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Fatigue and Dyspnea
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Fatigue and Dyspnea
June 01, 2015
By Sriram Yennurajalingam, MD [1] and Eduardo Bruera, MD [2]
Fatigue and dyspnea are two of the most common symptoms associated with advanced cancer.
Fatigue is also commonly associated with cancer treatment and occurs in up to 90% of patients
undergoing chemotherapy.
Fatigue and dyspnea are two of the most common symptoms associated with advanced cancer.
Fatigue is also commonly associated with cancer treatment and occurs in up to 90% of patients
undergoing chemotherapy. Both symptoms have many possible underlying causes. In most patients,
the etiology of fatigue or dyspnea is multifactorial, with many contributing interrelated
abnormalities. In one study of patients with advanced cancer, fatigue was found to be significantly
correlated with the intensity of dyspnea. This chapter will discuss the mechanisms, clinical features,
assessment, and management of both of these troublesome and often undertreated symptoms in
cancer patients.
Fatigue
Cancer-related fatigue is defined by the National Comprehensive Cancer Network as “a distressing,
persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related
to cancer or cancer treatment that is not proportional to recent activity and interferes with usual
functioning.” In cancer patients, fatigue is often severe; has a marked anticipatory component; and
results in lack of energy, malaise, lethargy, and diminished mental functioning that profoundly
impairs quality of life. It may be present early in the course of the illness, may be exacerbated by
treatments, and is present in almost all patients with advanced cancer.
Fatigue is sometimes referred to as asthenia, tiredness, lack of energy, weakness, and exhaustion.
Not all of these terms have the same meaning to all patient populations. Moreover, different studies
of fatigue and asthenia have looked at different outcomes, ranging from physical performance to the
purely subjective sensation.
Mechanism
The mechanisms of cancer-related fatigue are not well understood. Substances produced by the
tumor are postulated to induce fatigue. When injected into a rested subject, blood from a fatigued
subject has produced manifestations of fatigue. The host production of cytokines in response to the
tumor can also have a direct fatigue-inducing effect. Muscular or neuromuscular junction
abnormalities are a possible cause of chemotherapy- or radiotherapy-induced fatigue. In summary,
fatigue is the result of many syndromes—not just one. Multiple mechanisms are involved in causing
fatigue in most patients with advanced cancer.
Clinical Features
The causes of fatigue in an individual patient are often multiple, with many interrelated factors.
Figure 1 summarizes the main contributors to fatigue in cancer patients.
FIGURE 1: Contributors to fatigue in cancer patients.
Cachexia
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Cancer cachexia results from a complex interaction of host and tumor products. Host cytokines such
as tumor necrosis factor, interleukin (IL)-1, and IL-6 are capable of causing decreased food intake,
loss of body weight, a decrease in synthesis of both lipids and proteins, and increased lipolysis. The
metabolic abnormalities involved in the production of cachexia and the loss of muscle mass resulting
from progressive cachexia may cause profound weakness and fatigue. However, many abnormalities
described in Figure 1 are capable of causing profound fatigue in the absence of significant weight
loss.
Immobility
Decreased physical activity has been shown to cause deconditioning and decreased endurance to
both exercise and normal activities of daily living. On the other hand, overexertion is a frequent
cause of fatigue in noncancer patients. It should also be considered in younger cancer patients who
are undergoing aggressive antineoplastic treatments such as radiation therapy and chemotherapy
and who are nevertheless trying to maintain their social and professional activities.
Psychological distress
In patients without cancer who present with fatigue, the final diagnosis is psychological (eg,
depression, anxiety, and other psychological disorders) in almost 75% of patients. The frequency of
major psychiatric disorders in cancer patients is low. However, symptoms of psychological distress or
adjustment disorders with depressive or anxious moods are much more frequent. Patients with an
adjustment disorder or a major depressive disorder can have fatigue as their most prevalent
symptom.
Anemia
Low red blood cell count related to advanced cancer or chemotherapy has been associated with
fatigue, and its treatment results in improvement of fatigue and quality of life in these patients. In
terminally ill patients with advanced cancer, treatment of anemia may not resolve fatigue
adequately because of the multifactorial nature of its etiology. Fatigue may be the result of the more
intense nature of the other contributory factors.
Autonomic failure
Autonomic insufficiency is a frequent complication of advanced cancer. Autonomic failure has also
been documented in patients with severe chronic fatigue syndrome. Although the association
between fatigue and autonomic dysfunction has not been established in cancer patients, it should be
suspected in patients with severe postural hypotension or other signs of autonomic failure.
Hypogonadism
Both intrathecal and systemic opioid therapies, as well as cachexia and some antineoplastic
therapies, can result in hypogonadotropic hypogonadism. This condition can lead to fatigue,
depression, and reduced libido.
Chemotherapy/radiotherapy
Chemotherapy and radiotherapy are common causes of fatigue in cancer patients. The pattern of
fatigue reported by patients with cancer who receive myelosuppressive chemotherapy is cyclical. It
begins within the first few days after therapy is started, peaks around the time of the white blood
cell nadir, and diminishes in the week thereafter, only to recur again with the next cycle of
chemotherapy. Fatigue tends to worsen with subsequent cycles of chemotherapy, which suggests a
cumulative dose-related toxic effect. Compared with women who have no history of cancer, former
patients with breast cancer who had received adjuvant chemotherapy reported more fatigue and
worse quality of life due to this symptom. Similar results have been noted in breast cancer patients
who have been treated with high-dose chemotherapy and autologous stem cell support and in
patients treated for lymphoma.
Radiation therapy tends to cause a different pattern of fatigue. It is often described as a “wave” that
starts abruptly within a few hours after treatment and subsides shortly thereafter. Fatigue has been
noted to decrease in the first 2 weeks after localized treatment for breast cancer but then to
increase as radiation therapy persists into week 4. It then decreases again 3 weeks after radiation
therapy ceases. The mechanism for fatigue in these situations is not well understood.
Administration of chemotherapy and radiotherapy for malignancy causes a specific fatigue
syndrome. Combined therapy with the two modalities appears to cause worse fatigue than does
either modality given alone.
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Surgery
Surgery is another common cause of fatigue in patients with cancer. In addition, commonly used
medications, such as opioids and hypnotics, may cause sedation and fatigue.
Other
Comorbid conditions not necessarily related to cancer, such as renal failure and congestive heart
failure, may coexist and contribute to the problem. Other conditions include the chronic stress
response (possibly mediated through the hypothalamic-pituitary axis), disrupted sleep or circadian
rhythms, and hormonal changes (eg, premature menopause and androgen blockade secondary to
cancer treatment).
Assessment
Since fatigue is essentially a subjective sensation, it is by nature difficult to assess. There is
agreement that self-assessment should be the “gold standard.” Because of the complex nature of
the symptoms of fatigue, an effort to identify a set of diagnostic criteria similar to those for
depression has been attempted. This syndromal approach has been useful to assess the presence or
absence of the clinical syndrome of fatigue.
TABLE 1: Assessment of
fatigue
Table 1 summarizes the four most common measurable indices to assess fatigue. The first category
in Table 1 looks at the objective function that the patient is capable of performing when subjected to
a standard task. These functional tasks have limited value in cancer care, however, since they are
very difficult for the advanced cancer patient to perform.
The second category in Table 1 attempts to assess the subjective effects of standard tasks.
The third category in Table 1 has been the most commonly used in oncology. The two most common
scales, Eastern Cooperative Oncology Group and Karnofsky Performance Status, consist of a
physician’s rating of the patient’s functional capabilities after a regular medical consultation. A
physical therapist completes the Edmonton Functional Assessment Tool and attempts to determine
the functional status, as well as all the obstacles to clinical performance, of these patients.
The fourth category in Table 1 is the most relevant for both clinical management and clinical trials in
fatigue. Visual analog scales, numerical scales, the Brief Fatigue Inventory (BFI), and the Piper
Fatigue Self-Report Scale have been validated. In addition, there are validated functional
assessments in most quality-of-life questionnaires.
In addition to the assessment of the intensity of fatigue, the clinical assessment of these patients
requires clinicians to determine the impact of all factors on the presence of fatigue.
Management
FIGURE 2: Therapeutic approach to managing fatigue.
To treat fatigue optimally, it is vital to identify and prioritize the different underlying factors in the
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individual patient. Thorough records, including recent treatment history, physical examination, and
medication review, in addition to simple laboratory investigations, will help identify possible
underlying causes. Figure 2 outlines a therapeutic approach to fatigue management in cancer
patients. Whenever possible, an attempt should be made to treat these contributing factors. It is
impossible to be certain whether one of these identified problems is a major contributor to fatigue or
simply a coexisting problem in a given patient. Therefore, it is of great importance to measure the
intensity of fatigue and the patient’s performance before and after treating any contributing factor. If
the level of fatigue does not improve after correction of these abnormalities, it is clear then that
further treatment will not result in improvement in the future.
In patients with cancer treatment–related fatigue, it is important to exclude specific causes, such as
hypothyroidism, hypogonadism, and anemia, and to consider other potential adverse effects of
treatment. If specific problems are identified, they should be appropriately managed. For instance,
patients with anemia may experience symptomatic improvement with the administration of
erythropoietic therapy (epoetin alfa [Epogen, Procrit] and darbepoetin alfa [Aranesp]) at the dose
and administration schedule that best fit the patient’s need. Epoetin alfa may be administered
weekly by subcutaneous injection; darbepoetin alfa has a longer half-life, requiring less frequent
dosing. Dosages and schedules of both agents may be increased if necessary. (For up-to-date
information about the safety and use of erythropoiesis-stimulating agents from the US Food and
Drug Administration (FDA) visit the “Information on Erythropoiesis-Stimulating Agents (ESA), Epoetin
alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)” page on the FDA’s Web
site.
In most patients, there will be no identified reversible causes. A number of effective pharmacologic
and nonpharmacologic symptomatic treatments are available for these patients.
Pharmacologic treatments
Corticosteroids. There is substantial evidence that corticosteroids can reduce fatigue and other
symptoms in cancer patients. They are probably best retained for short-term use. Their beneficial
effects generally last between 2 and 4 weeks, and longer-term use carries the risk of serious adverse
effects. Most studies have used the equivalent of 40 mg/d of prednisone. In a recent double-blind
placebo controlled study of 84 advanced cancer patients with fatigue, oral dexamethasone at a
standard dose of 8 mg daily for 2 weeks was associated with significant improvement in
cancer-related fatigue. There were no significant differences in adverse events in patients in the
dexamethasone and placebo group.
Progestational agents. In recent studies of terminally ill patients, megestrol (60 to 480 mg/d) has
been shown to have a rapid (less than 1 week) beneficial effect on appetite, fatigue, and general
well-being. However, long-term use is associated with weight (fluid) gain, adrenal insufficiency, and
thromboembolic complications.
Psychostimulants. Psychostimulants (eg, methylphenidate, 5 to 10 mg in the morning and at noon
or 5 mg as needed) may be useful in treating fatigue in patients with advanced cancer. In a study by
Bruera et al, 141 advanced cancer patients were evaluated for a period of 15 days so as to compare
the effects of methylphenidate and placebo. The effects of combined intervention including
methylphenidate plus a nursing intervention were also assessed. The results of this study showed
that there was no significant improvement in fatigue in the methylphenidate group compared with
the placebo group. There was also no significant benefit from methylphenidate plus a nursing
telephone intervention on cancer-related fatigue. A 148-patient study by Moraska et al also found no
significant improvement in cancer-related fatigue with long-acting methylphenidate compared with
placebo. In a recent study by Spathis et al, 160 patients with advanced non–small-cell lung cancer
were randomized to modafinil or placebo for 28 days. Similar to the previous studies of Bruera et al
and Moraska et al, fatigue improved among patients treated with modafinil but there was no
significant difference between the active and placebo treatments. Based on these results, future
studies of psychostimulants should be focused on a specific patient group, such as fatigued patients
with depression or drowsiness.
Ginseng. Based on a preliminary study that found significant improvement of cancer-related fatigue
with a dose of 2,000 mg extract of ground root of American ginseng (Panax quinquefolius), Barton et
al recently completed a double-blind trial of 2,000 mg of American ginseng vs placebo for 8 weeks in
364 fatigued cancer survivors. At 4 weeks, the ginseng group showed a trend (P = .07) toward
improvement in fatigue compared with placebo, and at 8 weeks there was significant improvement
in fatigue in the ginseng group compared with the placebo group (P = .003), based on changes from
baseline score using the Multidimensional Fatigue Symptom Inventory-Short Form. There was no
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significant increase in toxicities in the ginseng group compared with the placebo group. In a recent
preliminary study of 30 cancer patients, we found that high-dose oral Panax ginseng extract (800
mg/d) was safe to use for 28 days and was associated with significant improvement in fatigue and
related symptoms. Further randomized studies are warranted.
Nonpharmacologic treatment
Physical activity. A recent Cochrane review suggests that physical activity (aerobic and/or
resistance) may be effective in improving cancer-related fatigue, specifically in patients with early
cancer and in cancer survivors. Studies suggest that moderate to intense (55% to 75% of maximum
heart rate) aerobic exercise for 10 to 90 minutes, 3 to 7 days per week is safe and effective.
Physical therapy and occupational therapy. When appropriate in patients with advanced
cancer, physical therapy may encourage increased activity and provide active range of motion to
prevent painful tendon retraction. Assessment of the home environment by an occupational
therapist can be useful. The provision of ramps, walkers, wheelchairs, elevated toilets, and hospital
beds may allow the patient to remain at home in a safe environment. Education regarding the
pattern of fatigue during treatment has been helpful. Counseling (more specifically,
cognitive-behavioral therapy [CBT]) for stress management, depression, and anxiety may reduce
distress and fatigue as well as improve mood.
Yoga. A recent controlled trial by Chandwani and Cohen et al assessed 163 breast cancer patients
receiving radiation therapy who were randomized to a yoga group, a stretching group, or a waitlist
group. Patients assigned to yoga for three 1-hour sessions a week for 6 weeks during radiation
therapy showed improvement in fatigue (BFI score, 0.23), as did the stretching group (BFI score,
0.45). However, patients in the yoga group had a greater improvement in physical functioning (Short
Form 36 Health Survey), compared with the stretching and waitlist groups.
Psychosocial interventions, such as CBT, have been found to be effective in improving cancer-related
fatigue in cancer patients receiving treatment. A recent randomized controlled trial by Montogomery
et al found that the benefits of CBT on cancer-related fatigue lasted long after the CBT was finished.
Dyspnea
Dyspnea has been defined as an uncomfortable awareness of breathing. It is a subjective sensation
and does not necessarily correlate with clinical findings in a given patient. It occurs in up to 75% of
patients with advanced cancer, and good symptom control is less frequently achieved in dyspneic
patients, even by experienced palliative care teams, than in patients with other symptoms of
terminal cancer, such as pain and nausea. The frequency of breathlessness increases rapidly with
disease progression in patients with advanced cancer.
Mechanisms
The pathophysiology of dyspnea is complex and has not been completely elucidated. The respiratory
center in the medulla controls breathing, but dyspnea is the result of cortical stimulation. This
respiratory center is stimulated by abnormalities of blood gases detected by both lung and central
chemoreceptors and by stimulation of lung and respiratory muscle mechanoreceptors.
Mechanoreceptors respond to stretching and irritants. Their activity also has a demonstrated effect
on the brain cortex, which can cause dyspnea. In addition, it is possible that both the
chemoreceptors and the medullary respiratory center stimulate the cerebral cortex, directly
contributing to the sensation of dyspnea. Figure 3 summarizes the mechanisms of dyspnea.
Clinical Features
dioxide.
FIGURE 3: Mechanisms of dyspnea. PCO2 = partial pressure of carbon
In patients with advanced cancer, there are many causes of dyspnea, such as pulmonary embolism,
lung metastasis, pleural effusion, congestive heart failure, anemia, psychological distress,
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pneumonia, muscle weakness, and preexisting pulmonary disease.
Direct tumor effects
Dyspnea may be the result of direct primary or metastatic tumor effects such as airway obstruction,
atelectasis, parenchymal lung involvement, phrenic nerve palsy, carcinomatous lymphangitis, or
superior vena cava obstruction.
Indirect tumor effects
Effects of cancer that can contribute indirectly to dyspnea include pneumonia, anemia, pleural
effusion, and pulmonary embolism. Cardiac complications of cancer, such as congestive heart
failure, pericarditis, or pericardial effusion, also may contribute to the problem. Intra-abdominal
disorders, such as gross ascites and hepatomegaly, may cause elevation of the diaphragm and may
interfere with respiratory function. Generalized muscle weakness due to cachexia or fatigue may
exacerbate breathlessness. Preexisting lung diseases, including asthma and chronic obstructive
pulmonary disease (COPD), may contribute to the problem.
Treatment side effects
Treatment adverse effects that can contribute to dyspnea include pneumonitis and fibrosis following
chemotherapy or radiotherapy.
Psychological conditions
Anxiety, depression, and somatization will alter a patient’s perception of dyspnea. Anxiety has been
found to be an independent correlate of the intensity of dyspnea in cancer patients with moderate to
severe dyspnea. Any of these factors may occur in isolation or in combination, and care is needed
during patient assessment because there are often many contributors to dyspnea in an individual
patient.
Assessment
TABLE 2: Management of specific causes of dyspnea in cancer patients
Dyspnea is a subjective sensation, and researchers have found much variability in the expression of
dyspnea in individuals with similar levels of functional abnormalities. In addition, patients’ perception
of dyspnea can be influenced by their beliefs and intrapsychic and cultural factors. The presence or
absence of physical signs, such as tachypnea, wheezing, and use of accessory muscles, is not a
reliable indicator of the degree of distress felt by patients. The intensity of dyspnea can be easily
assessed using verbal, numeric, or visual analog scales similar to those used in pain or nausea. A
descriptive study by Henoch et al examined dyspnea in correlation with other symptoms, as well as
personal and health factors in 105 patients with advanced lung cancer. More than 50% of patients
had perceived dyspnea. The intensity of dyspnea and the occurrence of activity-related dyspnea
correlated with the presence of anxiety, depression, fatigue, and cough. A lower coping capacity was
associated with a greater likelihood of dyspnea.
Recently, maximal inspiratory pressure has been found to be an independent correlate of the
intensity of dyspnea. Physical examination, chest radiography, and pulse oximetry should be
performed. Other investigations, such as complete blood cell count, echocardiography, and
pulmonary function tests, may be indicated.
Management
Specific causes
Underlying specific causes will require treatment as indicated in Table 2.
Symptomatic management
The three modalities of symptomatic treatment in cancer-related dyspnea are oxygen therapy, drug
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therapy, and counseling.
In patients with advanced malignant and nonmalignant disease, Bausewein et al found breathing
training, walking aids, neuroelectrical muscle stimulation, and chest wall vibration to be effective in
relieving dyspnea.
Oxygen therapy. In hypoxemic cancer patients with dyspnea, oxygen has been shown to provide
significant symptomatic relief. Oxygen can be administered by nasal cannula at 2 to 6 L/min or by
mask and titrated to maintain an oxygen saturation at greater than 90%. Care must be taken in
patients with COPD. Oxygen is not useful in patients with dyspnea and an oxygen saturation greater
than 90%. A recent preliminary study of high-flow oxygen and bilevel positive airway pressure for
management of dyspnea in 30 cancer patients found significant improvement in dyspnea with both
of the interventions, and they were found to be safe and feasible, with significant improvement in
physiological parameters such as oxygen saturation. Further studies are needed.
Drug therapy. There is substantial evidence that systemic opioids have a beneficial effect on
cancer-related dyspnea. This is possible without inducing respiratory depression. The optimal type,
dose, and mode of administration have not been determined. If the patient is already receiving
opioids, the breakthrough dose can be used to manage dyspnea as well as pain. If not, morphine can
be started at 5 to 10 mg PO (or 2.5 to 5 mg SC) every 4 hours with additional as-needed doses of 2.5
to 5 mg PO (or 2.5 mg SC) every hour for breakthrough dyspnea. Nebulized opiates are not
recommended, because there is insufficient evidence to support their use. A recent preliminary
study by Hui et al found that subcutaneous fentanyl when given prophylactically before exertion may
benefit dyspnea, fatigue, walking distance, and respiratory rate.
In a randomized crossover clinical trial to evaluate the efficacy of oral transmucosal fentanyl for
treatment of dyspnea on exertion in patients with advanced cancer, Pinna et al found no significant
improvement in dyspnea on exertion or oxygen saturation or other cancer-related symptoms with
the treatment of fentanyl, although there was a tendency toward decrease in the intensity of
dyspnea. Further studies are needed to determine effective treatments, including the role of opioids
for exertional dyspnea in patients with advanced cancer.
Benzodiazepines have not been found to be effective in the general management of dyspnea, but
they may be useful for treatment of episodes associated with anxiety attacks. Regular use of
benzodiazepines should be avoided when possible to limit adverse effects, such as confusion and
falls.
In a recent double-blind placebo-controlled study of 84 advanced cancer patients with fatigue,
published in the Journal of Clinical Oncology in 2013, oral dexamethasone at a standard dose of 8 mg
daily for 2 weeks compared with placebo was associated with improvement in dyspnea assessed by
the Edmonton Symptom Assessment Scale shortness of breath item at day 15 (−2.16 [2.92] vs
−0.89 [2.40]; P = .06). However, further studies are needed with dyspnea as a primary outcome.
Conditions that cause dyspnea in cancer patients and that respond to corticosteroid medication
include superior vena cava obstruction, carcinomatous lymphangitis, and COPD. However,
corticosteroids may adversely affect muscle function, and the diaphragm may be more susceptible
than other muscles. This may be of importance because of the frequency of muscle weakness and
fatigue in patients with advanced cancer.
In a Cochrane review, Simon et al found no evidence of beneficial effect from benzodiazepines given
to treat dyspnea in patients with advanced cancer and COPD.
Counseling. Dyspnea is a variable symptom and is exacerbated by physical activities. Patients and
families should be educated so they can identify factors likely to worsen dyspnea. Devices such as
bathroom aids and wheelchairs can help reduce physical activity, and the addition of portable
oxygen can enable the patient to remain active and autonomous. For symptomatic relief, medication
such as opioids can be administered 30 to 45 minutes before dyspnea-causing maneuvers. The
family should be informed that dyspnea is subjective and that tachypnea and use of accessory
muscles do not necessarily indicate that the patient is suffering. The aim of treatment is to relieve
the patient’s subjective dyspnea, not to abate physical signs of respiratory distress.
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[1] http://www.psychiatrictimes.com/authors/sriram-yennurajalingam-md
[2] http://www.psychiatrictimes.com/authors/eduardo-bruera-md
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