Fatigue has been defined as "a subjective state of overwhelming, sustained exhaustion and decreased capacity for physical and mental work that is not relieved by rest."[1] 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.
Cancer-Related Anemia
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]
Functional Capacity
Physical function may be measured in a great many ways; however, one of the most fundamental measures is maximal aerobic capacity or VO2max. VO2 (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(Drug information on adenosine) triphosphate production.
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).[9] 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(Drug information on 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.
Aerobic Capacity
Under most conditions, the delivery of oxygen (cardiac output) limits VO2max—that 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.[16] 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(Drug information on erythropoietin) (Figure 3).[17]
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.
Hemodialysis Patients
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[22] 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.[23] Akiba, too, described such a study in patients receiving hemodialysis.[24]
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.
Cancer Patients
In one of the few studies examining the effects of anemia and cancer on exercise capacity, Daneryd[6] 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.
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
