Fatigue and Dyspnea

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 NCCN 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 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.

FIGURE 1Contributors 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. 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 due to 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 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

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 treatments 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 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.

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.

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 or 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).