Fatigue has been defined
subjective state of overwhelming, sustained exhaustion and decreased capacity for physical and mental work
that is not relieved by rest." Fatigue can result in diminished physical
or mental performance, or both. However vague the definition of fatigue may be,
patients with cancer, and particularly those patients treated with chemotherapy
or radiation, overwhelmingly complain of fatigue. Fatigue may result from a
number of factors including lack of sleep, deconditioning, anemia, loss of
muscle mass, or muscle substrate depletion (in endurance athletes). For the
purposes of this article, fatigue related to lack of sleep and muscle substrate
depletion will not be considered.
The fatigue that is related to cancer and its treatment,
however, is most likely due to low hemoglobin resulting in a decreased maximal
rate of oxygen consumption, which will further limit physical activity and lead
to deconditioning (loss of fitness). To address the issue of fatigue in cancer
patients, a comprehensive rehabilitation strategy that treats each of the causes
of fatigue will very likely result in increased quality of life and a greatly
improved functional capacity.
The ability to perform most activities of daily living is
critical for an individual to remain independent. Advancing age is often
associated with decreased functional capacity and loss of independence. However,
the process leading to decreased functional status among elderly people is often
gradual, occurring over many years. The loss of functional capacity and the
fatigue that is associated with cancer (and its treatment) is too often very
rapid. Estimates of the proportion of cancer patients who complain of fatigue or
severe fatigue is astonishingly high; 70% to 96% of all cancer patients
experience fatigue during chemotherapy or radiation therapy.[2-4]
Physical function may be measured in a great many ways;
however, one of the most fundamental measures is maximal aerobic capacity or VO2max.
(volume of oxygen consumed during maximal aerobic exercise) is defined by the
Fick equation (VO2
= cardiac output times the arterial-venous oxygen difference). VO2max
is expressed as either milliliter O2
consumed per kilogram of body weight per minute (mL O2
x kg-1 x min-1) or
liters of O2
consumed per minute (L/min). VO2max
measured as mL O2
x kg-1 x min-1 is
most often used to define an individual’s aerobic capacity because it takes
into account differences in body weight. VO2max
is a total, integrated measurement and includes the capacity to inhale
sufficient quantities of oxygen, extract oxygen by the lungs, carry oxygen by
the red blood cells, deliver oxygen (blood) by cardiac output, diffuse oxygen
through capillaries, diffusion into muscle cells and binding to myoglobin, and
oxidative phosphorylation in muscle mitochondria for adenosine triphosphate
The Fick equation demonstrates two important determiners of VO2max:
Central factors that control the delivery of oxygen to skeletal muscle, and the
capacity of skeletal muscle to extract and utilize oxygen for adenosine
triphosphate during exercise. Regularly performed aerobic exercise increases VO2max
through several mechanisms: (1) increased cardiac output resulting from a plasma
volume expansion (approximately 15%), and increased stroke volume as a result of
cardiac hypertrophy; (2) improved capacity to extract and use oxygen by skeletal
muscle. This enhanced oxidative capacity of muscle is due to increased
capillarization, mitochondrial density, and myoglobin content.
While VO2max provides a measurement of the maximum capacity for oxygen consumption, few
individuals actually exercise or work at an intensity that is equal to their VO2max
during the normal course of a day (Figure 1). A diminished maximal aerobic
capacity can greatly limit the performance of activities of daily living. For
example, the oxygen cost of walking at a pace of 2 miles per hour (a relatively
slow pace) for a 60-kg individual is almost maximal for many patients with
cancer. If this individual has a VO2max of 15 mL/kg/min, he or she can only consume a maximum of 0.9 L of oxygen/min.
There are only a few studies that have reported the VO2max of men and women with cancer, and, therefore, these studies may not be truly
representative of the population of adult patients; however these reports
demonstrate very low levels of VO2max .
Table 1 shows the average values for
VO2max of cancer patients.[5-8] In individuals who are functionally intact with no
impairment in oxygen delivery, virtually all activities of daily living are
performed at a low to moderate exercise intensity. Most individuals pace
themselves as an intensity of about 50% of VO2max when asked to perform work over a sustained period (walking, for example).
For men and women with very low levels of VO2max,
one can see that self-paced activities at 50% to 60% of maximal capacity is
significantly lower than the oxygen costs of most activities of daily living.
One factor leading to fatigue in individuals with a low VO2max
is a phenomenon that has been termed the aerobic threshold. During exercise of
any intensity, skeletal muscle produces lactic acid and consumes lactic acid as
a fuel for energy production. As exercise intensity and VO2max increases, lactic acid production and consumption also increases. As the
intensity of exercise increases, at some point the production of lactic acid by
muscle exceeds consumption and blood lactate accumulation begins. This is the
anaerobic threshold. This increasing lactic acid level of blood (and muscle)
results in increased respiration and heart rate[10,11] and an overall feeling of
fatigue. The exercise intensity that generally corresponds to the anaerobic
threshold in sedentary individuals is approximately 60% of VO2max.
For a cancer patient with an already low VO2max,
this means that performing most activities of daily living requires an intensity
greater than the anaerobic threshold. It is, therefore, easy to see why most
physical activity will lead to an overwhelming feeling of fatigue. Figure 2
shows the oxygen cost of many activities of daily living compared with the VO2max
of a cancer patient with symptoms of fatigue.
Under most conditions, the delivery of oxygen (cardiac
output) limits VO2maxthat
is, the capacity to extract and use oxygen by skeletal muscle is greater than
the capacity to deliver oxygen. Because of this, a number of investigators have
demonstrated a remarkably close relationship between hemoglobin and VO2max.
Increasing blood hemoglobin concentration (from anemic to normal or from normal
to supernormal) has been demonstrated to increase VO2max and submaximal exercise performance.[12-15] Anemia due to malnutrition has been
demonstrated to limit functional status and work capacity. On the other
hand, aerobic exercise performance in athletes can be substantially improved by
increasing hemoglobin levels above normal through the use of recombinant human
erythropoietin (Figure 3).
Anemia is a frequent consequence of cancer and the use of
chemotherapy. This anemia of chemotherapy responds to the use of recombinant
human erythropoietin, with a number of studies demonstrating significant
improvements in hemoglobin levels.[18,19] The development of anemia in cancer
patients and its subsequent treatment with erythropoietin is strongly associated
with quality of life. Two large, multicenter trials demonstrated that increasing
hemoglobin levels were associated with a significant improvement in energy
level, activity level, functional status, and overall quality of life.[20,21]
These studies show a clear benefit for the treatment of anemia in enhancing
quality of life and decreasing symptoms of fatigue. However, these studies used
qualitative end points (ie, questionnaire, self-reported fatigue) and no direct
measure of functional status.
While there are very few studies in cancer patients examining
the effects of both correcting anemia and exercise training, there is evidence
of improvements in functional capacity by increasing hemoglobin levels in
hemodialysis patients. Lundin demonstrated a 50% (± 0.9%) increase
in VO2max when recombinant human erythropoietin was used to increase hemoglobin levels
from an average 7.1 (± 1.4) to 9.8 (± 2.1) g/dL in men and women
undergoing hemodialysis. Metra also demonstrated a significant improvement in VO2max
in severely anemic hemodialysis patients after use of recombinant human
erythropoietin. Akiba, too, described such a study in patients receiving
VO2max was measured in anemic dialysis patients before and following treatment with
erythropoietin. The patients experienced a significant increase in aerobic
capacity (approximately 20% improvement). The patients were then divided into a
3-month aerobic exercise training and sedentary control group. Those patients
randomized to the control group demonstrated a decrease in VO2max (despite unchanged hemoglobin levels), while those participating in exercise
showed a significant and substantial increase in exercise capacity. These
results demonstrated that erythropoietin can result in improved function, but
some of the decreased VO2max and functional capacity seen in these patients was because of inactivity.
In one of the few studies examining the effects of anemia and
cancer on exercise capacity, Daneryd examined 108 selected cancer patients
experiencing involuntary weight loss. They randomized these patients to
recombinant human erythropoietin (epoetin alfa [Epogen, Procrit]) or
indomethacin (Indocin) treatment. While there was no difference in mortality
between the two groups, the patients treated with erythropoietin did not become
anemic and preserved their exercise capacity. The patients who did not receive
erythropoietin demonstrated a significant decrease in hemoglobin and a
concomitant decrease in VO2max and functional capacity. These investigators concluded "the institution of
early and prophylactic erythropoietin treatment to patients with progressive
cancer prevents development of tumor-induced anemia. This achievement was
associated with a better preserved exercise capacity, which is explained in part
by improved whole-body metabolic and energy efficiency during work load."
This study demonstrates the importance of maintaining or
improving hemoglobin levels to prevent a decrease in functional capacity in men
and women with cancer.
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