Porth's Essentials of Pathophysiology, 4e

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Neoplasia

C h a p t e r 7

Fatigue and Sleep Disorders Fatigue and sleep disturbances are two of the side effects most frequently experienced by persons with cancer. 41–45 Cancer-related fatigue is characterized by feelings of tiredness, weakness, and lack of energy and is distinct from the normal tiredness experienced by healthy indi- viduals in that it is not relieved by rest or sleep. It occurs both as a consequence of the cancer itself and as a side effect of cancer treatment. Cancer-related fatigue may be an early symptom of malignant disease and has been reported by as many as 40% of patients at the time of diagnosis. 42 Furthermore, the symptom often remains for months or even years after treatment. The cause of cancer-related fatigue is largely unknown but is probably multifactorial and involves the dysregu- lation of several interrelated physiologic, biochemical, and psychological systems. The basic mechanisms of fatigue have been broadly categorized into two compo- nents: peripheral and central. Peripheral fatigue, which has its origin in the neuromuscular junction and muscles, results from the inability of the peripheral neuromus- cular apparatus to perform a task in response to cen- tral stimulation. Mechanisms implicated in peripheral fatigue include a lack of adenosine triphosphate (ATP) and the buildup of metabolic by-products such as lactic acid. Central fatigue arises in the central nervous system (CNS) and is often described as the difficulty in initiat- ing or maintaining voluntary activities. One hypothesis proposed to explain cancer-related fatigue is that cancer and cancer treatments result in dysregulation of brain serotonin (5-HT) levels or function. There is also evi- dence that proinflammatory cytokines, such as TNF- α , In addition to signs and symptoms at the sites of primary and metastatic disease, cancer can produce manifesta- tions in sites that are not directly affected by the disease. Such manifestations are collectively referred to as para- neoplastic syndromes. 46,47 Some of these manifestations are caused by the elaboration of hormones by cancer cells, and others result from the production of circulat- ing factors that produce hematopoietic, neurologic, and dermatologic syndromes (Table 7-3). These syndromes are most commonly associated with lung, breast, and hematologic malignancies. 2 A variety of peptide hormones are produced by both benign and malignant tumors. Although not normally expressed, the biochemical pathways for the synthesis and release of peptide hormones are present in most cells. 47 The three most common endocrine syndromes associated with cancer are the syndrome of inappropriate antidi- uretic hormone (ADH) secretion (see Chapter 8), Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) production (see Chapter 32), and hypercalcemia (see Chapter 8). Hypercalcemia also can be caused by osteolytic processes induced by cancer such as multiple myeloma or bony metastases from other cancers. Some paraneoplastic syndromes are associated with the production of circulating mediators that produce can influence 5-HT metabolism. Paraneoplastic Syndromes

be due, in part, to a dysregulation of iron metabolism, leading to a functional iron deficiency. 37 Cancer-related anemia is associated with reduced treatment effectiveness, increased mortality, increased transfusion requirements, and reduced performance and quality of life. Hypoxia, a characteristic feature of advanced solid tumors, has been recognized as a critical factor in promoting tumor resistance to radiotherapy and some chemotherapeutic agents. Cancer-related anemia is often treated with iron supplementation and recombinant human erythropoi- etin (rHuEPO, epoetin alfa). 37 Since iron deficiency may result in failure to respond to erythropoietin, it has been suggested that iron parameters be measured before initiation of erythropoietin therapy. When treat- ment with supplemental iron is indicated, it has been suggested that it be given intravenously, since oral iron has been shown to be largely ineffective in persons with cancer. 37 Anorexia and Cachexia Many cancers are associated with weight loss and wasting of body fat and muscle tissue, accompanied by profound weakness, anorexia, and anemia. This wasting syndrome is often referred to as the cancer anorexia–cachexia syn- drome . 38–40 It is a common manifestation of most solid tumors with the exception of breast cancer. The condi- tion is more common in children and elderly persons and becomes more pronounced as the disease progresses. Persons with cancer cachexia also respond less well to chemotherapy and are more prone to toxic side effects. The cause of the cancer anorexia–cachexia syn- drome is probably multifactorial, resulting from a persistent inflammatory response in conjunction with production of specific cytokines and catabolic factors by the tumor. Although anorexia, reduced food intake, and abnormalities of taste are common in people with cancer and often are accentuated by treatment methods, the extent of weight loss and protein wast- ing cannot be explained in terms of diminished food intake alone. There also is a disparity between the size of the tumor and the severity of cachexia, which sup- ports the existence of other mediators in the develop- ment of cachexia. It has been demonstrated that tumor necrosis factor (TNF)- α and other cytokines including interleukin-1 (IL-1) and IL-6 can produce the wast- ing syndrome in experimental animals. 3 High serum levels of these cytokines have been observed in per- sons with cancer, and their levels appear to correlate with progress of the tumor. Tumor necrosis factor- α , secreted primarily by macrophages in response to tumor cell growth or gram-negative bacterial infec- tions, was the first identified cytokine associated with cachexia and wasting. It causes anorexia by suppressing satiety centers in the hypothalamus and increasing the synthesis of lipoprotein lipase, an enzyme that facili- tates the release of fatty acids from lipoproteins so that they can be used by tissues. IL-1 and IL-6 share many of the features of TNF- α in terms of the ability to initi- ate cachexia.