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 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.
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.
