Fatigue and dyspnea

June 1, 2007

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 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

Fatigue has been defined as easy tiring and decreased capacity to maintain performance. It results in physical and/or mental weariness following exertion and is transient in most of us. 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 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. Blood from a fatigued subject when injected into a rested 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.

Cachexia Cancer cachexia results from a complex interaction of host and tumor products. Host cytokines such as tumor necrosis factor, interleukin-1 (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. Tumors are also capable of producing lipolytic factors (lipolytic factor, toxohormone L-2) and proteolytic by-products (proteolysis-inducing factor). 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 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 in almost 75% of patients (depression, anxiety, and other psychological disorders). 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 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 the symptom adequately due to the multifactorial nature of the etiology of fatigue. It 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 a subset of 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 Research has shown that both intrathecal and systemic opioid therapy, as well as cachexia and some antineoplastic therapies, can result in hypogonadotropic hypogonadism. This can lead to fatigue, depression, and reduced libido.

 

Chemotherapy These treatments are common causes of fatigue in cancer patients. Chemotherapy and radiotherapy for malignancy cause a specific fatigue syndrome. Combined therapy with the two modalities appears to cause worse fatigue than either modality given alone. 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 WBC 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 with 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.

Radiotherapy 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.

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 or congestive heart failure, may coexist and contribute to the problem. Other conditions include the chronic stress response (possibly mediated through 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." Due to 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 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, as 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 (ECOG [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 physiotherapist performs the Edmonton Functional Assessment Tool and attempts to determine the functional status, as well as all the obstacles to clinical performance in these patients.

The fourth category in Table 1 is the most relevant for both clinical management and clinical trials in fatigue. Visual analog scales (VAS), numerical scales, the Brief Fatigue Inventory, 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

To treat fatigue optimally, it is vital to identify and prioritize the different underlying factors in each individual patient. A thorough history, 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 is 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 frequency interval 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. (See section on "Dose and schedule of administration" in chapter 40 for specific information about dosages and schedules.)

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.

Progestational agents In recent studies of terminally ill patients, megestrol (60–480 mg/d) has been shown to have a rapid (less than 1 week) beneficial effect on appetite, fatigue, and general well-being.

Psychostimulants Psychostimulants (eg, methylphenidate, 5–10 mg in the morning and at noon or 5 mg as needed) may be of use in treating fatigue in patients with advanced cancer. The safety and efficacy of long-term use of methylphenidate for fatigue have not been established.

A National Cancer Institute-sponsored trial on the use of modafinil (Provigil) for treatment of cancer-related fatigue is under way. In addition, dexmethylphenidate (D-MPH, Focalin) has been found to be more effective than placebo in the treatment of fatigue and impaired memory after chemotherapy in adults with cancer in a randomized phase III trial.

In addition to these agents, a number of other drugs have been tried in preliminary studies in patients with fatigue. Early positive results have been observed with both thalidomide (Thalomid) and fish oils. In addition, there are donezepil for fatigue associated with opioid sedation and midodrine (ProAmatine) in cases of autonomic failure.

Nonpharmacologic treatment

Physiotherapy and occupational therapy Physiotherapy may encourage increased activity where appropriate and provide active range of motion to prevent painful tendon retraction. Recent evidence suggests that aerobic exercise may reduce fatigue during chemotherapy. 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 for stress management, depression, and anxiety may reduce distress and fatigue as well as improve mood.

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, even by experienced palliative care teams, than with other symptoms of terminal cancer such as pain or nausea.

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. Abnormalities of blood gases detected by both lung and central chemoreceptors and stimulation of lung and respiratory muscle mechanoreceptors stimulate the respiratory center. Mechanoreceptors respond to stretch and irritants and also have a demonstrated effect on the brain cortex, causing 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

There are many causes of dyspnea in patients with advanced cancer, such as pulmonary embolism, lung metastasis, pleural effusion, congestive heart failure, anemia, psychological distress, 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 caval obstruction.

 

Indirect tumor effects Indirect cancer effects include pneumonia, anemia, pleural effusion, and pulmonary embolism. Cardiac complications of cancer such as congestive heart failure, pericarditis, or pericardial effusion may contribute to the problem. Intra-abdominal disorders such as gross ascites or 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 or chronic obstructive pulmonary disease (COPD) may contribute to the problem.

Treatment side effects Contributing treatment side effects include pneumonitis or fibrosis following chemotherapy or radiotherapy.

Psychological conditions Anxiety, depression, or somatization will alter a patient's perception of dyspnea. Anxiety has been found to be an independent correlate with 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 assessment, as there are often many contributors in an individual patient.

ASSESSMENT

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, or 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. Recently, maximal inspiratory pressure has been found to be an independent correlate of the intensity of dyspnea. Physical examination, chest x-ray, and pulse oximetry should be performed. Other investigations such as CBC, echocardiogram, or 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 therapy, and counseling.

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 2–6 L/min or by mask and titrated to maintain an O2 saturation at > 90%. Care must be taken in patients with COPD. Oxygen is not useful in patients with dyspnea and an O2 saturation > 90%.

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 on opioids, the breakthrough dose can be used to manage dyspnea as well as pain. If not, morphine can be started at 5–10 mg PO (or 2.5–5.0 mg SC) q4h with additional prn doses of 2.5–5.0 mg PO (or 2.5 mg SC) every hour for breakthrough dyspnea. Nebulized opiates are not recommended, as there is insufficient evidence to support their use.

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 where possible to limit side effects such as confusion or falls.

A number of conditions that cause dyspnea in cancer patients respond to corticosteroid medication, including superior vena caval 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.

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. Medication used for symptomatic relief such as opioids can be administered 30–45 minutes prior to dyspnea-causing maneuvers. The family should be educated 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.

SUGGESTED READING

ON FATIGUE

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ON DYSPNEAAllard P, Lamontagne C, Bernard P, et al: How effective are supplementary doses of opioids for dyspnea in terminally ill cancer patients? A randomized continuous sequential clinical trial. J Pain Symptom Manage 17:256–265, 1999.

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