213

E D I T O R I A L

Fatigue Is Becoming an
Exhausting Problem
John C. Ruckdeschel,

M.D.

Karmanos Cancer Institute, Detroit, Michigan.

See referenced original article on pages 377 82.

Address for reprints: John C. Ruckdeschel, M.D.,
Karmanos Cancer Institute, Executive Ofce, 4100
John R, Detroit, MI 48201; Fax: (313) 993-7165;
E-mail: ruckdeschel@karmanos.org
Received September 13, 2004; accepted September 20, 2004.

ver the past quarter of a century, we have learned how to manage

the infectious complications of chemotherapy and the disabling
nausea and emesis that was such a feature of the early platinum era.
What we have been left with, however, is profound fatigue as one of
the major complaints of patients on chemotherapy. Brown and colleagues from Scotland have given us an intriguing study that sought to
sort out many of the issues related to fatigue, but, like any good
report, proposes more questions than it answers.1
Those authors examined a population of 38 patients with advanced lung cancer who were not on therapy and 15 age-matched and
gender-matched normal controls. They included measures of depression, anxiety, inammation, physical function, anemia, and performance status. Physical function was operationalized as either grip
strength or chair-rise time to make it somewhat less subjective. Not
surprisingly, the cancer patients were more fatigued, more depressed,
had poorer physical function and performance status, and had elevations of several markers of inammation. In a multivariate analysis
of the relation to fatigue, only performance status, a weakness score,
and the anxiety and depression scores were correlated signicantly.
Brown et al. concluded that physical functioning was poorer with
increasing fatigue and that fatigue was related to performance status
and psychological distress and not to weight loss or anemia.1
The failure to use chemotherapy in lung cancer (therapeutic
nihilism) and the failure of nonsmall cell lung carcinoma to cause
signicant anemia on its own removed the impact of anemia from the
trial by Brown et al. and, no doubt, led to the lack of a correlation with
fatigue. This helps us sort out the other contributory factors but
makes the results less universal.
Indeed, because there is such an extraordinarily lucrative market
in the therapy of anemia, our focus on fatigue has been skewed in this
direction. What this trial conrms is that, even absent signicant
anemia, there is signicant fatigue.
The trial is not without its problems, however, not the least of
which is the relatively small number of patients studied. There is only
a sparse description of the cancer patients, with only a series of
average scores with wide standard deviations presented. The attempt
to use chair-rise time as a surrogate for physical function is not
unreasonable; however, lacking a description of the numbers of patients with painful bone metastases or other conditions that may limit
mobility, we are left to wonder about the ability to generalize this
nding.

2004 American Cancer Society

DOI 10.1002/cncr.20770
Published online 22 November 2004 in Wiley InterScience (www.interscience.wiley.com).

214

CANCER January 15, 2005 / Volume 103 / Number 2

What is most unclear is the sequence of events.

Does diminished physical functioning predate and
contribute to fatigue, or does it always follow fatigue?
If fatigue is the rst step, then focusing on the psychological distress, anemia, and other contributors to
fatigue should be more productive. If diminished
physical functioning antedates fatigue, then focusing
on the behavioral and inammatory factors that may
lead to diminished physical activity would be more
productive. The ability of aerobic exercise programs to
overcome fatigue suggests that there are elements of
physical functioning that are important in the later
development of fatigue.2,3 Conversely, both fatigue
and diminished physical activity may be secondary to
an earlier event or series of events, including, for
example, depression.
An array of possible antecedent events, including
abnormalities of energy metabolism,4 neurophysiologic changes in muscle,5 chronic stress responses,6 8
anxiety and depressive disorders,9 11 specic treatments,1214 concomitant systemic diseases,15 and hypothalamic-pituitary axis dysfunction,6 8 have been
proposed and discussed extensively.16 What is lacking
to date is the ability to assess whether these changes
cause the later fatigue or whether they merely are
associated with its development.
I have long had a certain amount of skepticism
about the mind-body connection and its relation to
cancer.17 However, there is some intriguing and, at
rst glance, unrelated data that suggest there is a
systemic affect that precedes the development of the
clinical fatigue syndromes we are accustomed to seeing. In the middle 1980s, the Lung Cancer Study
Group took a relatively unsophisticated look at quality
of life in patients with early-stage, resected lung cancer.18 That group found that a simple quality-of-life
questionnaire administered to patients with earlystage lung cancer prior to any intervention was
strongly predictive of survival. Several different groups
have corroborated this nding in a number of different malignancies.19 21 The Lung Cancer Study Group
report was all the more signicant, because this nding was noted in a group of patients with early-stage
disease who had not yet had any of the confounding
effects of therapy. What is it that these patients sense
that causes them to report a lower quality of life
after controlling for disease stage, age, gender, and
performance status? Is it a product of tumor growth
and metabolism, such as proteolysis-inducing factor,2224 that leads to a catabolic state that can be
sensed but cannot be articulated well?
Depression has long been associated with cancer,
although the evidence is strongest that the depression
is reactive or secondary to the cancer diagnosis rather

than etiologic for the cancer itself. A broad metaanalysis of cancer and depression showed that, overall, 24% (range, 15 42%) of cancer patients were depressed without regard to tumor type, disease stage, or
disease status.9 This may have been an underestimate,
particularly for a disease like lung cancer, in which
therapeutic nihilism is rampant, and patients often
are given little or no hope of cure or lasting remission.
The current study by Brown et al. is compatible with
the concept that depression precedes fatigue, in that
all of the patients studied were end-stage lung cancer
patients who were receiving no therapy, and depression was one of the signicant correlates.
What is needed is a study of these events with
physical, behavioral, biologic, and hematologic measures taken serially over time. One problem will be
which measures to choose; however, hopefully, a consensus could be reached. More important is the population to study. It should be a population-based
study using individuals without cancer at the onset. It
is possible that much of these data reside in existing
populations and serum samples, such as the Womens
Health Initiative or the Framingham Heart Study.
Although there is no question that agents that
stimulate erythropoiesis are useful in combating some
of the symptoms of fatigue,25 it equally is clear that
anemia is not the mechanism for all cases of fatigue.
We need to move our exploration of the early events in
the development of fatigue far earlier in the pathway
that leads to clinical fatigue. If we are fortunate and
there is a common pathway by which multiple events
related to the tumor or its treatment can cause fatigue,
then addressing that pathway will be more productive
than trying to treat empirically.

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