Physical Function in Men and Women With Cancer

ABSTRACT: Fatigue is an extraordinarily common consequence of cancer and its treatment. Fatigue can result in diminished cognitive and physical functional capacity and may be the result of multiple causes. However, aside from psychological factors, the main physiological factors leading to fatigue in cancer patients are anemia, severe deconditioning, and muscle wasting that is secondary to cachexia. One of the most common measures of functional capacity is maximal aerobic capacity, also called VO2max. VO2max is a measurement of the maximal capacity of the entire cardiorespiratory system and muscles to consume oxygen. It is strongly predictive of functional status, and it is strongly related to circulating hemoglobin. Research has indicated that the use of recombinant human erythropoietin to treat anemia can preserve or increase VO2max. In addition, aerobic exercise training has been demonstrated to greatly relieve symptoms of fatigue in patients with cancer. It is both safe and effective in this patient population. Muscle wasting results in diminished protein reserve and extreme muscle weakness. Progressive resistance exercise training has been demonstrated to greatly increase strength, improve protein balance, and increase muscle mass even in very frail and old men and women. It should be strongly encouraged in patients experiencing muscle wasting and weakness. A comprehensive "cancer rehabilitation" program is described, which is made up of (1) correcting anemia related to cancer or its treatment; (2) aerobic conditioning to improve VO2max; and (3) progressive resistance exercise in patients experiencing muscle weakness or wasting. In this way, the physiological causes of fatigue may be addressed and quality of life improved. [ONCOLOGY 16(Suppl 10):109-115, 2002]

Fatigue has been definedas "asubjective state of overwhelming, sustained exhaustion and decreased capacity for physical and mental workthat is not relieved by rest."[1] Fatigue can result in diminished physicalor mental performance, or both. However vague the definition of fatigue may be,patients with cancer, and particularly those patients treated with chemotherapyor radiation, overwhelmingly complain of fatigue. Fatigue may result from anumber of factors including lack of sleep, deconditioning, anemia, loss ofmuscle mass, or muscle substrate depletion (in endurance athletes). For thepurposes of this article, fatigue related to lack of sleep and muscle substratedepletion 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 maximalrate of oxygen consumption, which will further limit physical activity and leadto deconditioning (loss of fitness). To address the issue of fatigue in cancerpatients, a comprehensive rehabilitation strategy that treats each of the causesof fatigue will very likely result in increased quality of life and a greatlyimproved functional capacity.

The ability to perform most activities of daily living iscritical for an individual to remain independent. Advancing age is oftenassociated with decreased functional capacity and loss of independence. However,the process leading to decreased functional status among elderly people is oftengradual, occurring over many years. The loss of functional capacity and thefatigue that is associated with cancer (and its treatment) is too often veryrapid. Estimates of the proportion of cancer patients who complain of fatigue orsevere fatigue is astonishingly high; 70% to 96% of all cancer patientsexperience 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 theFick equation (VO₂= cardiac output times the arterial-venous oxygen difference). VO₂maxis expressed as either milliliter O₂consumed per kilogram of body weight per minute (mL O₂x kg^-1 x min^-1) orliters of O₂consumed per minute (L/min). VO₂maxmeasured as mL O₂x kg^-1 x min^-1 ismost often used to define an individual’s aerobic capacity because it takesinto account differences in body weight. VO₂maxis a total, integrated measurement and includes the capacity to inhalesufficient quantities of oxygen, extract oxygen by the lungs, carry oxygen bythe red blood cells, deliver oxygen (blood) by cardiac output, diffuse oxygenthrough capillaries, diffusion into muscle cells and binding to myoglobin, andoxidative phosphorylation in muscle mitochondria for adenosine triphosphateproduction.

The Fick equation demonstrates two important determiners of VO₂max:Central factors that control the delivery of oxygen to skeletal muscle, and thecapacity of skeletal muscle to extract and utilize oxygen for adenosinetriphosphate during exercise. Regularly performed aerobic exercise increases VO₂maxthrough several mechanisms: (1) increased cardiac output resulting from a plasmavolume expansion (approximately 15%), and increased stroke volume as a result ofcardiac hypertrophy; (2) improved capacity to extract and use oxygen by skeletalmuscle. This enhanced oxidative capacity of muscle is due to increasedcapillarization, mitochondrial density, and myoglobin content.

While VO₂max provides a measurement of the maximum capacity for oxygen consumption, fewindividuals actually exercise or work at an intensity that is equal to their VO₂maxduring the normal course of a day (Figure 1). A diminished maximal aerobiccapacity can greatly limit the performance of activities of daily living. Forexample, the oxygen cost of walking at a pace of 2 miles per hour (a relativelyslow pace) for a 60-kg individual is almost maximal for many patients withcancer. 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 trulyrepresentative of the population of adult patients; however these reportsdemonstrate very low levels of VO₂max .

Table 1 shows the average values forVO₂max of cancer patients.[5-8] In individuals who are functionally intact with noimpairment in oxygen delivery, virtually all activities of daily living areperformed at a low to moderate exercise intensity. Most individuals pacethemselves 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 issignificantly lower than the oxygen costs of most activities of daily living.

One factor leading to fatigue in individuals with a low VO₂maxis a phenomenon that has been termed the aerobic threshold. During exercise ofany intensity, skeletal muscle produces lactic acid and consumes lactic acid asa fuel for energy production. As exercise intensity and VO₂max increases, lactic acid production and consumption also increases. As theintensity of exercise increases, at some point the production of lactic acid bymuscle exceeds consumption and blood lactate accumulation begins. This is theanaerobic threshold. This increasing lactic acid level of blood (and muscle)results in increased respiration and heart rate[10,11] and an overall feeling offatigue. The exercise intensity that generally corresponds to the anaerobicthreshold 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 intensitygreater than the anaerobic threshold. It is, therefore, easy to see why mostphysical activity will lead to an overwhelming feeling of fatigue. Figure 2shows the oxygen cost of many activities of daily living compared with the VO₂maxof a cancer patient with symptoms of fatigue.

Aerobic Capacity

Under most conditions, the delivery of oxygen (cardiacoutput) limits VO₂max—thatis, the capacity to extract and use oxygen by skeletal muscle is greater thanthe capacity to deliver oxygen. Because of this, a number of investigators havedemonstrated a remarkably close relationship between hemoglobin and VO₂max.Increasing blood hemoglobin concentration (from anemic to normal or from normalto supernormal) has been demonstrated to increase VO₂max and submaximal exercise performance.[12-15] Anemia due to malnutrition has beendemonstrated to limit functional status and work capacity.[16] On the otherhand, aerobic exercise performance in athletes can be substantially improved byincreasing hemoglobin levels above normal through the use of recombinant humanerythropoietin (Figure 3).[17]

Anemia is a frequent consequence of cancer and the use ofchemotherapy. This anemia of chemotherapy responds to the use of recombinanthuman erythropoietin, with a number of studies demonstrating significantimprovements in hemoglobin levels.[18,19] The development of anemia in cancerpatients and its subsequent treatment with erythropoietin is strongly associatedwith quality of life. Two large, multicenter trials demonstrated that increasinghemoglobin levels were associated with a significant improvement in energylevel, activity level, functional status, and overall quality of life.[20,21]These studies show a clear benefit for the treatment of anemia in enhancingquality of life and decreasing symptoms of fatigue. However, these studies usedqualitative end points (ie, questionnaire, self-reported fatigue) and no directmeasure of functional status.

Hemodialysis Patients

While there are very few studies in cancer patients examiningthe effects of both correcting anemia and exercise training, there is evidenceof improvements in functional capacity by increasing hemoglobin levels inhemodialysis patients. Lundin[22] demonstrated a 50% (± 0.9%) increasein VO₂max when recombinant human erythropoietin was used to increase hemoglobin levelsfrom an average 7.1 (± 1.4) to 9.8 (± 2.1) g/dL in men and womenundergoing hemodialysis. Metra also demonstrated a significant improvement in VO₂maxin severely anemic hemodialysis patients after use of recombinant humanerythropoietin.[23] Akiba, too, described such a study in patients receivinghemodialysis.[24]

VO₂max was measured in anemic dialysis patients before and following treatment witherythropoietin. The patients experienced a significant increase in aerobiccapacity (approximately 20% improvement). The patients were then divided into a3-month aerobic exercise training and sedentary control group. Those patientsrandomized to the control group demonstrated a decrease in VO₂max (despite unchanged hemoglobin levels), while those participating in exerciseshowed a significant and substantial increase in exercise capacity. Theseresults demonstrated that erythropoietin can result in improved function, butsome 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 andcancer on exercise capacity, Daneryd[6] examined 108 selected cancer patientsexperiencing involuntary weight loss. They randomized these patients torecombinant human erythropoietin (epoetin alfa [Epogen, Procrit]) orindomethacin (Indocin) treatment. While there was no difference in mortalitybetween the two groups, the patients treated with erythropoietin did not becomeanemic and preserved their exercise capacity. The patients who did not receiveerythropoietin demonstrated a significant decrease in hemoglobin and aconcomitant decrease in VO₂max and functional capacity. These investigators concluded "the institution ofearly and prophylactic erythropoietin treatment to patients with progressivecancer prevents development of tumor-induced anemia. This achievement wasassociated with a better preserved exercise capacity, which is explained in partby improved whole-body metabolic and energy efficiency during work load."

This study demonstrates the importance of maintaining orimproving hemoglobin levels to prevent a decrease in functional capacity in menand women with cancer.

Aerobic Conditioning

Decreased levels of physical activity result indeconditioning that is characterized by a decreased VO₂max.Complete bed rest results in a rapid and profound decrease in aerobiccapacity.[25-28] Because the fatigue related to cancer and its treatment may beassociated with deconditioning and reduced levels of physical activity, therehave been a few studies examining the effects of regularly performed exercise onfunctional status in cancer patients.

Cancer Patients

Dimeo and his colleagues[29] examined the effects of aerobicexercise in hospitalized cancer patients. They recruited patients receivinghigh-dose chemotherapy followed by autologous peripheral blood stem celltransplantation. A total of 33 patients were randomly assigned to a trainingprogram that consisted of interval type of training on a cycle ergometer whilesupine (30 min/d, 15 1-minute bouts at 50% of maximal heart rate reserve with1-minute rest periods) and a control group of patients who performed noexercise. The investigators saw a 27% greater loss in performance on a treadmillin controls compared with the exercised patients. Interestingly, theinvestigators observed significant decreases in duration of neutropenia andthrombocytopenia, severity of diarrhea, severity of pain, and duration ofhospitalization in the exercise group compared to control.

Schwartz et al[30] examined the effects of regular exerciseon self-reported fatigue in women (N = 72) with breast cancer receivingchemotherapy. They examined the effects of a home-based exercise program overthe first three cycles of chemotherapy and observed a significant reduction infatigue that was related to compliance to the exercise recommendations.

Segal et al[5] examined a large group of breast cancerpatients (N = 123) and demonstrated that when compared with control (noexercise) a self-directed and supervised exercise program produced a significantincrease in functional capacity and decrease in weight and fatigue.

In another study, Dimeo and coworkers[8] examined a smallnumber of cancer patients (N = 5), all of whom reported suffering from severefatigue for a time ranging from 5 weeks to 18 months and hindrance fromperforming normal daily activities because of this fatigue. All of the patientstrained on a motorized treadmill for 6 consecutive weeks at an intensity thathad been determined to correspond with a circulating lactate level of 3 mmol/L.(This value roughly corresponds to the anaerobic threshold.) As they becamebetter conditioned, their blood lactate levels began to fall during thetraining, and the speed of the treadmill was increased. In this way the trainingintensity remained constant.

The results were very instructive about the capacity ofcancer patients to respond to aerobic exercise training. The training speedincreased by 23% (P = .06) and the distance walked per session increasedby 100% (P < .05). Maximal exercise performance was also significantlyincreased. The authors concluded that "cancer patients suffering fromprimary fatigue should not be advised to increase the amount of daily rest.Rather they should be counseled to carry out aerobic exercise."

These studies demonstrated that regularly performed aerobicexercise training is both safe and effective in patients with cancer whetherthey are receiving chemotherapy or not. Increasing the amount of time that apatient is in bed resting will very likely cause a further deterioration of VO₂max,anaerobic threshold, and functional capacity—leading to an even greaterfeeling of fatigue.

Resistance Exercise

Strength conditioning, or progressive resistance training, isgenerally defined as training in which the resistance against which a musclegenerates force is progressively increased over time. Progressive resistancetraining involves few contractions against a heavy load. The metabolic andmorphologic adaptations resulting from resistance and endurance exercise arequite different. Muscle strength has been shown to increase in response totraining between 60% and 100% of the 1 repetition maximum (1 RM).[31] Themaximum amount of weight that can be lifted with one contraction is 1 RM.Strength conditioning will result in an increase in muscle size and thisincrease in size is largely the result of increased contractile proteins[32].

Cachexia

An important manifestation of cancer is cachexia, which maybe exacerbated by a variety of different methods of treatment. Cachexia ischaracterized by an accelerated loss of skeletal muscle, even with adequateenergy intake.[33] High-dose chemotherapy may accelerate this process, inaddition to having profoundly anorexigenic effects. Because of the greatlyreduced appetite that may result from the use of chemotherapy, orexigenic agentssuch as megestrol acetate (Megace) have been demonstrated to increase appetiteand body weight in patients with cancer.[34,35]

Megestrol acetate has a number of hormonal consequences, suchas greatly decreased testosterone and cortisol levels. Our laboratory recentlyreported the results of a randomized, double-blind trial designed to examine theeffects of megestrol acetate, resistance exercise training, and testosterone onfood intake, appetite, body weight and composition, and muscle size in elderly,underweight men. A total of 27 men, average age: 66 (±1.1) yrs, BMI: 23.2 (±0.6) kg/m²,were randomly assigned to one of four groups: megestrol acetate (800 mg/d) +placebo; megestrol acetate + testosterone (testosterone enanthate IM/once perwk); megestrol acetate + progressive resistance exercise training (80% of the 1RM, 3 times/wk) + placebo; megestrol acetate + progressive resistance exercisetraining + testosterone. The intervention was 3 months in duration. Aspreviously reported, megestrol acetate resulted in a large increase in appetite,food intake, and body weight.

On the other hand, megestrol acetate induced a large decreasein circulating testosterone levels that resulted in a significant andsubstantial decrease in muscle size (measured by computerized tomographyof the thighs). Testosterone replacement did not prevent the megestrolacetate-induced loss of muscle mass. Participation for 3 months in a progressiveresistance exercise training program prevented this loss of muscle and resultedin a substantial increase in strength.

Loss of Muscle Mass

While it is well recognized that testosterone ablationtherapy results in a loss of muscle mass[36], few studies have directly examinedthis phenomenon. Tayek et al[37] examined 10 men with advanced stage C and Dprostate cancer receiving testosterone ablation. They found that in allpatients, significant increases in body weight, triceps skin fold, cholesterol,and fat mass were noted (with no direct measure of muscle mass). Recently, Smithet al[38] examined the longitudinal effects of testosterone ablation on bodycomposition in men with prostate cancer and noted increased fat mass, decreasedfat-free mass, and increased insulin levels, suggesting that these changes inbody composition may affect insulin action.

Progressive bone loss and development of osteoporosis is acommon result of testosterone ablation in men with prostate cancer.[39,40]Accelerated loss of muscle mass in men with prostate cancer will not only resultin a substantial loss of strength, but a decrease in maximal aerobic capacity aswell. Treatment with hormones to arrest the loss in muscle mass is not aclinical option for this patient population. Use of progressive resistanceexercise, either prophylactically or to restore lost muscle mass in men withprostate cancer, would seem to be a useful strategy. Our studies examining theeffects of megestrol acetate in older men demonstrate that resistance exercisecan preserve muscle mass in the face of circulating testosterone at castratelevels.

We have applied a progressive resistance exercise program toa group of frail, institutionalized elderly men and women (mean age: 90 (±3)years; range: 87-96).[41] After 8 weeks of training, the 10 subjects in thisstudy increased muscle strength by almost 180% and muscle size by 11%.

More recently, a similar intervention on 100 frail nursinghome residents with multiple chronic diseases (25% with a diagnosis of cancer)demonstrated not only increases in muscle strength and size, but increased gaitspeed, stair climbing power, and balance.[42] In addition, spontaneous activitylevels increased significantly while the activity of a nonexercised controlgroup was unchanged. In this study the effects of a protein/calorie supplement,240 mL of liquid supplying 360 kcal in the form of carbohydrate (60%), fat(23%), and soy-based protein (17%), was designed to augment caloric intake byabout 20% and provide one-third of the RDA for vitamins and minerals) combinedwith exercise was also examined.

While no interaction was seen with muscle strength,functional capacity, or muscle size (no differences in improvements between thesupplemented group and a nonsupplemented control group), the men and women whoconsumed the supplement and exercised gained weight compared with the threeother groups examined (exercise/control, nonexercise/supplemented, andnonexercise/control). The nonexercising subjects who received the supplementreduced their habitual dietary energy intake so that total energy intake wasunchanged. It should be pointed out that this was a very old, very frailpopulation with diagnoses of multiple chronic diseases.

An increase in overall levels of physical activity has been acommon observation in our studies.[42-44] Since muscle weakness is a primarydeficit in many older individuals, increased strength may stimulate more aerobicactivities like walking and cycling.

Progressive resistance training has been demonstrated togreatly improve protein balance. That is, for any dietary protein intake,strength training results in decreased urinary nitrogen excretion and morepositive nitrogen balance. These effects of strength training have beendemonstrated in cachectic patients with AIDS[45] and in healthy elderly men andwomen.[46]

Conclusions

Decreasing mortality is, appropriately, the first and mostimportant consideration for clinicians treating patients with cancer.Unfortunately, all too often the consequences of this treatment are a feeling ofoverwhelming fatigue and a greatly diminished quality of life. An understandingof the potential benefits of an appropriate exercise program should lead to itsbecoming an integral component of a comprehensive treatment of fatigue relatedto cancer. More than 40 years ago, the clinical recommendation for patients witha recent myocardial infarction was increased rest. Cardiac rehabilitation is nowan important and life-saving intervention that results not only in decreasedmortality but also in a greatly improved quality of life.

A comprehensive program for the treatment of cancer-relatedfatigue must include a number of components. Among factors related to improvingphysiological functional capacity, the following should be strongly considered:

Treatment of anemia.Because a low hemoglobin level is strongly associated with aerobic capacity, thefirst line of treatment should be correction of hemoglobin to normal. This willmake the exercise recommendation much easier for the patient to perform. Whenpatients attempt to begin an exercise program while still anemic, it may resultin an exacerbation of their feeling of fatigue.

Aerobic exercisetraining. For many patients with cancer,anemia resulting from chemotherapy will result in fatigue and decreased physicalactivity. Deconditioning is likely a central factor in the etiology of fatigue.Aerobic exercise training has been demonstrated to be both safe and effective inreducing the symptoms of fatigue in cancer patients.

Progressive resistanceexercise training. Cancer and/or itstreatment often result in severe muscle wasting that leads to weakness andfatigue. Progressive resistance exercise may reduce the trajectory of loss ofmuscle or increase muscle mass in most patients. Patients with cancers that mayresult in bone metastases should be carefully studied to determine if aweight-bearing bone is involved.

A comprehensive fatigue management program should be thestandard of care in the treatment of this devastating problem. It is hoped that"cancer rehabilitation" is tested in a focused research program andimplemented as rapidly as possible by physicians and other medical personneltreating patients with cancer.

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