This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Flechtner, H. Articles by Bottomley, A. Search for Related Content PubMed PubMed Citation Articles by Flechtner, H. Articles by Bottomley, A.

Fatigue and Quality of Life: Lessons from the Real World

^a Clinic for Psychiatry and Psychotherapy of Children and Adolescents, University of Cologne, Cologne, Germany; ^b EORTC Data Center, Quality of Life Unit, Brussels, Belgium

Correspondence: Henning Flechtner, M.D., Ph.D., Clinic for Psychiatry and Psychotherapy of Children and Adolescents, University of Cologne, Robert-Koch-Str. 10, D, 50931 Cologne, Germany. Telephone: 49-221-478-6121; Fax: 49-221-478-6104; e-mail: henning.flechtner{at}medizin.uni-koeln.de

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction What Is Fatigue? Why Should We Assess... How Do We Assess... What Have We Learned? What Are Our Goals? References

 
After completing this course, the reader will be able to:

1. Explain the nature and prevalence of cancer-related fatigue.
   
2. Identify which instruments are currently in use for assessing fatigue.
   
3. Identify patterns of recovery in cancer patients.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction What Is Fatigue? Why Should We Assess... How Do We Assess... What Have We Learned? What Are Our Goals? References

 
The impact of fatigue on the quality of life of oncology patients is substantial and under-recognized. Fatigue in these patients may begin with a simple decrease in physical activity, but can progress to include a wide range of negative effects that often culminate in patients feeling out of control, lonely, and isolated. In general, surviving cancer patients experience some limitations after the end of treatment but ultimately attain a reasonably good level of functioning. An examination of subpopulations and further analyses of data suggest, however, four different recovery patterns. Patients may: A) improve in their functioning, reach a plateau at approximately year 2 or 3, and then remain at relatively high levels of functioning; B) improve initially, but deteriorate again after year 2 or 3, never reaching the normal stage; C) improve, returning to normal; or D) have a very mixed pattern of high levels of fatigue that is, to date, very difficult to interpret. Disturbingly, 60% of the survivors in our population of patients with Hodgkin’s disease, who were treated in recent trials of the German Hodgkin Study Group and the European Organization for Research and Treatment of Cancer Lymphoma Group, had medium to high levels of fatigue after 5 cancer-free years. Investigations are essential to determine the current status of long-term survivors in more detail and to link that status to conditions observed during the treatment of acutely ill patients.

Key Words. Fatigue • Quality of life • Anemia • Neoplasms

	INTRODUCTION

Top Learning Objectives Abstract Introduction What Is Fatigue? Why Should We Assess... How Do We Assess... What Have We Learned? What Are Our Goals? References

 
The years from 1966 to 2001 have produced increasing numbers of publications on cancer-related fatigue. More than 300 publications appear in the National Library of Medicine’s database, MEDLINE, under a search for "neoplasms" and "fatigue" in 2001 alone, and interest in the subject is still growing. Fatigue is said to be the symptom most frequently reported by oncology patients. Different studies state that about 75% of patients will report fatigue during or after treatment [1].

	WHAT IS FATIGUE?

Top Learning Objectives Abstract Introduction What Is Fatigue? Why Should We Assess... How Do We Assess... What Have We Learned? What Are Our Goals? References

 
In the languages of English and French, the word fatigue is a commonly used and understood term. In other languages, it is not, so it has to be defined. Fatigue refers broadly to a sense of malaise, tiredness, exhaustion, or feeling sick. There are also several other aspects of the term: affective and cognitive meanings such as "worn out," "overexerted," "overstressed," or "distracted." The clinical concept of fatigue is a much more complex and interesting idea.

Healthy people will typically feel exhausted and fatigued after sleep deprivation. But this is normal fatigue; if healthy people sleep, their fatigue dissipates, and they feel recovered. People with diseases, even very common diseases (e.g., a simple flu), can feel extremely fatigued. Once the flu is over, however, the fatigue is gone.

Fatigue in oncology patients is a very different concept. These patients experience fatigue, in relation to their therapy and their tumor, that has very specific phenomena and that differs not only from fatigue in healthy people, but also from fatigue in people suffering from other diseases. A simple definition of fatigue is that it is a feeling and a state of tiredness that exceeds the norm and is experienced as clearly unpleasant.

The medical context of fatigue is very broad. It can be a symptom (e.g., a symptom of depression) or a syndrome (e.g., fatigue syndrome in relation to cancer). It can even be regarded as—although this is still controversial—a disease on its own (e.g., chronic fatigue syndrome). It can be a result of side effects of chemotherapy or late effects after radiation.

Any discussion of fatigue should address at least two dimensions of the problem. There is the subjective dimension, or what patients say they experience when they talk about fatigue. In general, this dimension has at least three aspects: physical, emotional, and cognitive. There is also an objective dimension. This is related to the functional parameters of organ systems; for example, fatigue can originate in the hematopoietic system and may appear as anemia (for which drugs are available). But other organ systems, such as the respiratory system and the immune system, may also be responsible for fatigue. These two dimensions correlate with two descriptions of fatigue: A) as a general phenomenon relating to a patient’s overall well-being and B) as a specific phenomenon in the sense of cancer-related fatigue.

	WHY SHOULD WE ASSESS FATIGUE?

Top Learning Objectives Abstract Introduction What Is Fatigue? Why Should We Assess... How Do We Assess... What Have We Learned? What Are Our Goals? References

 
At a research level, the assessment of fatigue is clearly necessary to evaluate treatments. It is also necessary for the design of new approaches and new ways to monitor the effectiveness of interventions, for the improvement of clinicians’ knowledge and awareness of patients’ needs, and for the development of appropriate strategies for individual patient care.

The impact of fatigue on the quality of life of oncology patients is under-recognized. Fatigue is associated with a range of negative effects, starting with a decrease in activity requiring physical exertion and including the profound loss of the feeling of being in control. Many patients report that they cannot partake in activities as they did before, so they lose control of parts of their life; ultimately, this can lead to feelings of loneliness and isolation and a further decrease in activity. This vicious cycle puts the patient in a distressing position.

The prevalence of cancer-related fatigue is another major reason that fatigue assessment is important. As noted earlier, it is present in the majority of patients. An estimated 60%–96% of cancer patients in treatment experience fatigue, including 60%–93% of those on radiotherapy and 80%–96% of those on chemotherapy. Fatigue is very common after surgery or treatment with a biologic response modifier. In addition to treatment, fatigue is associated with neoplasms and other comorbid conditions. It increases with advanced disease and is related to anemia, depression, cachexia, pain, and insomnia [2].

In Germany, and within the European Organization for Research and Treatment of Cancer (EORTC), we recently conducted an investigation of fatigue levels in a patient population of 389 female cancer patients and 1,139 healthy female controls (Fig. 1) [3]. As expected, normal fatigue increased with age, as shown on a scale from 0 to 100 where 0 represented no fatigue and 100 represented the highest level of fatigue. Cancer patients reported much higher levels of fatigue. Scores for the healthy German female population ranged from around 10 to 15, although they increased to more than 30 in older women. The cancer patients scored much higher, with younger patients scoring in the range of 30 to 40 and older patients scoring higher. In general, levels over 40 suggest an inpatient population reporting on fatigue.

View larger version (24K): [in this window] [in a new window]   Figure 1. Fatigue scores in cancer patients versus the general female population using the EORTC QLQ-30.

View larger version (25K): [in this window] [in a new window]   Figure 2. Fatigue scores in cancer patients versus the general male population using the EORTC QLQ-30.

	HOW DO WE ASSESS FATIGUE?

Top Learning Objectives Abstract Introduction What Is Fatigue? Why Should We Assess... How Do We Assess... What Have We Learned? What Are Our Goals? References

Fatigue is objectively assessed using a variety of instruments. Some, like the EORTC questionnaire [4], the Functional Assessment of Cancer Therapy (FACT) questionnaire by Cella et al. [5], and the Profile of Mood States [6], address fatigue in certain parts of the instrument (e.g., the fatigue scale of the EORTC QLQ-C30). In addition, there have been new, fatigue-specific instruments developed that deal with fatigue as a multidimensional phenomenon. Some instruments measure the intensity of fatigue; others also deal with its interference in the activities of daily living or with the duration of fatigue.

A good fatigue scale requires minimal patient input. It is valid and reliable, with easily understood items. Scoring and interpretation are straightforward. It should be easily translated and cross-culturally valid. One example is the Multidimensional Fatigue Inventory (MFI), first published by Smets et al. in 1995 [7], which has many of these characteristics. It is a 20-item instrument that includes five different fatigue subdimensions: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. It has demonstrated good psychometric properties in some trials, but it is not yet fully internationally validated.

	WHAT HAVE WE LEARNED?

Top Learning Objectives Abstract Introduction What Is Fatigue? Why Should We Assess... How Do We Assess... What Have We Learned? What Are Our Goals? References

 
Fatigue During Treatment—Impact of Anemia
It is well known that anemia has a significant impact on a patient’s level of fatigue and quality of life. Some studies have focused on the way that erythropoietin treatment for anemia may affect fatigue and quality of life in patients undergoing chemotherapy. Abels [8], for example, found, in a placebo-controlled randomized trial, that patients who received erythropoietin to treat their anemia had a higher energy level, a greater ability to take part in the activities of daily living, and a better overall improvement in quality of life than did those who received a placebo. On a visual analogue scale (0–10), the change in overall quality of life was +6 for the erythropoietin group compared with -4 for the placebo group (p < 0.05).

Perhaps the most prominent study on this subject published over the past few years is by Littlewood et al. [9]. Using a randomized, controlled design and measuring the effect of the erythropoietin treatment using the FACT scales of anemia and fatigue, these investigators demonstrated that treatment with epoetin alfa to increase hemoglobin level had positive effects on patients’ quality of life.

But what do these data mean? Recent follow-on studies by Cella et al. [10] and Patrick et al. [11] using two different methodologies address the clinical significance of changes in quality of life scores. These studies independently conclude that the changes seen in the Littlewood trial [9] are clinically meaningful to patients.

Effect of Fatigue Intensity
In some trials from the EORTC Lymphoma Group and the German Hodgkin Study Group, we assessed fatigue using the subscale of a general assessment questionnaire, the EORTC QLQ-C30, and the five subscales of the MFI [12]. Longitudinal data obtained from healthy control groups and a cross-sectional trial indicate that patients scored quite high on the physical functioning scale of the EORTC quality-of-life instrument. Almost 7 years after the end of treatment, these people had recovered and stayed in the midrange of functioning; they did not recover fully, but they stabilized in general. This is a finding expected in many populations of cancer survivors; patients show limitations after the end of treatment, but ultimately reach a reasonably good level of functioning.

Looking into subpopulations of these total populations produces a totally different picture. The control group usually scored around 10 on the fatigue assessment scale. Cancer patients who expressed very low levels of fatigue, scoring less than 20 on the scale, showed almost no limitations in physical functioning, even at early time points after the end of treatment; they returned to normal after treatment. They resembled a healthy control group. Those who scored over 40 at the time of treatment, however, reported quite extreme limitations in physical functioning. They recovered after treatment, but they did not recover fully. At least some subpopulations experienced much higher levels of fatigue and limitations of functioning.

This phenomenon is evident in other quality-of-life domains as well. In the area of emotional functioning, again there are differences between patients who scored low on the fatigue scale and those who scored high. There were extreme limitations in emotional functioning among those with high fatigue scores; a low level of emotional functioning, a low spirit, was apparent. Even those who felt relatively well physically did not return to high levels of emotional functioning.

An examination of the overall quality of life produced a similar picture. The quality of life for those patients with low levels of fatigue returned essentially to normal, while that for those patients with high levels of fatigue remained substandard even 6–7 years after the end of treatment.

Patterns of Recovery
Analyses of these data suggest that there are at least four recovery patterns among people who have undergone cancer treatment for diseases like Hodgkin’s disease.

• Patients improve in their functioning, reach a plateau at approximately year 2 or 3, and then remain at relatively high levels of functioning.
  
• Patients may improve initially, but deteriorate again after year 2 or 3. They never reach the normal stage.
  
• Patients improve, returning to normal with very low fatigue levels.
  
• A final group of patients experience a mixed pattern of high levels of fatigue that is very difficult to interpret.
  

In various quality-of-life domains, we were able to separate patients into groups according to their limitations in functioning and patterns of recovery over time. We have assessments on these patients from 6 months until 6–8 years after the end of therapy. More than 40% of the patients scored lower than 60 on physical functioning (0–100 scale with 100 being the maximum of functioning) shortly after therapy, which we expected, and from which they did recover. This percentage went down as time passed after treatment, and at the end, only about 20% reported very low physical functioning and limitations. But still, 20% were physically not well. The percentage of the population reporting a high functioning level (i.e., scores of 80 and above) and the least limitation in physical functioning increased over time to almost 70% of all patients.

In the area of emotional functioning, findings are different. Not much change over time was evident here. Seven years after treatment, 50% of the patients still reported limitations in emotional functioning. The picture gets even worse in the area of global quality of life. After 6–7 years, only 40% reported a good quality of life, while almost 60% reported limitations—and this was in a cancer-free population.

Results from these trials point to the potential for a new and disturbing finding. Fatigue scores of 40 to 100 as the high parameter cover 45% of the patients. These patients reported higher levels of fatigue 6 months after the end of treatment. This percentage declined until year 2 to 3 (to 18%) and then rose again. At the end of the observation period, almost 30% reported high levels of fatigue again. The midrange population did not change very much, and the population reporting low levels of fatigue reached 40%; however, this means that 60% of patients had medium to high levels of fatigue after 5 cancer-free years.

Almost one third of patients reported severe limitations due to fatigue, and the profession must deal with this. We need to determine what is happening and to resolve this condition not only with psychological treatment, but also with other interventions. Investigations are essential to determine the current status of long-term survivors in more detail and to link it to the conditions observed during the treatment of acutely ill patients.

	WHAT ARE OUR GOALS?

Top Learning Objectives Abstract Introduction What Is Fatigue? Why Should We Assess... How Do We Assess... What Have We Learned? What Are Our Goals? References

 
One of the primary goals is to identify subgroups within any population being treated for cancer that are at high risk for an unfavorable outcome (i.e., for high levels of fatigue). A high degree of fatigue prevents patients from returning to work and keeps them from being able to lead a normal life. It is important to clarify further the differences between patients at high risk for this outcome and those at low risk. In addition, it is necessary to determine the significance of these differences. Are they clinically significant or are they only statistically significant? Finally, there is clearly a need to develop suitable interventions.

	ACKNOWLEDGMENT

Top Learning Objectives Abstract Introduction What Is Fatigue? Why Should We Assess... How Do We Assess... What Have We Learned? What Are Our Goals? References

 
Henning Flechtner has received honorarium from Ortho Biotech.

	REFERENCES

Top Learning Objectives Abstract Introduction What Is Fatigue? Why Should We Assess... How Do We Assess... What Have We Learned? What Are Our Goals? References

 

1. Curt GA. The impact of fatigue on patients with cancer: overview of FATIGUE 1 and 2. The Oncologist 2000;5(suppl 2):9–12.[Abstract/Free Full Text]
2. Cella D, Peterman A, Passik S et al. Progress toward guidelines for the management of fatigue. Oncology (Huntingt) 1998;12:369–377.[Medline]
3. Schwarz R, Hinz A. Reference data for the quality of life questionnaire EORTC QLQ-C30 in the general German population. Eur J Cancer 2001;37:1345–1351.
4. Aaronson NK, Ahmedzai S, Bergman B et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–376.[Abstract/Free Full Text]
5. Cella DF, Tulsky DS, Gray G et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 1993;11:570–579.[Abstract/Free Full Text]
6. McNair DM, Lorr M, Droppelman LF. Profile of Mood States Manual. San Diego: Educational and Industrial Testing Service, 1992.
7. Smets EM, Garssen B, Bonke B et al. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995;39:315–325.[CrossRef][Medline]
8. Abels R. Erythropoietin for anaemia in cancer patients. Eur J Cancer 1993;29A(suppl 2):S2–S8.
9. Littlewood TJ, Bajetta E, Nortier JW et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2001;19:2865–2874.[Abstract/Free Full Text]
10. Cella D, Zagari MJ, Vandoros C et al. Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol 2003;21:366–373.[Abstract/Free Full Text]
11. Patrick DL, Gagnon DD, Zagari MJ et al. Assessing the clinical significance of health-related quality of life (HrQOL) improvements in anaemic cancer patients receiving epoetin alfa. Eur J Cancer 2003;39:335–345.
12. Flechtner H, Rueffer JU, Henry-Amar M et al. Quality of life assessment in Hodgkin’s disease: a new comprehensive approach. First experiences from the EORTC/GELA and GHSG trials. Ann Oncol 1998;9(suppl 5):S147–S154.

This article has been cited by other articles:

				E. J. Corwin, L. E. Murray-Kolb, and J. L. Beard Low Hemoglobin Level Is a Risk Factor for Postpartum Depression J. Nutr., December 1, 2003; 133(12): 4139 - 4142. [Abstract] [Full Text] [PDF]

				E. K. Rowinsky Crossing the Cancer Cell Membrane to Improve Clinical Outcomes Oncologist, December 1, 2003; 8(90003): 1 - 4. [Full Text] [PDF]

				P. A. Daly Introduction: All Ireland Fatigue Coalition Oncologist, February 1, 2003; 8(90001): 1 - 2. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Flechtner, H. Articles by Bottomley, A. Search for Related Content PubMed PubMed Citation Articles by Flechtner, H. Articles by Bottomley, A.