hypnotics and anti-emetics. 

Heiskanen 

2000 

21075895 

not stated Cancer/metastases Inclusion: adult patients presenting with chronic, 

stable cancer pain requiring opioid analgesics. 

Patients had to be cooperative and able to take oral 

medication 

Hunt 

1999 

99414499 

not stated Cancer Inclusion: Hospice patients were eligible to 

participate if they were taking opioids for pain relief, 

were able to give informed consent, and were likely 

to complete the 6-day study. Exclusion: 

patients were excluded if hematology and 

biochemistry results were known to be grossly 

abnormal, the patient was likely to die or be 

discharged within the 6 days of the study or if for 

some other reason staff felt that the patient would be 

unable to comply with the protocol. For example 

patients were excluded if there was a clear history of 

morphine intolerance. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part IV

205 

Author 

Year 

UI 

Chronicity of 

cancer pain 

(range or 

average) 

Source of Pain 

(cancer / sequela of 

treatment / 

procedure related) Inclusion/Exclusion criteria 

Bruera 

1999 

99349918 

Patients who 

completed the 

study had been 

receiving 

opioids for an 

average of 

1.8±1.8 years. 

Cancer Patients were not receiving any antineoplastic 

medication and each required between 60 and 

1200mg oral morphine (or its equivalent) per day for 

the management f cancer pain. 

Mercadante 

1998 

99032200 

Morphine 

group: 53±5 

days on 

opioids prior to 

the study 

Methadone 

group: 47±5 

days on 

opioids prior to 

the study 

Cancer Patients with advanced cancer requiring strong 

opioids for pain management. Patients with 

coexisting liver or renal diseas or cognitive 

impairment at referral were excluded. 

Parris 

1998 

99019888 

Not stated Cancer Inclusion: adult patients who were receiving 6 to 12 

tablets or capsules per day of fixed-combination 

analgesics for cancer related pain, of either sex, with 

stable coexistent disease. Exclusion: patients 

were excluded if their pain was not already 

acceptably controlled; if they had surgery or 

radiotherapy within 10 days prior to study or 

anticipated these procedures during the study; of 

they had compromised function of a major organ 

system; or if they were receiving non-opioid 

analgesics before the protocol was amended. 

Concomitant non-analgesics were allowed during 

the study. The protocol was amended to allow 

participation of patients undergoing or recently given 

radiotherapy and those receiving stable doses of 

non-opioid analgesics or analgesic adjuvants. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part IV

206 

Author 

Year 

UI 

Chronicity of 

cancer pain 

(range or 

average) 

Source of Pain 

(cancer / sequela of 

treatment / 

procedure related) Inclusion/Exclusion criteria 

BREAKTHROUGH PAIN, n=1 

Portenoy 

1999 

99165545 

Not stated Tumor: 51 (78%) 

Treatment: 9 (14%) 

Other: 5 (8%) 

Inclusion: adult patients with cancer-related pain 

were eligible if they: a) were receiving a scheduled 

oral opioid regimen equivalent to 60-1000 mg oral 

morphine per day, b) had experienced at least one 

breakthrough episode per day between 0700 and 

1600 h in the three days immediately preceding 

screening, c) had achieved at least partial relief of 

this breakthrough pain by the use of an oral opioid 

rescue dose. If patients had more than one type of 

breakthrough pain or had breakthrough pain in more 

than one location they were asked to identify one 

pain as a "target" breakthrough pain for the study. 

Exclusion: recent history of substance abuse, 

neurologic or psychiatric impairment sufficient to 

compromise data collection, any major organ 

impairment that could increase the risk of 

supplemental opioids for treating breakthrough pain, 

or any recent therapy that could potentially alter pain 

or response to analgesics during the study. Specific 

exclusion criteria included renal or hepatic function 

tests greater the three times the upper limit of 

normal, treatment with Strontium-89 within 60 days, 

and treatment with radiotherapy to a painful site 

within 30 days prior to the study. Patients with 

moderate to severe oral mucositis were also 

excluded. 

ADJUVANTS n=5 

Dahm 

2000 

20462757 

Not stated Non-cancer: six 

patients, cancer: 16 

patients 

Patients were consecutively included in the study 

when a) the pain dominated the patients' life totally, 

b) other methods to provide acceptable pain relief 

had failed, and c) the patients showed intolerance to 

and/or unacceptable side effects from opioids. 

Criteria for withdrawing patients from the study 

included: a) moribund patients and those with an 

estimated life expectancy shorter than the duration 

of the trial, b) those with an overt psychosis, making 

cooperation with the patient and assessment of 

treatment efficacy impossible. Criteria for 

withdrawing patients during the study were: a) 

patients who died before completion of the trial 

period and b) patients in whom a "secular" change 

occurred, i.e. a condition not under the researchers' 

control. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part IV

207 

Author 

Year 

UI 

Chronicity of 

cancer pain 

(range or 

average) 

Source of Pain 

(cancer / sequela of 

treatment / 

procedure related) Inclusion/Exclusion criteria 

Mercadante 

2000 

99032200 

Not stated Cancer Inclusion: patients with unrelieved pain by their 

dose of morphine and Karnofsky status of 50 or 

more were selected for this study. No adjuvant 

drugs had been previously used. Exclusion: 

patients with coexisting liver or renal disease or with 

encephalopathy. 

Lauretti 

1999 

99287592 

Not stated Cancer Inclusion: patients were suffering from cancer pain 

were systemic opioid/NSAID therapy was 

ineffective, or pain were presented with intolerance 

to systemic opioids. 

Lauretti 

1999 

99287592 

The period 

from the first 

dose of oral 

morphine 

administration 

until the time of 

the test drug 

administration 

was similar 

among groups 

and was 28-74 

days (range). 

Cancer Inclusion: cancer patients with pain for whom 

tramadol or NSAIDs were ineffective. Exclusion: not 

stated 

Van Dongen 

1999 

99452099 

Morphine 

group: mean 

pain intensity 

VAS initial 5-8 

(mean 7) 

Morphine plus 

bupivacaine 

group: VAS 

initial 6-10 

(mean 7.7) 

Cancer Patients with "refractory" malignant pain: 16/20 

inadequate pain relief with "analgesic ladder"; 4/20 

unacceptable side-effects (sedation in 3, nausea in 

1) 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part V

208 

Author 

Year 

UI 

Treatment of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes assessed 

(pain relief, QOL, 

etc) 

Instruments used for the assessment of 

studied effects 

NSAIDs VS NSAID n=1 

Pannuti 

1999 

99291253 

No other 

medication was 

given during the 

study 

Pain Intensity, 

nausea, sedation, 

rescue analgesic 

dose. 

Variables were assessed after single-dose 

administration (8 hr after administration) and at the 

end of a 7-day repeated dose administration 

period. Instruments used: VAS (0-10cm) and 5-

point Verbal Rating Scale (VRS; 0=no pain; 

1=mild; 2=moderate; 3=severe; 4=extreme pain). 

Three variables were assessed: 

1) AUC0-8-Area under the pain intensity timecurve, calculated as the sum of pain 

reductions (mm on VAS) during the 8-hr 

observation period, defining the overall 

efficacy after a single administration. 

2) ME, maximum drug efficacy, the difference 

between baseline pain intensity and minimal 

pain intensity observed during the 8-hr 

observation period. 

3) DE, duration of the efficacy, the number of 

hourly observations with pain intensity lower 

than baseline pain intensity. During multiple 

administration (7-day treatment) pain intensity 

and compliance were evaluated daily by selfreport assessment form, in which patients 

reported pain score (0-4, VRS) and tretment 

compliance (regular intake or not). Quality of 

life was assessed by the Spitzer test before 

the start of the study and at the end of each 

treatment. Overall drug efficacy of the two 

drugs was evaluated at the end of each 

multiple treatment by the patient and the 

investigator using a numerical 5-point scale 

(0=no relief, 1=inadequate relief, 2=moderate 

relief, 3=good relief, 4=complete relief). 

Adverse reactions were reported by the 

patient at each treatment. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part V

209 

Author 

Year 

UI 

Treatment of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes assessed 

(pain relief, QOL, 

etc) 

Instruments used for the assessment of 

studied effects 

OPIOID VS OPIOID n=6

Moolenaar 

2000 

20407008 

Acetaminophen 

(500 mg) 

Pain intensity, sideeffects and rescue 

medication, plasma 

levels of M, M-6-G 

and M-3-G at 0, 1, 2, 

4, 6 and 12 hr at day 

5 and day 10 

VAS, 0-10cm assessed by patient every 2 hr, 

side-effects and rescue medication were recorded.

Heiskanen 

2000 

21075895 

The respective 

oral solution 

was 

administered as 

escape 

medication in a 

dose 

approximately 

1/6 to 1/8 of the 

daily dose of CR 

oxycodone or 

CR morphine. 

Plasma levels of 

drugs and 

metabolites at the last 

day of each period of 

dosing and before the 

start of the next 

period. Plasma levels 

were determined at 0 

(before dosing), 1h, 

3h and 5h after 

dosing. 

Pharmacodynamic 

assessments at the 

same days and prior 

to dosing and 

determinations of 

plasma levels were 

pain intensity 

VASpi, 4-point verbal rating scale, subjective drug 

effect questionnaire and modified specific drug 

effect questionnaire. Phenotyping to determine 

CYP2D6 was also performed. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part V

210 

Author 

Year 

UI 

Treatment of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes assessed 

(pain relief, QOL, 

etc) 

Instruments used for the assessment of 

studied effects 

Hunt 

1999 

99414499 

Meperidine s.c. 

was used as a 

breakthrough 

pain medication 

using a dose of 

one/sixth of the 

24-hour sc 

infusion dose 

and a 

conversion 

factor of 

morphine 

sulfate 10 mg sc 

meperidine 100 

mg sc. Two or 

more doses of 

breakthrough 

medication in a 

24-hour period 

resulted in a 

30% increase in 

the sc infusion 

dose for the 

following day. 

Routine 

administration of 

nonopioid 

medication 

continued 

throughout the 6 

days of the 

study period. 

Pain intensity and 

pain relief, nausea, 

mental status, itching, 

hallucinations, 

myoclonus. 

Patients were asked three questions to quantify 

their pain at the end of the morning and afternoon 

shifts. 1) VAS, 0-10 pain intensity now, 2) VAS, 0-

10 pain intensity overall over the shift period, and 

3) Has the pain been controlled for 50% of the 

shift (Y/N). Pain scores and nausea scores (0-10, 

0 no nausea, 10 worst imaginable nausea) were 

recorded by nurses on a daily observation sheet. 

Mental status was assessed using the Saskatoon 

Delirium Checklist at the same times as pain 

intensity and nausea. A record of medication used 

during the study and the number of bowel 

movements were maintained for the 6 days of the 

study. Side-effects such as itching, myoclonus and 

hallucinations were asked about and recorded if 

present. Trail making and semantic fluency tests 

were used to assess cognitive function at the end 

of days 3 and 6. Overall preference for the first or 

the second opioid was recorded at the end of the 

sixth day. Venous blood samples for plasma drug 

concentrations were collected at the end of each 

72-hour period. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part V

211 

Author 

Year 

UI 

Treatment of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes assessed 

(pain relief, QOL, 

etc) 

Instruments used for the assessment of 

studied effects 

Bruera 

1999 

99349918 

Patients were 

allowed to 

receive extra 

doses of 

immediaterelease 

morphine as 

frequently as 

needed in the 

form of a tablet 

or a 

suppository, 

each such 

rescue dose 

being 

approximately 

10% of the daily 

opioid dose. 

Patients who 

required more 

than three 

rescue doses 

had their MSCRS dose 

increased and 

underwent a 

further 24-hr 

observation and 

dose 

stabilization 

period. 

a) pain intensity, b) 

sedation, c) nausea, 

d) overall 

effectiveness by 

patient and 

investigator, e) 

treatment preference, 

f) type, severity and 

frequency of adverse 

events was recorded 

a) pain intensity using a 5-point categorical 

scale, and 0-100mm VAS 

b) sedation using a 0-100mm VAS 

c) nausea using a 0-100mm VAS 

d) overall effectiveness of treatment was 

assessed by patient and investigator blindly 

using a 4-point categorical scale (0=not 

effective to 3=highly effective) 

e) treatment preference was blindly assessed at 

the completion of phase 2 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part V

212 

Author 

Year 

UI 

Treatment of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes assessed 

(pain relief, QOL, 

etc) 

Instruments used for the assessment of 

studied effects 

Mercadante 

1998 

99032200 

The use of other 

drugs was 

allowed. 

Nonopioid 

analgesics were 

continued if not 

contraindicated. 

No other 

information is 

available on 

breakthrough 

pain medication. 

a) performance status 

b) opioid starting 

dose (OSD) in 

milligrams at referral 

c) maximum dose of 

opioids (OMD) in 

milligrams d) days of 

opioid treatment e) 

adjuvant medication, 

which included 

nonopioid analgesics 

administered for at 

least 10 days and 

their doses f) 

symptoms associated 

with opioid therapy 

and or commonly 

present in patients 

with advanced 

cancer, such as 

nausea or vomiting, 

drowsiness, 

confusion or 

xerostomia 

g) pain intensity was 

measured using the 

patient's self report or 

a doctor's rated visual 

analogue scale 

h) pain syndromes 

were considered on 

the basis of clinical 

history, anatomic site 

of the primary tumor 

and known 

metastases, physiscal 

examination, and 

investigations when 

available. 

The following indices were calculated: 

a) opioid escalation index percentage (OEI%), 

the mean increase in the percentage of opioid 

dosage from OSD, using the formula ([OMDOSD]/OSD)/days X 100, 

b) opioid escalation index in milligrams 

(OEMmg), the mean increase of opioid 

dosage in milligrams, using the formula 

(OMD-OSD)/days, 

c) The effective analgesia scale (EAS) was 

calculated at fixed weekly intervals on the 

basis of the following formula: VASx - 

VASy)(1+O/10x)/(1+O/10y), where 1 indicates 

the administration of nonsteroidal antiinflammatory drugs at fixed times and at full 

dosage, O indicates the dosage in milligrams 

of the opioid used, VAS indicates the pain 

intensity on 0- to 10-cm scale, and x and y 

indicate the different weeks taken into 

consideration (for example the third versus the 

second week before death). This score 

monitors the analgesic consumption/pain relief 

ratio. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part V

213 

Author 

Year 

UI 

Treatment of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes assessed 

(pain relief, QOL, 

etc) 

Instruments used for the assessment of 

studied effects 

Parris 

1998 

99019888 

Patients who 

required 

supplemental 

analgesia were 

excluded. 

Patients 

needing titration 

of analgesic or 

supplemental 

medication were 

required to 

discontinue from 

the study. 

Primary efficacy 

measures were: 

a) mean pain intensity 

by day (the average 

of the four categorical 

scale ratings for pain 

intensity for each 

study day) b) mean 

acceptability of 

therapy by day (the 

average of the two 

categorical scale 

ratings for 

acceptability of 

therapy for each 

study day). Other 

efficacy measures 

included mean pain 

intensity and mean 

acceptability of 

therapy by time of 

day, overall mean 

pain intensity and 

acceptability of 

therapy and 

discontinuation rates 

both overall and by 

reason. Safety was 

evaluated by adverse 

effects obtained by 

questioning and/or 

examining the 

patients. 

Discontinuation rates 

because of adverse 

effects were 

determined. 

During the double-blind period patients rated: 

a) pain intensity in a diary four times daily: 

morning (overnight pain rating), midday (morning 

pain rating), evening (afternoon pain rating), and 

bedtime (evening pain rating). A four-point 

categorical (CAT) scale of 0=none, 1=slight, 

2=moderate, and 3 = severe was used for these 

ratings. 

b) acceptability of therapy considering both pain 

intensity and side-effects for both day and night. 

Acceptability of therapy was rated on a five-point 

CAT scale of 1=very poor, 2=poor, 3=fair, 

4=good,, and 5=ecxellent. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part V

214 

Author 

Year 

UI 

Treatment of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes assessed 

(pain relief, QOL, 

etc) 

Instruments used for the assessment of 

studied effects 

BREAKTHROUGH PAIN, n=1

Portenoy 

1999 

99165545 

Not applicable, 

because the 

study is on the 

treatment of 

breakthrough 

pain. 

The primary outcome 

data comprised pain 

scores collected 

during the treatment 

of one or two 

episodes of 

breakthrough pain 

during both baseline 

days and the 2 days 

following successful 

titration of the OTFC 

dose. 

Immediately before drug administration, patients 

recorded pain intensity using an 11-point 

numerical scale (0, no pain; 10, pain as bad as 

you can imagine). Measurements of pain intensity 

and pain relief were recorded at approximately 15, 

30 and 60 min after starting treatment. Pain relief 

was assessed using a four-point categorical scale 

(0, "none"; 4, "complete"). A global impression of 

the drug's performance which used a rating from 0 

(poor) through 4 (excellent), was recorded once 

daily. Adverse events were elicited by the study 

nurse at the time of each patient contact. Data on 

pain intensity, pain relief and global performance 

were averaged per patient and across patients for 

each phase of the study (baseline and titration 

phases). Pain intensity difference (PID) was 

calculated for three intervals (i.e. 0-15 min, 12-30 

min and 30-60 min). 

ADJUVANTS n=5

Dahm 

2000 

20462757 

During the IT 

treatment, the 

patients had ad 

libitum access 

to non-opioid 

analgesics/seda

tives and to 

opioids 

administered by 

the oral and/or 

parenteral route 

until they 

obtained 

acceptable pain 

and anxiolytic 

relief. 

a) daily doses of local 

ansthetics 

administered IT and 

of opioids 

administered by the 

oral/parenteral routes, 

expressed as mg 

parenteral morphineEq/day. b) selfreported pain 

intensity c) sleep 

pattern d) side-effect 

and complications 

(i.e. paresthesia, 

paresis, urinary 

retention, transient 

cerebral ischemic 

attacks, etc.) e) 

patients assessment 

of the trial periods. 

a) daily doses of local anesthetics administered 

IT and of opioids administered by the 

oral/parenteral routes, expressed as mg 

parenteral morphine-Eq/day. 

b) self-reported pain intensity 

c) sleep pattern 

d) side-effect and complications (i.e. paresthesia, 

paresis, urinary retention, transient cerebral 

ischemic attacks, etc. 

e) patients assessment of the trial periods. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part V

215 

Author 

Year 

UI 

Treatment of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes assessed 

(pain relief, QOL, 

etc) 

Instruments used for the assessment of 

studied effects 

Mercadante 

2000 

99032200 

Not stated a) pain intensity 

b) assessment of 

nausea, vomiting, 

drowsiness, 

confusion, and dry 

mouth 

c) Mental state 

d) arterial pressure 

e) side effects 

All outcomes were 

recorded before drug 

administration (T0), 

and 30 min (T30), 60 

min (T60), and 180 

min (T180) after. 

a) pain intensity (0-10 numerical scale) 

b) assessment of nausea, vomiting, drowsiness, 

confusion, and dry mouth (0-3 scale: not at all, 

slight, a lot, awful 

c) Mental state (Mini-Mental State Examination 

(MMSE) (0-30)). 

d) arterial pressure 

e) side effects 

Lauretti 

1999 

99287592 

Patients were 

free to 

manipulate and 

increase their 

daily morphine 

consumption by 

selfadministration 

only at the time 

the epidural 

study drug was 

added, in order 

to maintain VAS 

below 4/10. 

Duration of effective 

analgesia, incidence 

of adverse effects, 

consumption of 

morphine. 

Duration of effective analgesia was measured as 

time from the study drug administration to the first 

patient's VAS score >=4/10 recorded in days. 

Lauretti 

1999 

99287592 

After the test 

drug was 

introduced all 

patients were 

free to 

manipulate their 

daily morphine 

consumption by 

adding more 

morphine to the 

80- to 90- mg 

dose, to keep 

pain VAS less 

than 4. 

Daily morphine 

consumption, pain 

intensity, adverse 

effects. All 

measurements were 

repeated on days 1, 

5, 10, 15, 20, and 30 

after the test drug 

was introduced. 

VAS (0-10) for pain intensity. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part V

216 

Author 

Year 

UI 

Treatment of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes assessed 

(pain relief, QOL, 

etc) 

Instruments used for the assessment of 

studied effects 

Van Dongen 

1999 

99452099 

Not reported Pain intensity, side 

effects. 

Verbal rating scale, numerical rating scale, VAS; 

use of concomitant analgesics; quality of pain 

relief from general physician (frequency of 

assessment not reported); increase in IT morphine 

dose by linear regression analysis from day 10 to 

30 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part VI

217 

Author 

Year 

UI 

Outcomes (significant/ non-significant) as reported in 

the paper 

Comments 

NSAIDs VS NSAID n=1 

Pannuti 

1999 

99291253 

Ketorolac and diclofenac were both effective in reducing 

pain (in 77% and 76% patients respectively) and analgesic 

efficacy was observed at a median of 3 hr after the first drug 

administration. There were no significant differences in the 

overall analgesic efficacy, ME or DE in relation to the single 

administration of ketorolac and diclofenac. The Westlake 

90% confidence interval of the AUC0-8 ratio 

(ketorolac:diclofenac), of the ME ratio and of the DE ratio 

indicated the bioequivalence of the two drugs. The overall 

analgesic efficacy of the two drugs as assessed by 

investigators and patients did not differ significantly. The 

pattern and incidence of side-effects were comparable after 

the two treatments. 

This is a well designed, 

performed and reported 

study. One of the few studies 

that provides a detailed 

description of the power 

analysis performed to identify 

the number of patients to 

include. It is of note that no 

breakthrough pain or any 

other medication that might 

had interfered with the 

outcomes was administered 

during the study. A sequence 

effect was found in toxicity: 

gastrointestinal disorders 

(gastralgia, pyrosis and 

nausea/vomiting) after 

ketorolac were mainly 

observed (in 10 of 15 

observed events) when the 

drug was given to patients as 

a second treatment. 

OPIOID VS OPIOID n=6

Moolenaar 

2000 

20407008 

There were no significant differences in pain intensity score 

between oral and rectal forms within the two groups 

regardless of the treatment sequence. No treatment 

differences in nausea, sedation or the demand on escape 

medication between the oral and rectal forms were 

observed. None of the pk parameters apart for TmaxM6Gmet criteria for bioequevalnce, but there were no 

significant differences on pk variables for morphine. 

Significantly lower pk variables were observed after rectal 

administration. 

Very small group of patients. 

Heiskanen 

2000 

21075895 

The VASpi values during the last day of each stable phase 

showed no statistically significant differences between the 

treatments. An average of only four patients reported a 

verbal rating score (VRSpi) exceeding 1.0 (slight pain) 

during the last day of each treatment. The plasma 

oxycodone and morphine concentrations did not differ 

significantly, when the sequence of opioid administration 

was taken into account. There were no difference in the 

side-effects nausea, sedation, itch and dizziness. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part VI

218 

Author 

Year 

UI 

Outcomes (significant/ non-significant) as reported in 

the paper 

Comments 

Hunt 

1999 

99414499 

Patient preference: only 10 patients expressed a 

preference, 4 preferred morphine, and 6 preferred fentanyl 

(non significant difference). 

Pain intensity: there was no significant difference in the pain 

scores between the drugs overall. On a shift-by-shift 

analysis, the patients receiving morphine on the second 

shift of day 2 reported more pain than those patients 

receiving morphine on the same shift. No other differences 

were observed. 

Opioid consumption: overall, the morphine-first group had a 

lower had a lower dose of opioid throughout the study than 

those patients who received fentanyl first. Nausea: there 

was no significant difference in the prevalence of nausea 

between the two groups. 

Saskatoon delirium scores: there were no differences 

between the two groups. Semantic fluency and trail making: 

there were no significant differences between the two drugs 

in both tests. 

Bowel movements: the patients receiving fentanyl as the 

second drug demonstrated significantly more bowel 

movements than the patients on morphine. There were no 

differences in the first arm of the study. 

Seven patients withdrew due 

to confusion or hallucinations 

during the study. 

Bruera 

1999 

99349918 

There were no significant differences between groups in the 

intensity of symptoms (pain, nausea and sedation) overall 

opioid doses, and clinical effectiveness as assessed by 

patients and investigators, although pain scores during q24 

h dosing were numerically lower. There was no evidence of 

carryover effect. 

Of the 6 patients who were 

not evaluable, 5 withdrew in 

the titration phase (3 because 

of inadequate pain control, 1 

because of nausea, and 1 

because of severe bowel 

obstruction), and 1 patient 

withdrew during phase 1 

(q2hr) because upcoming 

surgery was available earlier 

than expected. 

Retrospectively, the authors 

calculated that their study 

could discern a difference of 

5.9mm in pain intensity with a 

power of 0.80. They comment 

that "since a difference of this 

maginitude is not likely to be 

clinically meaningful, this 

suggests that major 

differences in efficacy 

between the 12-hourly and 

24-hourly dosing are unlikely 

to be demonstrated even in a 

larger study. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part VI

219 

Author 

Year 

UI 

Outcomes (significant/ non-significant) as reported in 

the paper 

Comments 

Mercadante 

1998 

99032200 

Statistically significant differences were observed in all the 

indices used. Patients in the methadone group reported 

values significantly less than those observed in the 

morphine group. No dose escalation was reported in seven 

patients in the methadone group whereas only one patient 

in the morphine group did not require increasing doses of 

opioid. Eight patients in the morphine group had one or 

more gaps* in the EAS (six patients had one gap, one 

patient had two gaps, and one patient had three gaps). Only 

three patients in the methadone group had gaps in the EAS 

(two patients had one gap and one patient had two gaps). 

The mean VAS score and symptom intensity were similar 

between groups. 

*A rapid increase in the EAS score (increments of more 

than 100% when compared with that calculated the previous 

week) represents a gap, which corresponds to a stressful 

period of uncontrolled pain and rapid escalation. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part VI

220 

Author 

Year 

UI 

Outcomes (significant/ non-significant) as reported in 

the paper 

Comments 

Parris 

1998 

99019888 

Efficacy: 

a) Pain intensity. Mean (+/-SE) baseline pain scores did not 

differ between the CR-oxycodone and IR oxycodone groups 

and were slight to moderate. Mean pain intensity scores by 

day were slight to moderate in both groups throughout the 

study with some tendency towards decreased scores by day 

five. No significant differences in mean pain intensity were 

detected for any of the five study days. 

There were no significant differences between treatments in 

the mean pain scores either by time of day or overall. 

Eleven patients with neuropathic pain reported higher 

baseline pain intensity scores for both current pain 

(P<0.03) and pain over the past day (p=0.01) than patients 

with other pain types. Overall pain intensity scores in this 

group decreased from 2.0 at baseline to 1.6 compared with 

a decrease from 1.3 at baseline to 1.2 with patients with 

other pain types. 

b) mean baseline acceptability of therapy scores for both 

current acceptability and acceptability over the past day 

were fair to good and comparable for both treatment groups. 

There were no significant treatment differences in mean 

acceptability of therapy scores for any of the 5 study days or 

by time of day or in overall scores. c) sixty-six (59%) 

patients completed the 5 day study period; 37 (33%) 

discontinued. Discontinuation rates for bit treatment groups 

were equivalent. 

Safety: 

Of the 111 patients enrolled, 109 were evaluated for safety. 

Seventy-six (70%) (69% CR oxycodone and 70% IR 

oxycodone) reported at least one adverse event considered 

by the investigators to be at least possibly related to 

treatment. Differences in the incidence of patients reporting 

adverse events were not significant between treatment 

groups, although there was a trend toward less nausea, 

vomiting and sweating in patients receiving CR oxycodone. 

The sample size was 

sufficient to detect 40% 

difference in pain intensity 

between treatments with a 

statistical power equal to 0.80
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part VI

221 

Author 

Year 

UI 

Outcomes (significant/ non-significant) as reported in 

the paper 

Comments 

BREAKTHROUGH PAIN, n=1 

Portenoy 

1999 

99165545 

Analysis of pain scores following the first last doses of 

OTFC in all patients who underwent dose escalation 

demonstrated that the higher dose produced a significantly 

greater mean pain intensity difference (p<0.002) and pain 

relief (p<0.0001) at the 15 min assessment than the lower 

dose as well as better global rating (p<0.0001). A 

comparison of the time-action relationships of the usual 

rescue dose and the OTFC in successfully titrated patients 

(n=48) demonstrated a more rapid onset of analgesia 

following OTFC treatment. In this subgroup the decline in 

pain intensity during the initial 15 min period was 56% of the 

total pain reduction following OTFC and 32% of the total 

following the usual rescue dose (p<0.0001). The side 

effects associated with the OTFC were typical opioid-related 

events. These side effects during the days of administration 

of any dose of OTFC were somnolence (28%), dizziness 

(14%), nausea (10%) and headache (5%). During the last 

two days of OTFC when its dose had been appropriately 

titrated the side effects that occurred with a frequency of 

>=5% and were considered to be at least "possibly" related 

to the study drug again included somnolence (15%), 

dizziness (6%), and nausea (5%). 

Innovative study design. 

Detailed and clear reporting. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part VI

222 

Author 

Year 

UI 

Outcomes (significant/ non-significant) as reported in 

the paper 

Comments 

ADJUVANTS n=5

Dahm 

2000 

20462757 

Significantly higher daily doses for a similar degree of pain 

relief were used with the ropivacaine than with the 

bupivacaine treatment: means +/- standard deviation (SD) 

= 62 +/- 20 versus 48 +/- 45 mg/d (p<0.02). There was no 

statistically significant difference between the groups 

(p>0.8). There was no significant difference between the 

bupivacaine and ropivacaine treatments in non-opioid 

analgesic and sedative drug consumption scores. The VAS 

mean scores were significantly lower during the IT treatment 

than before it, but there was no statistically significant 

difference between the ropivacaine and bupivacaine 

regarding the VAS scores recorded during the IT treatment. 

Also there was no significant difference between the two 

groups in the inverse Bromage relaxation scores. Gait and 

ambulation pattern scores were similar before the start of 

the IT treatment and during both the ropivacaine and 

bupivacaine periods. Nocturnal sleep pattern scores 

improved significantly during the IT treatment and during 

both the ropivacaine and bupivacaine periods of the 

treatment (p<0.02 to p<0.057), but there was no statistically 

significant difference between the two groups. The daily 

cost of the IT ropivacaine treatment was significantly higher 

than that of IT bupivacaine; mean+/-1SD = $3.2 +/-1.0 and 

$1.2 +/- 0.6 respectively (p<0.003). No differences were 

found between the ropivacaine and bupivacaine treatments 

in the rates of side effects and complications. No significant 

differences between ropivacaine and bupivacaine were 

found in partial and total estimators, except a significantly 

higher dose of IT ropivacaine than of IT bupivacaine in the 

group of total estimators. No statistically significant 

differences were found with the exception that the pain 

intensity (VAS mean scores) in the patients with cancer pain 

was significantly lower during the IT bupivacaine treatment 

than during the IT ropivacaine treatment (p<0.05). Finaly 

there were no significant differences in trhe patients' 

assessments of the trial periods. 

The authors summarizing 

their findings suggest that 

"they do not support the 

hypothesis that IT infusion of 

0.5% ropivacaine might offer 

advantages over IT infusion of 

0.5% bupivacaine when 

administered for relief of the 

"refractory" pain from 

malignant or nonmalignant 

pathologic conditions. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part VI

223 

Author 

Year 

UI 

Outcomes (significant/ non-significant) as reported in 

the paper 

Comments 

Mercadante 

2000 

99032200 

Ketamine but not saline significantly reduced the pain 

intensity in almost all patients at both doses. A highly 

significant decrease in pain intensity was found in 

comparison to saline injection. The effect was evident at the 

end of the infusion and significantly persisted until T180. 

The analgesic effect of 0.50 mg/kg was significantly more 

intense than that of the 0.25 mg/kg ketamine at T180. 

Ketamine injection produced central adverse effects in 4 of 

10 patients. Hallucinations occurred in 4 patients (one 

patient after 0.25 mg/kg and 3 patients after 0.50 mg/kg of 

ketamine). Flashes and a buzzing feeling in the head and a 

sensation of insobriety were aslo reported by two patients. 

These episodes reversed after intravenous administration of 

1 mg diazepam. Two of these patients were globally 

considered unresponsive at the doses of ketamine for the 

short effect produced. Drowsiness was significantly more at 

T30 and T60 (p<0.01 and p<0.05, in the two ketamine 

groups respectively). The level of confusion was also 

significantly more pronounced in the two ketamine groups 

(p<0.05). No significant changes were observed in the 

MMSE. No significant changes were observed in arterial 

pressure. 

The authors conclude that 

ketamine improves morphine 

analgesia in difficult pain 

syndromes, namely 

neuropathic pain. However 

the occurrence of central side 

effects should be taken in to 

account especially when 

higher doses are used. 

Lauretti 

1999 

99287592 

Only patients in the ketamine group demonstrated lower 

VAS scores compared to morphine group (p=0.018). Time 

since the epidural study drug administration until patient 

complaint of pain >=4/10 was higher for both the ketamine 

(KG) and neostigmine (NG) groups compared to control 

group (CG) (KG>CG, p=0.049; NG>CG;p=0.0163). Only the 

ketamine group used less epidural morphine compared to 

the CG during the study (25 days) (p=0.003). 

Lauretti 

1999 

99287592 

The VAS scores were similar among groups before the oral 

morphine treatment. The VAS pain scores after the study 

drug was introduced were not significantly different among 

groups. Regarding the daily oral morphine consumption: on 

day 15 only the ketamine group had significantly lower 

morphine consumption compared to control group; on days 

20 and 30 both the ketamine and nitroglycerin groups had 

significantly lower consumption compared to control. The 

dipyrone group did not differ significantly from control group 

in the consumption of morphine. The incidence of adverse 

events did not differ between the groups. 
Evidence Table 9. Randomized Controlled Trials on Drug Treatments 

for the Management of Cancer Pain – Part VI

224 

Author 

Year 

UI 

Outcomes (significant/ non-significant) as reported in 

the paper 

Comments 

van Dongen 

1999 

99452099 

VAS during stable phase reduced in all patients compared 

with initial; good pain relief in all patients; reduction in need 

for concomitant drugs, no supplemental drugs & control with 

IT therapy alone morphine: 2/9, morphine plus bupivacaine: 

5/11. One patient in the morphine group required oral 

morphine - dose not reported; 19/20 patients received no 

oral morphine after initial titration. Five patients transferred 

from the morphine group to the combined treatment Side 

effects in the morphine group were: urinary retention 1/9; 

nausea 1/9; post-spinal headache 1/9; arm weakness 1/9; 

depression 1/9; sedation 1/9. Side effects in the morphinebupivacaine group were leg weakness 3/11 (one did not 

effect mobilization; 2 bed ridden); post-spinal headache 

2/11; nausea 2/11. No comparison in side effects is 

reported. The dose progression in morphine alone was 

significantly higher (slope of linear regression line) than in 

morphine/bupivacaine group (0.05 vs 0.0003, p=0.0001). 

An open label study and a 

double-blind study are 

reported. 
Evidence Table 10. Randomized Controlled Trials on the Efficacy of 

Bisphosphonates for the Management of Cancer Pain – Part I

225 

Author 

Year 

UI 

Studied treatment(s) 

(Rx, dose, route) 

N of 

study 

arms 

Study Design 

(cross-over, cohort, 

etc) 

EDTMP

Tian 

1999 

99134535 

Samarium-153 ethylene diamine tetramethylene 

phosphonate 37 MBq/kg versus samarium-153 

EDTMP 18.5 MBq/kg single dose, i.v. No other tumororiented tx was allowed. 

2 Parallel 

Clodronate 

Arican 

1999 

99456328 

800 mg/d oral clodronate 

versus 1600 mg/d oral clodronate versus control (not 

stated). Tid. 

Duration 3 mos. 

3 Parallel 

Pamidronate 

Lipton 

2000 

20164356 

Disodium (3-amino-1-hydroxy-propyliden) 1.1 

bisphosphonate (disodium pamidronate) 90 mg versus 

placebo i.v. 

Follow-up 24 mos. 

2 Parallel; 

longterm FU of 2 

RCTs 

Hultborn 

1999 

20095088 

Disodium (3-amino-1-hydroxy-propyliden) 1.1 

bisphosphonate (di-sodium pamidronate) 60 mg 

versus placebo i.v. 

Duration 2yr. Antitumor tx given at the discretion of dr. 

2 Parallel 

Koeberle 

1999 

99124160 

Disodium (3-amino-1-hydroxy-propyliden) 1.1 

bisphosphonate (disodium pamidronate) 60 mg versus 

90 mg i.v. 

Every 3 wk for 6 cycles. Antitumor tx given at the 

discretion of physician 

2 Parallel 
Evidence Table 10. Randomized Controlled Trials on the Efficacy of 

Bisphosphonates for the Management of Cancer Pain – Part II

226 

Author 

Year 

UI 

Randomization 

method Blinding 

Total N 

(evaluable)

Mean or median age or range 

 (% male) 

EDTMP

Tian 

1999 

99134535 

Not stated single-blind (only 

immediate family & 

referring physician 

informed) 

105 Group1 = 57.0 

Group 2 = 57.3 (30-82) 65.7% male 

Clodronate

Arican 

1999 

99456328 

Not stated Not stated 50 55.6 (27-70) 

20% male 

Pamidronate

Lipton 

2000 

20164356 

Computer 

generated list 

Double blind 754 Not stated 

Hultborn 

1999 

20095088 

Permuted blocks Double blind 404 Group1 = 59.7 

Group2 = 58.8 

Koeberle 

1999 

99124160 

Not stated Double blind 70 62.5 (38-82) 

40% male 
Evidence Table 10. Randomized Controlled Trials on the Efficacy of 

Bisphosphonates for the Management of Cancer Pain – Part III

227 

Author 

Year 

UI Type(s) of Cancer Baseline Pain Severity

Type of pain (neuropathic, 

somatic, visceral) 

EDTMP 

Tian 

1999 

99134535 

Lung 39% 

Breast 13% 

Esophagus 14% 

Prostate 11% 

Kidney/bladder 5.7% 

72 patients were using 

analgesics 2-8 

doses/day 

Bone pain 

Clodronate

Arican 

1999 

99456328 

Breast 68% 

NSLC 22% 

Stomach 6% 

Colorectal 4% 

Not stated Bone pain 

Pamidronate

Lipton 

2000 

20164356 

Breast cancer Stage IV Not stated Bone pain 

Hultborn 

1999 

20095088 

Breast cancer At entry, 34% patients in 

active treatment group 

used opiates, 36% in 

placebo group. 

Bone pain 

Koeberle/ 

1999 

99124160 

Breast cancer 58.6% 

Mult Myeloma 22.9% 

Other tumors 

Mean analgesic score at 

baseline = 3. 

On average patients had 

considerable residual 

pain despite full dose of 

NSAID (diclofenac 200 

mg/day) in combo 

w/opioid. 

Bone pain 
Evidence Table 10. Randomized Controlled Trials on the Efficacy of 

Bisphosphonates for the Management of Cancer Pain – Part IV

228 

Author 

Year 

UI 

Chronicity of 

cancer pain 

(range or 

average) 

Source of Pain 

(cancer / sequela of 

treatment / 

procedure related) Inclusion/Exclusion criteria 

EDTMP

Tian 

1999 

99134535 

Not stated Cancer/bone 

metastases 

No criteria organ dysfunction; 

No irradiation/hormone treatment or 

chemotherapy within 6 wk 

Clodronate 

Arican 

1999 

99456328 

Not stated Cancer/bone 

metastases 

Life expectancy <3 mos, previous 

bisphosphonates, radiotherapy within 4 wk, 

new chemotherapy or hormone therapy within 

4 wk, ECOG status between 3-4, 

hypercalcemia or renal function test abnormal, 

any metabolic bone diseases 

Pamidronate

Lipton 

2000 

20164356 

Not stated Cancer/bone 

metastases 

Patients previously treated with 

bisphosphonates, manifesting hypercalcemia, 

patients <9 mos life expectancy and no renal, 

hepatic, or cardiac impairment 

Hultborn 

1999 

20095088 

Not stated Cancer/bone 

metastases 

Not stated 

Koeberle/ 

1999 

99124160 

Not stated Cancer/bone 

metastases 

No bisphosphonate treatment within 2 months 

from enrollment 
Evidence Table 10. Randomized Controlled Trials on the Efficacy of 

Bisphosphonates for the Management of Cancer Pain – Part V

229 

Author 

Year 

UI 

Treatment of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes assessed 

 (pain relief, QOL, 

etc) 

Instruments used for the assessment of 

studied effects 

EDTMP

Tian 

1999 

99134535 

Vaious analgesics, 

Chinese herbs 

Pin score, change in 

analgesic 

consumption, blood 

counts, organ 

function tests 

Analgesic consumption & symptoms 

recorded by VAS; SEP (sum of effect 

product calculated based on pain score and 

time after tx.); Karnovsky; PGA (Physicians 

Global Assessment) 

Clodronate

Arican 

1999 

99456328 

Naproxen, 

Morphine sulfate 

pain score, 

performance status, 

analgesic use 

pain score (0-10), performance status accord 

to ECOG criteria, analgesic use scored by 0-

3 scale; VAS 

Pamidronate

Lipton 

2000 

20164356 

Wide range of 

hormonal, 

cytotoxic 

medications 

Pain score, analgesic 

scores, ECOG 

performance status, 

QOL 

Bone pain evaluated by quantifying severity 

& frequency; bone pain score determined by 

multiplying bone pain severity by bone pain 

frequency. Analgesic use assessed as 

composite narcotic score by multiplying type 

of medication by frequency. Spitzer QOL 

index. 

Hultborn 

1999 

20095088 

Not stated Pain progression free 

survival 

VAS 

Koeberle/ 1999 

99124160 

Not stated Pain intensity, pain 

score, analgesic 

score, ECOG 

performance status 

Pain score rated by analogy with WHO 

advice for grading toxic effects (0-4). 

Analgesic medications recorded w/5 pt score. 

Scores for pain (WHO)m analgesia (WHO 

modified), & ECOG added together into 

baseline PPA score. VAS pt self-judgment 

scores for pain intensity, pain frequency, 

general well-being. 
Evidence Table 10. Randomized Controlled Trials on the Efficacy of 

Bisphosphonates for the Management of Cancer Pain – Part VI

230 

Author 

Year 

UI 

Outcomes (significant / nonsignificant) as reported in 

the paper Comments 

EDTMP

Tian 

1999 

99134535 

83%pts w/higher dose had positive response & 86% 

patients/lower dose.88% patients who took analgesics 

reduced consumption. Flare phenomenon (temp increase in 

pain after radionuclide) observed in 24% patients exposed 

in high dose patients. 

Appropriate dose needs 

more testing. 

Clodronate

Arican 

1999 

99456328 

Significant decreases in pain score of clodronate gps 

compared to control (P=0.024, P=0.007). Pain score 

decreased in 5 patients in control versus 13 patients in 

each clodronate group. Non narcotic analgesic use 

decreased in 11 patients of low dose gp (P=0.038) and 8 

patients in high dose g (P>0.05).Pain score increased in 5 

patients in control versus 3 patients in each active group. 

Low dose oral clodronate 

is as effective as high 

dose. Control group makeup or treatment unclear. 

Pamidronate

Lipton 2000 

20164356 

Pain score significantly worse in placebo group (P=0.015 

over 24 mos, P=<0.001 since last visit). Analgesic score 

significantly worse in placebo group (P=<0.001 over 24 

mos, P=<0.001 since last visit). 

Hultborn 

1999 

20095088 

Pain progression free survival significant in favor of 

pamidronate (P=0.006). Patents' self-judgment of pain 

favored pamidronate, no significant results. Proportion of 

patients on opiates during study was 37% in active 

treatment group (up from 34%), 55% in placebo group (up 

from 36%), but not statistically significant (P=0.14). 

Koeberle 

1999 

99124160 

After 1 infusion, a mean reduction in pain intensity 

observed in 60mg group, 14% in 90mg. Mean reduction 

after 3 was 23.8% in 60mg p, 29.8% in 90mg group: no 

statistically significant (P=0.8). 60% 60mg group and 63% 

in 90mg classified as pain responders. Median duration of 

pain similar in both. Median times to pain response were 

5.8 wk in 60 group, 5.5 wk in 90. Mean analgesic score 

remain unchanged in majority of responders while 26% had 

reduction. Significant reduction in pain intensity after 2 

infusions observed in patients with severe pain with both 

treatments (P<0.01) but not in patients with moderate pain. 

WHO analgesic score improved in 16% of 60mg group and 

23% of 90 mg group, no significant difference. 
Evidence Table 11. Randomized Controlled Trials on the Efficacy of 

Chemotherapeutic agents for the Management of Cancer Pain – Part I

231 

Author 

Year 

UI 

Studied treatment(s) 

(Rx, dose, route) N of study arms

Study Design (cross-over, 

cohort, etc) 

Kantoff 

1999 

20030045 

Mitoxantrone 14mg every 3 wks + 

hydrocortisone po 40mg/d versus 

hydrocortisone alone (CALBG 9182 trial) 

2 Parallel 

Osoba 

1999 

20029930 

 

Mitoxantrone 12mg iv x 3wks + 

prednisone 5mg po bid versus 

prednisone alone. Patients on prednisone 

alone who had no improvement in pain 

after 6 wk were eligible to add 

mitoxantrone to prednisone. 

2 Parallel 

Detailed QOL analysis of 

previously published paper 

Kramer 

2000 

20389251 

Paclitaxel 200mg by 3hr infusion q 3wks 

until progression, followed by doxorubicin 

75mg (max 7 cycles) iv bolus q 3wks 

compared w/reverse regimen doxorubicin 

followed by paclitaxel (EORTC 10923) 

2 Phase II/III crossover 

Small 

2000 

2020496 

Suramin versus placebo. Suramin 1000 

mg in 2 hr infusion day 1. 1 hr infusions of 

400, 300, 250, 200 mg given on days 

2,3,4,5 followed by 275 mg infusions x2 

wks, then once wkly for wks 8-12. 

Hydrocortisone 40mg/d to all patients. 

2 Parallel 

Fossa 

2000 

20229671 

Bilateral orchiectomy vs bilateral 

orchiectomy followed by 1 wk mitomycin 

15mg iv q 6 wks EORTC Trial 

30893 

2 Parallel 

Riccardi 

2000 

20184074 

Epirubicin 60mg iv versus epirubicin 

120mg iv on d1 every 21d (6 cycles max). 

In effect, single dose epirubicin versus 

double dose epirubicin as part of regimen 

containing fixed 5-FU and 

cyclophosphamide. The double dose 

epirubicin arm also received GCSF. 

2 Parallel Phase II 
Evidence Table 11. Randomized Controlled Trials on the Efficacy of 

Chemotherapeutic agents for the Management of Cancer Pain – Part II

232 

Author 

Year 

UI 

Randomization 

method Blinding 

Total N 

(evaluable) 

Mean or median age or range (% 

male) 

Kantoff 

1999 

20030045 

Not stated Not blinded 242 

(242) 

72 

100% (male) 

Osoba 

1999 

20029930 

Not stated Not blinded 161 

(161) 

68 (63-75) 

100% (male) 

Kramer 

2000 

20389251 

Minimization 

technique 

Information 

published in 

previous paper

331 

(294) 

Information published in previous 

paper 

Small 

2000 

2020496 

Not stated Double blind 458 68 median (38-87) 

100% (male) 

Fossa 

2000 

20229671 

Minimization 

technique 

Double blind 113 Stratified 

100% (male) 

Riccardi 

2000 

20184074 

Computerized 

procedure 

Double blind 74 54 (29-68) 

0% (male) 
Evidence Table 11. Randomized Controlled Trials on the Efficacy of 

Chemotherapeutic agents for the Management of Cancer Pain – Part 

III

233 

Author 

Year 

UI Type(s) of Cancer 

Baseline Pain 

Severity 

Type of pain (neuropathic, 

somatic, visceral) 

Kantoff 

1999 

20030045 

Hormone-refractory prostate cancer Not stated Bone Pain 

Osoba 

1999 

20029930 

Metastatic prostate cancer Not stated Bone Pain 

Kramer 

2000 

20389251 

Advanced breast cancer Not stated Bone Pain 

Small 

2000 

2020496 

Symptomatic hormone-refractory 

prostate cancer 

Not stated Bone Pain 

Fossa 

2000 

20229671 

poor prognosis M1 prostate cancer Not stated Bone Pain 

Riccardi 

2000 

20184074 

Advanced breast cancer Not stated Bone Pain 
Evidence Table 11. Randomized Controlled Trials on the Efficacy of 

Chemotherapeutic agents for the Management of Cancer Pain – Part 

IV

234 

Author 

Year 

UI 

Chronicity of 

cancer pain (range 

or average) 

Source of Pain (cancer 

/ sequela of treatment / 

procedure related) Inclusion/Exclusion criteria 

Kantoff 

1999 

20030045 

Not stated Bone metastases 75% 

Lymph nodes: 20% 

Lung: 8% 

Liver:11% 

Information published in previous paper: 

inadequate hepatic, renal, and bone 

marrow function; anti-androgen 

withdrawal before start of trial 

Osoba 

1999 

20029930 

Not stated Bone metastases 96% 

Lymph nodes: 16% 

Visceral:3% 

Other:9% 

Information published in previous paper 

Kramer 

2000 

20389251 

Not stated Not stated Not stated 

Small 

2000 

2020496 

Not stated Not stated Systemic corticosteroids, any prior nonhormonal systemic treatment, 

radiotherapy w/in 28 days, strontium-89 

therapy within 90 days, prior malignancy 

Fossa 

2000 

20229671 

Not stated Not stated Not stated 

Riccardi 

2000 

20184074 

Not stated Not stated Information published in previous paper 
Evidence Table 11. Randomized Controlled Trials on the Efficacy of 

Chemotherapeutic agents for the Management of Cancer Pain – Part V

235 

Author 

Year 

UI 

Tx of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes 

assessed 

(pain relief, 

QOL, etc) 

Instruments used for the assessment of studied 

effects 

Kantoff 

1999 

20030045 

Not stated QOL at 6wks, 

12 wks, q12 

wks; pain 

frequency and 

severity 

Functional Living Index-Cancer (FLIC): 22 items (1-7); 

sub-scales included well-being (12 items), emotional 

state (5), family disruption (2). Symptom Distress 

Scale, 11 items (1-5) incl 2 items for pain, how often, 

how severe. Impact of Pain on Daily Acitivities, 7 items 

(0-10). 

Osoba 

1999 

20029930 

 

Analgesic 

medications 

adjusted to give 

opt pain control 

Pain relief, 

QOL 

Patients examined every 3 wks. PROSQOLI Linear 

Analog Self-Assessment scores; Analgesic score 

calculated from pts' diaries; Present Pain Intensity 

Scale of McGill Pain Questionnaire (6 pt); EORTC 

QLQ-C30 (30 items w/5 domains + 3 symptoms 

domains) and QOLM-P14 (14 items) 

Kramer 

2000 

20389251 

Not stated longitudinal QL 

measurement 

EORTC QLQ-C30 (30 items w/5 domains, physical, 

role, emotional, cognitive, social + 3 symptoms 

domains, fatigue, nausea/vomiting, pain, and global QL 

scale):30 self-rating items (0-100) ; Rotterdam 

Symptom Checklist (RSCL) w/4 scales: physical 

symptom distress, Psychological distress, activity level, 

overall QL, 4 pt scale 0-100. 6 added items included 

VAS for global QOL. 

Small 

2000 

2020496 

Opioid 

analgesics 

Pain and opioid 

analgesic use; 

QOL; 

performance 

status 

Brief Pain Inventory (0-10); Pain Responder Analysis 

(11 pt scale w/div into 3 ranges, 0-4, 4-7, 7-10); 

Functional Assessment of Cancer Therapy-General 

(FACT-G), 5 patient-rated domains, physical wellbeing, functional well-being, social well-being, 

emotional well being, relationship w/dr. Revised Rand 

Functional Limitations Scale (RRFLS):patients' 

activities (scale 8-40). 

Fossa 

2000 

20229671 

Not stated QOL 

assessment 

EORTC QLQ-C30 (30 items w/5 domains, physical, 

role, emotional, cognitive, social + 3 symptoms 

domains, fatigue, nausea/vomiting, pain, and global QL 

scale):30 self-rating items (0-100) ;Global Health Status 

/QL scale 

Riccardi 

2000 

20184074 

Not stated QOL EORTC QLQ-C30 (30 items w/5 domains, physical, 

role, emotional, cognitive, social + 3 symptoms 

domains, fatigue, nausea/vomiting, pain, and global QL 

scale):30 self-rating items (0-100); QLQ-BR-23 (23 

questions, w/2 functional scales body image and 

sexuality and 3 symptom scales. Pt responses based 

on 2, 4, 7 pt scales w/max value 100. Spitzer's QL 

index which covers 5 ares, 2 pts each dimension. 
Evidence Table 11. Randomized Controlled Trials on the Efficacy of 

Chemotherapeutic agents for the Management of Cancer Pain – Part 

VI

236 

Author 

Year 

UI Outcomes (significant / nonsignificant) as reported in the paper Comments 

Kantoff 

1999 

20030045 

No statistically significant differences in global QOL (total FLIC score), 

problems of daily activity, and summary score of impact of pain scale. 

There was indication of better QOL in M+H arm. Differences in FLIC 

emotional scale sub-scale (P=.04), FLIC family disruption scale 

(P=.02), and frequency of pain (P=.06) severity (P=.03) all favored 

M+H arm. Symptom distress scale favored HC alone. 

Osoba 

1999 

20029930 

 

There was a trend towards higher analgesic score for M+P patients. 

Details indicated no apparent differences in any functioning scales. 

After 6 wks, only 62 of 81 patients in P arm remained, compared to 

71/80 patients with M+P. 48 patients crossed over to M+P. Of patients 

who remained on tx after 6 wks, P patients improved in social 

functioning, global QOL and the impact that pain had on mobility 

(P=.01) compared with baseline scores. M+P patients improved in 

physical functioning, social functioning, global QOL, pain, the impact of 

pain on mobility, the degree of pain relief. 6 wks after adding M, the 

crossover gp (n=35) improved in pain, and impact of pain on mobility 

(.0001<P<.01). After 12 wks, there was no statistically significant 

improvement compared with baseline in any HQL scores in P patients, 

but there was insignificant decrease in pain (P=.05). Patients 

continuing M+P tx since randomization (n=54) showed continuing 

improvement over baseline in 4 functioning scores (.0001<P<.004), 

global QOL (P=.009), and 9 symptoms (.0001<P<.01). The crossover 

group (n=25) improved in global QOL (P=.003) and pain relief 

(P=.0001). After 18 wks, patients with P (n=19) improved only on 

impact of pain on mobility (P=.004) compared with baseline. Those 

with M+P (n=43) improved in 11/14 function and symptom scales. 

Crossovers (n=17) had improvement in pain, impact of pain on mobility 

and pain relief (.001<P<.003). 

Kramer 

2000 

20389251 

On RSCL, there were significant differences between treatment arms 

at the end of cycle 3 observed for bone pain (worse in paclitaxel arm, 

P=0.042); bone pain was present in 58% patients on paclitaxel and in 

41% on doxorubicin. For both txs, QLQ-C30 recorded improvements in 

emotional function and pain. There were no statist signif differences in 

any variable. For bone pain, RSCL showed borderline significance 

(P=0.053) with improvement in bone pain for those on doxorubicin and 

deterioration in those on paclitaxel. This finding contrasts with general 

questions on pain in QLQ-C30 which showed mean improvement in 

both arms (P=0.086). QLQ-C30 showed a trend towards less pain in 

doxorubicin arm between baseline and cycle 3, especially for bone 

pain. There was a trend towards decreasing mean pain score (less 

pain) in D arm and increasing mean pain score (especially bone pain) 

in P arm in those receiving more than 3 cycles. 
Evidence Table 11. Randomized Controlled Trials on the Efficacy of 

Chemotherapeutic agents for the Management of Cancer Pain – Part 

VI

237 

Author 

Year 

UI Outcomes (significant / nonsignificant) as reported in the paper Comments 

Small 

2000 

2020496 

Averaging pain and narcotic rank scores, suramin + HC was superior 

to placebo + HC at both 6 wks and EOT (P=.0001). Suramin plus HC 

was also superior in univariate rank testing of each of the individual 

parameters at 6 wks and EOT (P<.007). Parametric ANCOVA results 

comparing mean changes from baseline at both time points revealed 

reductions for both treatment, but reductions were larger for suramin + 

HC at both 6 wks (P=.023) and EOT (P=.0008.) ANCOVA results also 

showed that although narcotic use increased for patients receiving 

either tx, the increase for placebo + HC patients was higher at both 6 

wks (37.5 v 16.5 mg morphine) and EOT (54.1 v 32.4 mg), but results 

were not statistically significant. In Pain Responder Analysis, a signif 

higher percentage of patients on suramin achieved a pain response 

(43% v 28%: P=.005). Proportion of patients with pain response based 

on pain reduction alone was superior in suramin patients (24% v 13%, 

P=.005), as was proportion of patients with pain response based on 

reduction in narcotic analgesic intake alone (37% v 23%, P=.001). 

Proportion of patients with pain response based on both pain reduction 

and reduction in opioid analgesic intake was also superior in suramin 

group (18% v 8%, P=.001). Kaplan-Meier estimate of duration of pain 

response among pain responders was significantly longer for suramin 

patients (P=.0027) with estimated median duration of 240 days vesrus 

 69 days 

Fossa 

2000 

20229671 

In both arms, pain improved significantly within first 12 wks after 

randomization. The baseline mean scale score for pain and overall QL 

were slightly better in ORCH group than in ORCH+MMC arm, but 

differences were not significant. Compared with patients on ORCH 

arm, the use of adjuvant mitomycin C was associated with significant 

reduction in global health status/QL and with impairment in 7 of 11 QL 

dimensions of questionnaire. Some QL improvement was seen after 

discontinuation of MMC. 

The use of 

adjuvant 

mitomycin C not 

recommended as 

adjuvant tx due to 

negative impact on 

QL. 

Riccardi 

2000 

20184074 

There was no significant ? baseline score between low dose and high 

dose patients for either functioning or symptom items. The mean 

global QLQ-C30 QL improved over time, to a greater degree in high 

dose patients (by 8.9 points) than in low dose patients (by 2.5 points). 

Three months after chemotherapy, pain score was reduced with 

respect to baseline (P=0.003), by 14 (P=0.009 over baseline), and 9 

(P=0.06 over baseline) in high dose patients, with no significant 

difference between arms. Functional parameters improved to a lesser 

degree. Among QLQ-BR23 scales, body image score deteriorated 

over time, but without statistical significance. With regard to Spitzer/QL 

index, high dose patients showed substantial stability but worse for low 

dose patients. 
Evidence Table 12. Randomized Controlled Trials on the Efficacy of 

Radiation Treatments for the Management of Cancer Pain – Part I

239 

Author 

Year 

UI 

Studied treatment(s) 

(Rx, dose, route) 

N of 

study 

arms 

Study Design (cross-over, 

cohort, etc) 

Adequacy of concealment 

"The bone pain 

trial working 

party" 

1999 

20043645 

Comparison of long-term benefits and 

short-term side effects of: 

a) a single fraction of 8 Gy 

b) a multi-fraction radiotherapy 

in cancer patients with painful skeletal 

metastases 

2 Parallel 

Duration: 12 months 

Roos 

2000 

20171357 

Comparison of the benefit of: 

a) a single fraction of 8 Gy 

b) a multi-fraction regiment (20 Gy in 5 

fractions) 

in cancer patients with neuropathic 

bone pain. An interim report. 

2 Parallel 

Duration: ongoing 

Steenland 

1999 

20043644 

Comparison of effectiveness of: 

a) a single fraction of 8 Gy X1 

b) a multi-fraction regiment (4 Gy X 6 

fractions) 

in cancer patients with painful bone 

metastases. 

2 Parallel 

Duration: 60 weeks 

Whelan 

1999 

20283039 

Comparison of the effect breast 

irradiation (12.5 Gy X 5) versus no 

further treatment on quality of life, 

including cosmetic outcome in patients 

with lymph node negative carcinoma 

who had undergone lumpectomy and 

axilary lymph node dissection. 

2 Parallel 

Duration: two phases; 0-2 months 

and 2 months to 2yr 
Evidence Table 12. Randomized Controlled Trials on the Efficacy of 

Radiation Treatments for the Management of Cancer Pain – Part II

240 

Author 

Year 

UI 

Randomization 

method Blinding 

Total N 

(evaluable) 

Mean age or range and 

(%) male 

"The bone 

pain trial 

working 

party" 

1999 

20043645 

Randomization 

performed via 

telephone or fax. 

No other 

information stated 

Not blinded 761 (761 at baseline; 

364 at six months; 

226 at 12 months) 

Median (range) = 67 (20-

91) 

52% male 

Roos 

2000 

20171357 

The randomization 

charts were based 

on an adaptive 

biased coin 

procedure 

Not blinded 90 (90) Median (range) = 68 (37-

89) 

Steenland 

1999 

20043644 

Not stated Not blinded 1171 (variable 

depending on the 

progress of the 

study) 

Median (range) = 65 (32-

89) 

54% male 

Whelan 

1999 

20283039 

Not stated Not blinded 837 (91% for the first 

phase, 75% for the 

second phase) 

Median (range) = 65 (32-

89) 

0% male 
Evidence Table 12. Randomized Controlled Trials on the Efficacy of 

Radiation Treatments for the Management of Cancer Pain – Part III

241 

Author 

Year 

UI Type(s) of Cancer 

Severity of pain of included 

patients 

Type of pain (neuropathic 

somatic visceral) 

"The bone 

pain trial 

working 

party" 

1999 

20043645 

Breast: 273 (36%) 

Prostate: 260 (34%) 

Lung: 89 (12%) 

Unknown primary: 20 

(3%) 

Other: 119 (15%) 

None: 32 (4%), mild 211 

(29%), moderate 325 (44%), 

severe: 168 (23%). 

bone pain 

Roos 

2000 

20171357 

Breast: 10% 

Prostate: 34% 

Lung: 28% 

Unknown primary: 6% 

Other: 22% 

mild 16%, moderate 42%, 

severe 38%, unknown 3%. 

bone pain 

Steenland 

1999 

20043644 

Type Group 4Gy, 8Gy 

Breast: 38%, 40% 

Prostate: 24%, 22% 

Lung: 25%, 25% 

Other: 13%, 13% 

Pain score at admission: 6.30 

on a 11-point scale 

bone pain 

Whelan 

1999 

20283039 

Breast: 100 % 

 

Not stated pain due to irradiation 
Evidence Table 12. Randomized Controlled Trials on the Efficacy of 

Radiation Treatments for the Management of Cancer Pain – Part IV

242 

Author 

Year 

UI

Chronicity of 

cancer pain 

(range or 

average) 

Source of Pain 

(cancer / sequela of 

treatment / 

procedure related) Inclusion/Exclusion criteria 

"The bone 

pain trial 

working 

party" 

1999 

20043645 

Not stated Cancer metastases Inclusion: histological and cytological diagnosis of 

malignant disease, age over 18 years, a clinical 

diagnosis of skeletal pain due to malignant disease, 

willingness on the part of patient to complete 

questionnaires for 12 months. 

Exclusion: pathological fracture of long bones, 

previous radiation therapy to the index site and 

earlier entry into the same trial for pain at a 

different site. 

Roos 

2000 

20171357 

Not stated Cancer metastases Inclusion: plain x-ray and/or bone scan evidence of 

osseous metastases, expected survival at least 6 

weeks, no previous radiation therapy to the index 

site, no clinical/radiological evidence of cord or 

cauda equina compression, no change in systemic 

anticancer treatment within 6 weeks before the 

proposed radiation therapy, ability to complete pain 

chart. 

Steenland 

1999 

20043644 

Not stated Cancer metastases Inclusion: at least 2 on a 11-point pain intensity 

scale, bone metastases treatable in one target 

volume. 

Exclusion: prior radiation, pathological fracture, 

spinal cord compression, malignant melanoma or 

renal cell carcinoma, patients with metastases at 

cervical sites. 

Whelan 

1999 

20283039 

Not stated Breast pain due to 

radiation 

Inclusion: patients with breast carcinoma treated by 

lumpectomy and axilary lymph node dissection, 

tumor size<= 4 cm in diameter, local excision 

microscopically complete, no evidence of histologic 

involvement of axilary lymph nodes. 
Evidence Table 12. Randomized Controlled Trials on the Efficacy of 

Radiation Treatments for the Management of Cancer Pain – Part V

243 

Author 

Year 

UI 

Tx of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes 

Assessed 

(pain relief, 

QOL, etc) 

Instruments used for the assessment of studied 

effects 

"The bone 

pain trial 

working 

party" 

1999 

20043645 

Not stated Pain 

intensity, 

analgesic 

consumption, 

adverse 

effects. 

For pain intensity patients were given a questionnaire that 

included a body plan on which patients marked the area of 

pain, a question relating to pain severity over the previous 

24-h period scored on a 4-point graded scale (none, a 

little, quite a bit, very much) and a record of analgesics 

and co-analgesics. Post treatment assessments of pain 

and analgesic usage were collected at 2 weeks and at 

1,2,3,4,5,6,8,10 and 12 months after the start of treatment. 

Patients were given diary cards on which to score nausea 

and vomiting as separate items using 4-point graded 

scales (none, a little, quite a bit, very much) daily for 14 

days starting n day 1 (day 1 defined as the 24 hr prior to 

first treatment. 

Roos 

2000 

20171357 

Not stated Pain 

intensity, 

analgesic 

consumption 

Patients assessed their pain as severe, moderate, mild or 

none with the distribution of their neuropathic pain drawn 

on to anterior and posterior body diagrams on the 

pretreatment pain assessment chart. Their analgesics and 

co-analgesics were recorded. Follow up was undertaken 

at 2 and 4 weeks after commencement of treatment, then 

at 2 months, 3 months, and 3 monthly thereafter until 

treatrment failure or death, using similar pain assessment 

charts. Response was defined as an improvement in pain 

score by at least one category, with no increase in 

analgesia for the index pain. Treatment failure was defined 

as a worsening in pain score by at least one category 

and/or significant increase in analgesia for the index pain. 

Progression of preexisting pathological fracture, 

development of new pathological fracture, development of 

cord/cauda equina syndrome or subsequent treatment 

given to the index site were also considered to be 

treatment failures. 
Evidence Table 12. Randomized Controlled Trials on the Efficacy of 

Radiation Treatments for the Management of Cancer Pain – Part V

244 

Author 

Year 

UI 

Tx of 

breakthrough 

pain or escape 

medication 

(applies to all 

arms) 

Outcomes 

Assessed 

(pain relief, 

QOL, etc) 

Instruments used for the assessment of studied 

effects 

Steenland 

1999 

20043644 

Not stated Pain 

intensity, 

analgesic 

consumption 

Patients assessed their pain on an 11-point numerical 

scale. Their pain medications were recorded as: phase 1: 

NSAIDs acetamionophen, nonopioids, phase 2: weak 

opioids and combinations, phase 3: strong opioids like 

morphine. The Rotterdam Symptom Checklist was used to 

assess quality of life. Response was defined as a 

decrease in the initial pain score by at least two points. A 

subsequent increase to the initial pain score or higher was 

considered progression. Time to response and time to 

progression were calculated from the date of 

randomization until the date of response and the date of 

progression respectivelly. Patients were considered 

complete responders if they lowered their pain scores to 0 

or 1, independent of analgesic consumption. 

Whelan 

1999 

20283039 

Not stated Quality of Life A modified version of the Breast Cancer Chemotherapy 

Questionnaire containing 17 items was administered by a 

nurse. Two items specific to radiation therapy were added. 

The items were: "How much of the time during the past 

two weeks have you been troubled by pain, itchiness or 

discomfort to the skin of your chest?" and "How much 

trouble or inconvenience have you had during the past two 

weeks as a result of not being able to bathe or wash your 

chest. The questionnaire was administered at baseline, 4 

weeks ands 8 weeks after randomization. For the long 

term quality of life assessment, three questions were 

asked: a) During the past 2 weeks, have you been 

troubled by pain, itchiness, or discomfort of the skin of 

your chest? b) During the past 2 weeks, have you been 

troubled or inconvenienced as a result of pain in the breast 

that was operated on? and c) During the past 2 weeks, 

have you been troubled or upset as a result of feeling 

upset that the breast that was operated on is unattractive?
Evidence Table 12. Randomized Controlled Trials on the Efficacy of 

Radiation Treatments for the Management of Cancer Pain – Part VI

245 

Author 

Year 

UI 

Outcomes (significant/ nonsignificant) as reported in the 

paper Comments 

"The bone 

pain trial 

working 

party" 

1999 

20043645 

Overall survival at 12 months was 44%. There were no 

differences in the time to first improvement of pain, time to 

complete pain relief or in time to first increase in pain at any 

time up to 12 months from randomization, nor in the class of 

analgesics used. Re-treatment was twice as common after 

single fraction radiation compared to multi-fraction, although retreatment of residual pain did not reflect a difference between 

randomized groups in the probability of pain relief. 

Roos 

2000 

20171357 

The overall RR (intention-to treat basis) was 59/90 = 59% (95% 

CI = 48 - 69%) with 27% achieving a complete response and 

32% a partial response. However 11 of the 90 patients were not 

assessable for response due tp early death. No information is 

provided on comparison between the single versus the multiple 

fraction regiment. 

This is an interim report of 

an ongoing trial 

Steenland 

1999 

20043644 

There was no difference in survival between the two groups 

(median survival = 28 weeks in the 4 Gy and 33 weeks in the 8 

Gy). There was a clear reduction in pain by the first 4 to 6 

weeks but there was no significant difference between the two 

groups. even towards the end of the year. Time to progression 

was analyzed only for responders and there were no 

differences between the two groups. Similarly analgesic 

consumption was not different among groups. 

Whelan 

1999 

20283039 

Short term quality of life was significantly different (worse) in 

radiation group as compared to control group. Long term effect 

on quality of life: radiation significantly increased the proportion 

of patients who reported that they were troubled by skin 

irritation. This was most evident at the 3-month assessment, 

28% in the radiation group versus 14% in the control group 

(p=0.0001). Radiation therapy increased the number of patients 

who were troubled by breast pain. This was most evident at 6 

months (33% radiation group, 20% control group, p=0.0002). 
Evidence Table 13. Randomized Controlled Trials on Cognitive 

Behavioral and Other Interventions for the Management of Cancer 

Pain – Part I

247 

Author 

Year 

UI 

Studied treatment(s) 

(Rx, dose, route) 

N of study 

arms Study Design (cross-over, cohort, etc) 

Reflexology and acupuncture 

Stephenson 

2000 

Foot reflexology 2 Crossover 

Wen 

1998 

Acupuncture compared 

with acupuncture and 

"human transfer factor" 

 and Western medicine 

4 Parallel 

Controls for blood measurements but not for 

pain 

Cognitive behavioral interventions

Ward 

2000 

20505578 

Educational intervention 

by nurse and booklet 

with follow up phone 

call 

2 Parallel 

Clotfelder 

1999 

99120134 

Educational intervention 

with booklet and video 

2 Parallel 

de Wit 

1999 

20029919 

 

Use of pain diary to 

record twice per day 

2 

(only 

experimental 

group was 

reported) 

Parallel 

Du Pen 

1999 

99386437 

Use of algorithm to 

manage pain in 

community setting 

2 Parallel 
Evidence Table 13. Randomized Controlled Trials on Cognitive 

Behavioral and Other Interventions for the Management of Cancer 

Pain – Part II

248 

Author 

Year 

UI 

Randomization 

method 

Blinding Total N 

(evaluable) 

Mean or median age or range 

(% male) 

Reflexology and acupuncture 

Stephenson 

2000 

Coin toss No 23 23 

35 % male 

Wen 

1998 

Not stated No 48 (+ 16 

normal 

controls for 

blood 

measures) 

54 

sex not stated 

Cognitive behavioral interventions

Ward 

2000 

20505578 

Not stated No 43 (25) 58 

0% male 

Clotfelder 

1999 

99120134 

Drawing from box No 60 (53) 76 

35% male 

de Wit 

1999 

20029919 

Not stated No 159 56 

40% male 

Du Pen 

1999 

99386437 

Permuted blocks Doubleblinded 96 (63) 58 

36 % male 
Evidence Table 13. Randomized Controlled Trials on Cognitive 

Behavioral and Other Interventions for the Management of Cancer 

Pain – Part III

249 

Author 

Year 

UI 

Type(s) of 

Cancer 

Severity of pain of included 

patients 

Type of pain (neuropathic, 

somatic, visceral) 

Reflexology and acupuncture 

Stephenson 

2000 

Breast and lung 29 (VAS 0-100) Not stated 

Wen D 

1998 

Gastric On 0-3 scale, all had at least 

mild pain 

Not stated 

Cognitive behavioral interventions

Ward 

2000 

20505578 

Ovarian 

Endometrial 

Uterine 

Cervical 

Other 

gynecologic 

Baseline worst in past week 

control 4.6, experimental 3.3 

(0-10) 

Not stated 

Clotfelder 

1999 

99120134 

Lung 

Breast 

Bladder 

Prostate 

Colon 

Lymphoma 

Baseline control 17.5, 

experimental 14.2 (VAS) 

Not stated 

de Wit 

1999 

20029919 

 

Breast, 

genitourinary, 

bone, lung, 

gastrointestinal, 

oral, other 

Graphically approximately 5 Not stated 

Du Pen 

1999 

99386437 

Breast, 

Lung 

Prostate 

Multiple myeloma 

3.5 (on 0-10 Brief Pain 

Inventory) 

Not stated 
Evidence Table 13. Randomized Controlled Trials on Cognitive 

Behavioral and Other Interventions for the Management of Cancer 

Pain – Part IV

250 

Author 

Year 

UI 

Chronicity 

of cancer 

pain (range 

or average) 

Source of Pain (cancer / 

sequela of treatment / 

procedure related) Inclusion/ Exclusion criteria 

Reflexology and acupuncture 

Stephenson 

2000 

Not stated Not stated No anxiety on VAS, surgery within past 6 

weeks, open wounds on feet, foot tumor or foot 

metastasis, radiation to feet, dementia, 

peripheral neuropathy. 

Inclusion - breast or lung cancer, English 

speaking, anxiety on VAS 

Wen 

1998 

Not stated Not stated Not stated 

Cognitive behavioral interventions

Ward 

2000 

20505578 

Not stated Not stated Not spelled out per se. Inclusion criteria - 

female, gynecologic cancer with cancer-related 

pain 

Clotfelder 

1999 

99120134 

Not stated Not stated Not spelled out per se. Inclusion criteria - 

diagnosis of cancer, at least 65 years old, 

English speaker, cognitively alert, intact vision 

and hearing, have a telephone 

de Wit 

1999 

20029919 

 

11 months Direct tumor (77%) 

Cancer therapy (23%) 

Associated with disease 

(9%) 

Life expectancy less than 3 months, no 

telephone, resident of nursing or retirement 

home 

Du Pen 

1999 

99386437 

Not stated Not stated On investigational therapy, history of substance 

abuse, current major psychiatric disorder. 

For inclusion, needed at least 6-month life 

expectancy, initial screening pain score at least 

3 on 0-10, and be ambulatory 
Evidence Table 13. Randomized Controlled Trials on Cognitive 

Behavioral and Other Interventions for the Management of Cancer 

Pain – Part V

251 

Author 

Year 

UI 

Tx of breakthrough 

pain or escape 

medication (applies to 

all arms) 

Outcomes 

assessed 

(pain relief, QOL, 

etc) 

Instruments used for the assessment 

of studied effects 

Reflexology and acupuncture 

Stephenson 

2000 

Not stated Pain VAS; Short-Form McGill Pain 

Questionnaire 

Wen 

1998 

Unclear " all of the 

groups received 

analgesic therapy on 

the basis of routine 

chemotherapy". World 

Health Organization 

groupings of 

medications used for 

Western medicine 

group 

Pain response 

markedly effective, 

improved, or 

ineffective; also 

measured life quality 

either good, 

moderate, or poor; 

blood chemistries 

3 options of verbal descriptors. Also 

plasma leucine-enkephalin, E-rosette 

forming rate, leukocyte counts 

Cognitive behavioral interventions

Ward 

2000 

20505578 

Not stated Pain intensity 

Pain interference 

with daily life 

Medication 

Side effect severity 

Brief Pain Inventory 

Medication Side Effect Checklist 

Functional Assessment Cancer Therapy - 

General 

Clotfelder 

1999 

99120134 

Not stated Pain VAS 

de Wit 

1999 

20029919 

Non-opioids (26%) 

Weak opioids (25%) 

Strong opioids (40%) 

Pain intensity VAS 

Du Pen 

1999 

99386437 

Non-steroidal 

antiinflammatory drugs 

and opioids; also 

mentions 

antidepressants and 

anticonvulsants but 

does not specify 

breakthrough versus 

scheduled 

Pain 

Total opioid dose 

Other symptoms 

Quality of life 

VAS (Brief Pain Inventory); 
Evidence Table 13. Randomized Controlled Trials on Cognitive 

Behavioral and Other Interventions for the Management of Cancer 

Pain – Part VI

252 

Author 

Year 

UI 

Outcomes (significant / nonsignificant) 

as reported in the paper Comments 

Reflexology and acupuncture 

Stephenson 

2000 

Breast cancer patients had significantly 

decreased by descriptive words on McGill 

score. 

Only 56% of patients had pain at study entry; 

study duration at maximum was 7 days, with 

mean time 2 days; only received one massage 

session 

Wen 

1998 

After 2 months of treatment, both 

acupuncture groups with higher 

percentage rating pain response as 

"markedly effective" compared with 

Western medicine group but overall same 

for both groups for total effective numbers. 

However in 1st 10 days the Western 

medicine group was more effect ive than 

the 2 others 

Difficult to understand the study in numerous 

aspects. 

Reference made to "normal control group" 

used for comparing WBC count and other 

blood results. But for pain, 48 all with gastric 

cancer 37/48 with recurrent postoperative 

cancer but does not state timing of operation 

vis-a-vis study 

Cognitive behavioral interventions

Ward 

2000 

20505578 

No difference between the two groups Only gynecologic cancers; study duration 2 

months; only 43 patients total 

Clotfelder 

1999 

99120134 

Significant reduction in pain in 

experimental group 

Potential bias in selection for study; office staff 

selected based on stability at office visit to 

private oncologists' office 

de Wit 

1999 

20029919 

 

Control group data not reported Compared pain diary scores with scores from 

patient interview. Present Pain Intensity scores 

more accurate than Average Pain Intensity 

score obtained by recall 

Du Pen 

1999 

99386437 

Significant reduction in usual pain in 

experimental group 
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI N Population/ Setting Medication Dose range

Study 

Duration

Johnston

1972

73004523

50 Terminal cancer patients, 

various cancers, outpatients 

And inpatients

thioridazine 25 mg tid 6 weeks

Purohit

1978

79088620

39 Hospitalized cancer patients 

receiving XRT

imipramine 25-50mg 4 weeks

Bruera

1985

85254551

40 Terminal patients, various 

cancers

methylprednisolone 16 mg bid 13 days 

and 33 

days

Costa

1985

86022183

73 Women >18 yrs old with cancer 

and diagnosed depression with 

ZSRDS 41 or > and HDRS 16 

or greater, 70/73 inpatients

Mianserin 30-60 mg/day 4 weeks

Bruera

1986

86133365

26 Terminal patients, various 

cancers

mazindol 1mg tid 12 days

255
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI

Depression 

Instruments Results Tolerability Data

In Cancer 

Treatment? Comments

Johnston

1972

73004523

Physician 

symptom 

ratings

Better than placebo 

for depressed mood 

at 1 week, but not 

week 3 and 6. 

Helpful for insomnia 

and crying spells at 

all time points 

(p<.05)

“No untoward 

effects were 

observed or 

reported at any time 

during the study”

Yes Black box warning 

now from FDA, nonstandardized 

ratings, no clear 

diagnosis of 

depression

Purohit

1978

79088620

Physician 

diagnosis and 

ratings, 

Hamilton 

Depression 

Scale

80% imipramine 

patients Improved, 

42% of controls

Dosages adjusted 

for “side effects” but 

not noted

Yes, XRT No statistical 

evaluation of 

significance of 

difference

Bruera

1985

85254551

Hamilton 

Depression 

Scale

Day 13 MP patients 

had improved 

depression (p<.05), 

day 33 no 

significant 

difference with 

placebo

5% patients 

Cushingoid, 5% 

patients had 

increased anxiety

No No comment on 

recruitment of 

patients with high 

HDRS scores

Costa

1985

86022183

HDRS, 

ZSRDS, CGI

Exp. group greater 

improvement in 

HDRS (p<.01) and 

ZSDRS (p<.05) at 4 

weeks; significantly 

more responders 

on CGI in exp. 

Group (p<.025)

No significant 

difference in side 

effects between 

group, drowsiness 

reported

97.26% 

receiving 

chemo or 

radiation

Bruera

1986

86133365

Hamilton 

depression 

scale

No significant 

difference with 

placebo

“serious toxity”, 

nervousness, 

sweating, delirium, 

weakness

No No comment on 

recruitment of 

patients with high 

HDRS scores

256
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI N Population/ Setting Medication Dose range

Study 

Duration

Holland

1991

91237385

147 Any cancer, KPS>60 Alprazolam vs. 

progressive muscle 

relaxation

0.5 mg tid 10 days

Van 

Heeringen

1996

97049464

55 Breast cancer mianserin 60 mg/day 6 weeks

Eija

1996

96303779

15 Breast cancer patients with 

neuropathic pain from 

treatment

amitriptyline 25 to 100 mg/ 

day

4 weeks

257
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI

Depression 

Instruments Results Tolerability Data

In Cancer 

Treatment? Comments

Holland

1991

91237385

DSM-III 

interview, 

Hamilton 

Depression 

Scale, Affects 

Balance 

Scale

Both groups 

improve, 

alprazolam group 

significantly more 

improvemt with 

ABS (p=.04) and 

HDRS (p=.08)

Drowsiness, 

sedation, 

lightheadedness

Yes more drop outs in 

drug arm, included 

in study if had cut 

off score for 

depression OR 

anxiety

Van 

Heeringen

1996

97049464

DSM-III 

interview, 

HRSD

HDRS scores lower 

than placebo at 2 

weeks (p=.056), 4 

weeks (p=.004), 

and 6 weeks 

(p=.004), number of 

responders 

significantly greater 

than placebo 

(p<.05) at 4 and 6 

weeks

Postural symptoms, 

sedation

Received 

XRT

More placebo 

patients terminated 

study early

Eija

1996

96303779

2 questions 

re: 

depression 

with 4 pt. 

scale

No significant 

differences

Sedation, dry mouth, 

constipation, 

sweating

ND Primarily a pain 

study, Nonstandardized 

measurement of 

depressive 

symptoms, patients 

not depressed 

entering the study, 

20% of patients 

dropped out of intial 

20 because of side 

effects

258
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI N Population/ Setting Medication Dose range

Study 

Duration

Razavi

1996

97046167

91 

randomize

d

Patients with various cancers 

with DSM-III diagnosis of 

depression and HADS score of 

13 or >

fluoxetine 20mg qd 5 weeks, 

one week 

of placebo 

before 

randomiza

tion

Holland

1998

98413502

37 Women with cancer Fluoxetine vs. 

desipramine

F 20

D 100

Variable with 

response

6 weeks

Razavi

1999

20190434

27 Breast cancer patients. Trazodone vs. 

clorazepate

T 50-150

C 10-30

4 weeks

259
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI

Depression 

Instruments Results Tolerability Data

In Cancer 

Treatment? Comments

Razavi

1996

97046167

HADS, 

MADRS, 

SCL90-R

No significant 

difference in 

change in 

depression scores 

or percentage of 

responders (HADS 

<8)

No significant 

difference in side 

effects between 

groups, digestive 

and neuropsychiatric 

side effects more 

common

ND HADS scores not 

broken down into 

anxiety and 

depression scales; 

4 weeks of 

antidepressant 

treatment; physical 

morbidity and 

medical treatment 

not controlled 

Holland

1998

98413502

DSM-III-R 

interview, 

HAM-D, CGI

Both groups 

improved 

significantly by both 

scales, no 

significant 

differences between 

drugs

Nausea, headache, 

dry mouth, 

insomnia, dyspepsia

Yes Mean med doses 

not noted, small 

sample size unable 

to yield significant 

differences between 

meds

Razavi

1999

20190434

DSM-III-R 

criteria for 

adj. D.o. w. 

depressed 

mood, HADS, 

CGI

By CGI, 91% T 

group responders, 

57% C group, but 

no significant 

differences; by 

HADS scores 

decreased in both 

but no significant 

differences

Yes Study of adjustment 

disorders, sample 

doesn’t allow 

enough power for 

comparison

260
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI N Population/ Setting Medication Dose range

Study 

Duration

Musselman

2001

21146521

20 per 

group

Patients melanoma receiving 

interferon

paroxetine 10 then 20mg/ 

day, up to 40 

mg/day

2 weeks 

preinterferon, 

then 12 

weeks 

after

261
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI

Depression 

Instruments Results Tolerability Data

In Cancer 

Treatment? Comments

Musselman

2001

21146521

HDRS, HAS, 

Carroll 

Depression 

scale

Patoxetine 

significantly 

reduced the 

incidence of 

depression (p=.04), 

11% in paroxetine 

vs. 45% in control; 

paroxetine had 

significant effect on 

severity of 

depressive 

symptoms (p<.001)

Adverse events did 

not differ between 

groups, but 3 

paroxetine patients 

developed retinal 

hemorrhages

100% 

receiving 

interferon

262
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI N Population/ Setting Medication Dose range

Study 

Duration

Johnston

1972

73004523

50 Terminal cancer patients, 

various cancers, outpatients 

And inpatients

thioridazine 25 mg tid 6 weeks

Purohit

1978

79088620

39 Hospitalized cancer patients 

receiving XRT

imipramine 25-50mg 4 weeks

Bruera

1985

85254551

40 Terminal patients, various 

cancers

methylprednisolone 16 mg bid 13 days 

and 33 

days

Costa

1985

86022183

73 Women >18 yrs old with cancer 

and diagnosed depression with 

ZSRDS 41 or > and HDRS 16 

or greater, 70/73 inpatients

Mianserin 30-60 mg/day 4 weeks

Bruera

1986

86133365

26 Terminal patients, various 

cancers

mazindol 1mg tid 12 days

255
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI

Depression 

Instruments Results Tolerability Data

In Cancer 

Treatment? Comments

Johnston

1972

73004523

Physician 

symptom 

ratings

Better than placebo 

for depressed mood 

at 1 week, but not 

week 3 and 6. 

Helpful for insomnia 

and crying spells at 

all time points 

(p<.05)

“No untoward 

effects were 

observed or 

reported at any time 

during the study”

Yes Black box warning 

now from FDA, nonstandardized 

ratings, no clear 

diagnosis of 

depression

Purohit

1978

79088620

Physician 

diagnosis and 

ratings, 

Hamilton 

Depression 

Scale

80% imipramine 

patients Improved, 

42% of controls

Dosages adjusted 

for “side effects” but 

not noted

Yes, XRT No statistical 

evaluation of 

significance of 

difference

Bruera

1985

85254551

Hamilton 

Depression 

Scale

Day 13 MP patients 

had improved 

depression (p<.05), 

day 33 no 

significant 

difference with 

placebo

5% patients 

Cushingoid, 5% 

patients had 

increased anxiety

No No comment on 

recruitment of 

patients with high 

HDRS scores

Costa

1985

86022183

HDRS, 

ZSRDS, CGI

Exp. group greater 

improvement in 

HDRS (p<.01) and 

ZSDRS (p<.05) at 4 

weeks; significantly 

more responders 

on CGI in exp. 

Group (p<.025)

No significant 

difference in side 

effects between 

group, drowsiness 

reported

97.26% 

receiving 

chemo or 

radiation

Bruera

1986

86133365

Hamilton 

depression 

scale

No significant 

difference with 

placebo

“serious toxity”, 

nervousness, 

sweating, delirium, 

weakness

No No comment on 

recruitment of 

patients with high 

HDRS scores

256
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI N Population/ Setting Medication Dose range

Study 

Duration

Holland

1991

91237385

147 Any cancer, KPS>60 Alprazolam vs. 

progressive muscle 

relaxation

0.5 mg tid 10 days

Van 

Heeringen

1996

97049464

55 Breast cancer mianserin 60 mg/day 6 weeks

Eija

1996

96303779

15 Breast cancer patients with 

neuropathic pain from 

treatment

amitriptyline 25 to 100 mg/ 

day

4 weeks

257
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI

Depression 

Instruments Results Tolerability Data

In Cancer 

Treatment? Comments

Holland

1991

91237385

DSM-III 

interview, 

Hamilton 

Depression 

Scale, Affects 

Balance 

Scale

Both groups 

improve, 

alprazolam group 

significantly more 

improvemt with 

ABS (p=.04) and 

HDRS (p=.08)

Drowsiness, 

sedation, 

lightheadedness

Yes more drop outs in 

drug arm, included 

in study if had cut 

off score for 

depression OR 

anxiety

Van 

Heeringen

1996

97049464

DSM-III 

interview, 

HRSD

HDRS scores lower 

than placebo at 2 

weeks (p=.056), 4 

weeks (p=.004), 

and 6 weeks 

(p=.004), number of 

responders 

significantly greater 

than placebo 

(p<.05) at 4 and 6 

weeks

Postural symptoms, 

sedation

Received 

XRT

More placebo 

patients terminated 

study early

Eija

1996

96303779

2 questions 

re: 

depression 

with 4 pt. 

scale

No significant 

differences

Sedation, dry mouth, 

constipation, 

sweating

ND Primarily a pain 

study, Nonstandardized 

measurement of 

depressive 

symptoms, patients 

not depressed 

entering the study, 

20% of patients 

dropped out of intial 

20 because of side 

effects

258
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI N Population/ Setting Medication Dose range

Study 

Duration

Razavi

1996

97046167

91 

randomize

d

Patients with various cancers 

with DSM-III diagnosis of 

depression and HADS score of 

13 or >

fluoxetine 20mg qd 5 weeks, 

one week 

of placebo 

before 

randomiza

tion

Holland

1998

98413502

37 Women with cancer Fluoxetine vs. 

desipramine

F 20

D 100

Variable with 

response

6 weeks

Razavi

1999

20190434

27 Breast cancer patients. Trazodone vs. 

clorazepate

T 50-150

C 10-30

4 weeks

259
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI

Depression 

Instruments Results Tolerability Data

In Cancer 

Treatment? Comments

Razavi

1996

97046167

HADS, 

MADRS, 

SCL90-R

No significant 

difference in 

change in 

depression scores 

or percentage of 

responders (HADS 

<8)

No significant 

difference in side 

effects between 

groups, digestive 

and neuropsychiatric 

side effects more 

common

ND HADS scores not 

broken down into 

anxiety and 

depression scales; 

4 weeks of 

antidepressant 

treatment; physical 

morbidity and 

medical treatment 

not controlled 

Holland

1998

98413502

DSM-III-R 

interview, 

HAM-D, CGI

Both groups 

improved 

significantly by both 

scales, no 

significant 

differences between 

drugs

Nausea, headache, 

dry mouth, 

insomnia, dyspepsia

Yes Mean med doses 

not noted, small 

sample size unable 

to yield significant 

differences between 

meds

Razavi

1999

20190434

DSM-III-R 

criteria for 

adj. D.o. w. 

depressed 

mood, HADS, 

CGI

By CGI, 91% T 

group responders, 

57% C group, but 

no significant 

differences; by 

HADS scores 

decreased in both 

but no significant 

differences

Yes Study of adjustment 

disorders, sample 

doesn’t allow 

enough power for 

comparison

260
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI N Population/ Setting Medication Dose range

Study 

Duration

Musselman

2001

21146521

20 per 

group

Patients melanoma receiving 

interferon

paroxetine 10 then 20mg/ 

day, up to 40 

mg/day

2 weeks 

preinterferon, 

then 12 

weeks 

after

261
 Evidence Table 14. Psychopharmacologic Studies of Treatment of

 Depression in Cancer. Double-blind Randomized Control Trials

Author

Year

UI

Depression 

Instruments Results Tolerability Data

In Cancer 

Treatment? Comments

Musselman

2001

21146521

HDRS, HAS, 

Carroll 

Depression 

scale

Patoxetine 

significantly 

reduced the 

incidence of 

depression (p=.04), 

11% in paroxetine 

vs. 45% in control; 

paroxetine had 

significant effect on 

severity of 

depressive 

symptoms (p<.001)

Adverse events did 

not differ between 

groups, but 3 

paroxetine patients 

developed retinal 

hemorrhages

100% 

receiving 

interferon

262
 Evidence Table 15. Meta-analyses on Effects of Psychological

 Interventions on Depressive Symptoms in Cancer Patients

Author

Year

UI

Number of 

studies/N Types of Studies Inclusion/Exclusion Criteria

Devine

1995

96123962

98/5326 68% randomized

18% nonrandomized

13% pre-post 

single group

Inclusion:

1. Provision of psycho-educational care to adults with 

cancer.

2. Use of experimental, quasi-experimental, or pre-post 

single group design.

3. Outcome measures of physical and emotional wellbeing in which direction of treatment effect could be 

determined.

Exclusion:

1. Studies that included comparison arms with other 

types of treatments (psycho-pharmacology).

2. Studies with <5 subjects.

3. All treatment groups not selected from the same 

setting.

Meyer

1995

95309215

45/2840 100% randomized Inclusion:

1. Published randomized trials.

2. Psychosocial intervention compared to control or 

minimal intervention.

3. Outcome variables included behavioral, emotional, 

physiological, or medical state.

Exclusion:

Hospice or terminal home care studies.

Sheard

1999

99396371

20/1101 70% randomized

30% nonrandomized

Inclusion:

1. Evaluated psychosocial of psychiatric interventions 

specifically for psychosocial distress in cancer patients.

2. Control condition.

3. Published in English in journal of indexed as 

dissertation.

Exclusion:

Single group designs without control groups.

263
 Evidence Table 15. Meta-analyses on Effects of Psychological

 Interventions on Depressive Symptoms in Cancer Patients

Author

Year

UI

Number of 

Groups Type of Treatment Effect size Comments

Devine

1995

96123962

116 Educational

Noncognitive-behavioral therapy

Cognitive behavioral therapy

Positive effect in 92% 

of studies including 

depression. Average 

effect size was 

medium-sized, 

statistically significant, 

and homogeneous.

D=.54 (n=40)

95% CI 0.43-0.65

Q=39

Not necessarily on 

patients with 

depression.

Meyer

1995

95309215

62 Cognitive behavioral therapy

Informational and educational 

treatments

Nonbehavioral counseling or 

psychotherapy

Non-professional social support

"Unusual" therapies (i.e. music 

therapy)

D=0.24

95% CI 0.17-0.32

Measures of 

emotional adjustment, 

not depression. No 

significant difference 

between types of 

treatment.

Sheard

1999

99396371

Individual treatment

Relaxation

Group treatment (not psychoeducational)

Group psycho-educational

Effect size 0.36, 

p=.0027 for 

heterogeneity test.

Higher quality, more 

reliable studies: effect 

size 0.18

Not necessarily on 

patients with 

depression. Effect 

size not associated 

with randomization.

264
 Evidence Table 16. RCTs of Treatment of Fatigue in Cancer Patients

Author

Year

UI N Treatment

Mean age 

(range) % Male Cancers

Inclusion/ Exclusion 

Criteria

Spiegel

1981

81206415

86 weekly 

support 

group for 

one year

Group 1: 54 

(ND) 

Control: 55 

(ND) 

0% Metastatic 

breast cancer

Inclusion:

documented metastatic breast 

cancer

Exclusion:

ND

Forester

1985

85094657

100 PsychotherapyGroup 1: 

62(23-78)

Control:

62(25-81)

Group 1:

54%

Control:

46%

Multiple ND

Decker

1992

92291348

82 Relaxation 

therapy

61(37-84) 37% Multiple Inclusion:

"all recently diagnosed cancer 

patients"

Exclusion:

prior cancer; prior radiation 

therapy; inpatients; suicidal 

ideation

265
 Evidence Table 16. RCTs of Treatment of Fatigue in Cancer Patients

Author

Year

UI

Fatigue 

Scales Outcome

Author’s 

Conclusions Comments

Spiegel 

1985

POMS Declines in vigor and 

increasing fatigue were 

seen in control group 

but not the treatment 

group (p<.01). Those 

who participated in 

weekly group session 

for one year had 

significantly lower 

scores on POMS fatigue 

subscale. 

Support group was 

effective in 

preventing 

psychological 

deterioration in 

women with 

advanced breast 

cancer

Stratification and randomization 

methods not reported. The two 

groups received equivalent 

amounts of chemotherapy but 

treatment group had higher 

socioeconomic status. Dropout 

rate was very high (30 subjects 

completed POMS at all four time 

points).

Forester

1985

85094657

Schedule of 

Affective 

Disorders 

and Schizophrenia 

(SADS)

SADS administered at 

baseline, near midpoint 

of RT, at end of RT and 

4 weeks and 8 weeks 

post-RT. Only at 4 

weeks post RT was 

there a significantly 

greater change from 

baseline fatigue scores 

in the therapy group 

compared with control 

group.

Gender and 

diagnosis affect 

pattern and 

magnitude of 

response to 

psychotherapy.

This study suggests there may 

be a decrement in fatigue at 4 

weeks after RT in patients who 

received weekly psychotherapy. 

However, the patient population 

is poorly characterized and the 

finding of significance at one 

time point is of questionable 

validity - no power calculation.

Decker

1992

92291348

POMS Treatment group had a 

nonsignificant change in 

fatigue score over the 

course of treatment, 

whereas in controls, 

fatigue increased 

significantly.

Relaxation training 

improves 

psychological 

parameters.

1. Absence of patient 

characteristics a problem.

2. Methods of randomization and 

selection sketchy.

3. Unexplained baseline 

differences between control and 

treatment group on all POMS 

scales.

266
 Evidence Table 16. RCTs of Treatment of Fatigue in Cancer Patients

Author

Year

UI N Treatment

Mean age 

(range) % Male Cancers

Inclusion/ Exclusion 

Criteria

Mock

1997

97387565

46 Exercise Group 1:

48±5.5

Control:

50±8.5

0% Breast, stage I, 

II

Inclusion:

consecutive pts undergoing 

evaluation for radiation 

therapy for breast CA; all had 

received breast conserving 

surgery for newly diagnosed 

stage I or II breast CA

Exclusion:

Concurrent major health 

problems (cardiovascular or 

respiratory disease); cognitive 

dysfunction; age>65 or <35; 

already participating in 

structured exercise

Ahles

1999

99446233

34 Massage 

vs. quiet 

time

Group 1:

41±9.4

Control:

42±9.5

Group 1: 

12%

Control: 

33%

Multiple Inclusion:

patients undergoing 

autologous BMT

Exclusion: ND

267
 Evidence Table 16. RCTs of Treatment of Fatigue in Cancer Patients

Author

Year

UI

Fatigue 

Scales Outcome

Author’s 

Conclusions Comments

Mock

1997

97387565

Piper Fatigue 

Scale; SAS 

Fatigue 

Scale

Exercise group scored 

significantly higher than 

usual care group on 

physical functioning 

(p=0.003) and symptom 

intensity, especially 

fatigue.

Self-paced homebased walking 

exercise program 

manages 

symptoms.

Data presented graphically but 

scores and p values not 

reported for the Piper Fatigue 

Scale and only scores reported 

for SAS.

Ahles

1999

99446233

Symptom 

Distress 

Scale; POMS

Borderline significant 

results for fatigue 

(p=0.06). Most robust 

effects at Day –7 

assessment (first week 

of treatment).

Patients on 

massage 

treatment 

demonstrated 

significant 

reductions in 

fatigue.

The applicability of this study is 

limited by the design of 

measuring fatigue immediately 

pre- and post-massage and 

comparing this to a control 

group treated with a 20 minute 

period of quiet time. Although p 

values suggest a significant 

effect in reducing fatigue, the 

duration of this effect is 

unknown. Therefore, the impact 

of massage on fatigue is difficult 

to assess.

268
 Evidence Table 16. RCTs of Treatment of Fatigue in Cancer Patients

Author

Year

UI N Treatment

Mean age 

(range) % Male Cancers

Inclusion/ Exclusion 

Criteria

Dimeo

1999

99256640

59 Aerobic 

exercise 

(biking) vs. 

control

Group 1:

40±11

Control: 

40±10

Group 1:

33%

Control:

41%

Multiple Inclusion:

active malignancy; 

histologically confirmed; 

selected for autologous stem 

cell transplant; able to 

understand written German

Exclusion:

“psychiatric, muscular, 

cardiovascular or pulmonary 

disease”

GastonJohansson

2000

20395088

110 Comprehensive 

Coping 

Strategy 

Program 

vs. no 

treatment

ND 0% Breast, stage II, 

III, IV

Inclusion:

Stage II, III, or IV breast CA; 

scheduled to ungergo 

autologous BMT at Johns 

Hopkins; age≥18; ability to 

read and write English

Exclusion: ND

Oyama

2000

20440886

30 Bedside 

Wellness 

System 

using 

virtual 

reality 

technology 

vs. chemo 

as usual

Group 1:

55.7

Control:

51.2

Group 1:

20%

Control:

20%

Multiple Inclusion:

cancer pts receiving chemo; 

age 18-70; no ‘conscious 

disturbance or orientation 

disorder’; no history of mental 

disorder, heart disorder, 

active ucer; adequate visual 

and hearing function

Exclusion:

tuberculosis; MRSA

269
 Evidence Table 16. RCTs of Treatment of Fatigue in Cancer Patients

Author

Year

UI

Fatigue 

Scales Outcome

Author’s 

Conclusions Comments

Dimeo

1999

99256640

POMS; 

Symptom 

Check List 

(SCL-90-R)

No significant 

differences were 

present at baseline; 

control group had 

significantly more 

fatigue at discharge 

compared with baseline 

(p<0.02), exercise group 

did not.

Aerobic exercise 

reduces fatigue 

and improved 

psychological 

distress.

Unusual analysis of data makes 

this study difficult to interpret. 

Although this was a randomized 

trial, the only reported results 

were change in the scales and 

subscales compared to baseline 

within each arm. The two arms 

do not appear to have been 

compared to one another. 

Therefore, while it is intriguing 

that the patients in the exercise 

group had no significant 

increase in fatigue from 

9.6±10.0 to 11.7±8.9 (p=0.28), 

and those in the control group 

did, this does not carry the same 

weight as a statistically 

significant difference between 

the two arms at time of 

discharge.

GastonJohansson

2000

20395088

VAS Fatigue significantly less 

in treatment group 

compared with control at 

day 7. Significance 

disappears in 

multivariate analysis 

when controlled for 

demographic variables 

and fatigue at day –2.

CCSP reduces 

nausea and 

fatigue and 

indirectly affects 

reduction of other 

symptoms.

A well-conducted study.

Oyama

2000

20440886

Cancer 

Fatigue 

Scale

There was a statistically 

significant difference 

between level of fatigue 

in treatment and control 

groups after 2 

treatments, but not after 

1.

BSW has positive 

effect in improving 

physical fatigue.

1. Given the number of 

parameters that are reported, it 

is unclear what importance to 

attach to one significant value at 

one time point. It’s not clear that 

this was prospectively identified 

as an endpoint.

2. Population studied is small 

and very heterogeneous - 

generalizability is questionable.

270
 Evidence Table 16. RCTs of Treatment of Fatigue in Cancer Patients

Author

Year

UI N Treatment

Mean age 

(range) % Male Cancers

Inclusion/ Exclusion 

Criteria

Mock

2001

11879296 

PMID

48 walking 

program vs. 

usual care

47.98(28-75) 0% Breast, stage I, 

II, IIIa 

undergoing 

adjuvant chemo 

or XRT

Inclusion:

recent treatment by definitive 

surgery, scheduled to receive 

outpatient chemo or XRT

Exclusion:

health problems 

contraindicating exercise

Littlewood

2001

21281037

251 Epoetin alfa 

vs. placebo

Group 1:

58(18-85)

Control:

60(21-88)

Group 1:

34%

Control:

31%

Multiple; breast 

most common

Inclusion:

age>18; confirmed diagnosis 

of solid or nonmyeloid 

hematologic tumor; life 

expectancy ≥6 months; 

scheduled to receive nonplatinum chemo; hemoglobin 

≤10.5 or hemoglobin >10.5 

and ≤12 with a 1.5g/dL drop

Exclusion:

acute leukemia; uncontrolled 

hypertension; untreated iron, 

B12, folate deficiency; major 

bleeding or infection in last 

month; prior BMT

271
 Evidence Table 16. RCTs of Treatment of Fatigue in Cancer Patients

Author

Year

UI

Fatigue 

Scales Outcome

Author’s 

Conclusions Comments

Mock 

2001

modified 

Piper Fatigue 

Scale

Fatigue scores did not 

differ significantly 

between exercise and 

usual care groups at 

end of treatment. 

50% of controls 

were excercising, 

30% of treatment 

group did not 

adhere to exercise 

regimen, possibly 

contributing to 

negative result. 

"High walkers" had 

significantly less 

fatigue than "low 

walkers" in pooled 

analysis of 

treatment and 

control groups.

Negative RCT based on initial 

study design. Differences in 

fatigue between high and low 

walkers based on post-hoc 

change in study design to nonrandomized comparison. 

Littlewood

2001

FACT-An, SF36

There was a strong 

statistically significant 

correlation between 

hemoglobin levels and 

QOL. The mean 

increase in hemoglobin 

level from baseline to 

last value was 

significantly greater in 

the epoetin alfa group 

than the placebo group 

(2.2 g/dL v. 0.5 g/dL, 

P<0.001). Significant 

differences observed for 

epoetin for all 5 cancer 

and anemia-specific 

primary QOL measures 

(P≤.0048)

Epoetin 

significantly 

improves fatigue 

and QOL in this 

setting.

272
Appendix A 

Abbreviations 

ACS American Cancer Society 

AHRQ Agency for Healthcare Research and Quality 

AIDS Acquired immunodeficiency syndrome 

ANOVA Analysis of Variance

APD Aminohydropropyloxidine disodium pamidronate 

APAP Acetaminophen 

ARS Adjective rating scale 

BMT Bone marrow transplant

CARES Cancer Rehabilitation Evaluation System

CCSI Cognitive Coping Strategizing Inventory

CFS Cancer Fatigue Scale

CNS Central nervous system

CRF Cancer-related Fatigue

CRFDS Cancer related Fatigue Distress Scale

CSA Controlled Substances Act 

CSF Cerebrospinal fluid 

CT scan Computed tomographic scan 

DSM Diagnostic and Statistical Manual of Mental Disorders

ECOG Eastern Cooperative Oncology Group

EMLA Eutectic mixture of local anesthetic 

EORTC European Organization for Research and Treatment of Cancer

273 
FACT Functional Assessment of Cancer Therapy

FDA Food and Drug Administration 

FLIC Function of Living Index Cancer

FSI Fatigue Symptom Inventory

GHQ General Health Questionnaire

GI Gastrointestinal 

HADS Hospital Anxiety and Depression Scale

HIV Human immunodeficiency virus 

HRQOL Health-related Quality of Life

IM Intramuscular 

IV Intravenous 

IRS Immediate release hydromorphone

JCAHO Joint Commission for the Accreditation of Healthcare Organizations

LASA Linear Analogue Self-Assessment

LFS Lee Fatigue Scale

MAC Mental Adjustment to Cancer

MAF Multidimensional Assessment of Fatigue

MAOI Monamine oxidase inhibitors 

MFI Multidimensional Fatigue Inventory

MFSI Multidimensional Fatigue Symptom Inventory

MHIQ McMaster Health Index Questionnaire

MMS Mini-Mental State

MRI Magnetic resonance imaging 

274 
MSAS Memorial Symptom Assessment Scale

NCCW National Comprehensive Cancer Network

NCPB Neurolytic celiac plexis block 

NHP Nottingham Health Profile

NRS Numerical rating scale 

NSAID Nonsteroidal anti-inflammatory drug 

OMAR Office of Medical Applications of Research

OTTAT Oncology Treatment Toxicity Assessment Tool 

PAC Psychological Adjustment to Cancer Scale

PACIS Perceived Adjustment to Chronic Illness Scale 

PCA Patient-controlled analgesia 

PCC Percutaneous cervical cordotomy 

PFS Piper Fatigue Scale

PID Pain intensity difference (from baseline) 

POMS Profile of Moods States

QOL Quality of Life

RCT Randomized controlled trial 

RFS Rhoten Fatigue Scale

RSCL Rotterdam Symptom Checklist

SCFS Schwartz Cancer Fatigue Scale

SIP Sickness Impact Profile

SPID Summed pain intensity difference

275 
SRH Slow release hydromorphone

TENS Transcutaneous electrical nerve stimulation 

TOTPAR Total pain relief

TRSC Therapy-related Symptom Checklist

VAS Visual analogue scale 

WHO World Health Organization 

276 
Appendix B 

Glossary for Fatigue Assessment Scales 

Brief Fatigue Inventory – 9 items, scored 1-10 to assess severity of fatigue, 

amount of interference with function caused by fatigue, presence of factors 

that worsen fatigue. 

Cancer Fatigue Scale – 15 items and 3 subscales (physical, affective, and 

cognitive) generated by factor analysis. Maximum score = 60. Physical = 

easily tired, urge to lie down, exhaustion, etc. Affective = lack of energy, lack 

of interest, lack of concentration. Cognitive = forgetfulness, speaking errors, 

carelessness. Each item is rated on a scale from 1-5. 

Cancer-Related Fatigue Distress Scale (CRFDS) – 35 cognitive distress 

questions reduced to 3; 147 physical distress questions reduced to 8; 142 

psychological distress questions reduced to 7; 52 social distress questions 

reduced to 3; 21 spiritual distress questions reduced to 2. Total = 20 items, 

rated on a scale of 0 (none) to 10 (severe). 

Checklist Individual Strength (CIS) – 20 item questionnaire measuring 4 aspects 

of fatigue: fatigue severity (8 items); concentration (5 items); motivation (4 

items); physical activity (3 items). Each item is scored on a 7-point Likert 

scale. 

EORTC QLQ-C30 – 6 functioning scales: physical functioning (5 items); role 

functioning (2 items); cognitive (2 items); emotional (4 items); social (2 items); 

QOL (2 items). 3 symptom scales: pain (2 items); fatigue (3 items); emesis (2 

items). 

Fatigue Questionnaire – to estimate severity. Asks about fatigue symptoms in

last month. Two items ask about duration and extent of fatigue. Seven items 

cover physical fatigue. Four cover mental fatigue. 

Fatigue Severity Scale – 9 item scale with statements scored from 1 (strongly 

disagree) to 7 (strongly agree). 

Fatigue Symptom Inventory – 13 item self-report measure for intensity and 

duration of fatigue and impact on QOL. 

Functional Assessment of Cancer Therapy/Anemia (FACT-An) – Composed of 

FACT-F plus 7 miscellaneous nonfatigue items related to anemia. FACT-F is 

composed of FACT-G plus Fatigue Subscale (13 items) = 20 items total. 

GLQ-8 – 8 item LASA instrument to measure cancer related QOL. 

277 
Lee Fatigue Scale – VAS modified to numeric rating of 1-10, with descriptions of 

anchors from 1 (least) to 10 (extremely tired). 

McCorkle and Young – see Symptom Distress Scale. 

Memorial Symptom Assessment Scale (MSAS) – patient rates frequency, 

severity, distress for 32 symptoms. Frequency and severity are rated from 1-

4, and distress is rated on a 5-point scale. 

Multidimensional Assessment of Fatigue (MAF) – severity, distress, interference 

items scaled from 0-10, ends anchored by “not at all” to “a great deal”. 

Frequency item is categorical scale (0-4). Global fatigue calculated by 

summing severity and distress, adding item mean for interference, and adding 

the product of the categorical score on frequency by 2.5. 

Multidimensional Fatigue Inventory (MFI-20) – 5 scales relating to general 

fatigue, physical and mental fatigue, reduced activity and motivation. Each 

scale has 4 items, and each is rated on a 5-point response. 

Multidimensional Fatigue Symptom Inventory (MFSI) – 83 items to assess global 

(11 items), somatic (21 items), affective (17 items), cognitive (14 items), and 

behavioral (7 items) symptoms of fatigue. 

Nottingham Health Profile (NHP) – 6 subscales: energy (3 items); pain (8 items); 

emotional reactions (9 items); sleep (5 items); social isolation (5 items); 

physical mobility (9 items). Items were scored in a yes/no format. 

Pearson Byars Fatigue Feeling Checklist – 13 statements describing fatigue 

symptoms, rated on a scale of 1 (better than), 2 (same as) or 3 (worse than) 

and having a total range of 13-39. 

Piper Fatigue Scale – 22 items rated from 0-10 measuring 4 dimensions of 

subjective fatigue for a total score between 0-220. Each item is anchored by 

strong/weak. 

Profile of Mood States (POMS): Fatigue Subscale – self-rating measure of six 

emotions; tension/anxiety, depression/dejection, anger/hostility, vigor, fatigue, 

and confusion. Seven items, rated on a scale of 0-28. 

Rhoten Fatigue Scale (RFS) – 1 item VAS to measure fatigue. Stem is ‘not tired; 

full of energy’ and the other is ‘totally exhausted’. 

Rotterdam Symptom Checklist – 30 items assessing physical and psychological 

symptom distress on a 4-point scale. 8 other items describe performance of 

daily activities. 2 items (tiredness and lack of energy) selected. 

Schwartz Cancer Fatigue Scale (SCFS) – 28 items measured using a 5-point 

scale. 

278 
SF-36 – 5 variables: “lots of energy” rated from 1-6; “worn out” rated from 1-6; 

“tired” rated from 1-6; “full of pep” rated from 1-6; “vitality” rated from 4-24. 

Subjective Symptom Test of Fatigue (Japanese Association of Industrial Health) 

– 30 items in 3 categories (drowsiness/dullness, difficulty in concentration, 

projection of physical disintegration). Rated on a 4-point scale. 

Swedish Occupational Fatigue Inventory (SOFI) – 25 verbal expressions rated on 

a scale of 0-6. 0 = not at all Æ 6 = high degree. 

Symptom Distress Scale (SDS) (also referred to as McCorkle and Young) – 13 

items: nausea, insomnia, pain, fatigue, bowel pattern, concentration, 

appearance, outlook, breathing, and cough.

Symptom Transition Scale – measured severity of illness aspect of side effects 

burden. 

Therapy-Related Symptom Checklist (TRSC) – 25 items rated on a 5-point scale. 

Visual Analogue Scale (VAS) – 100 mm scale

279