Table 67.2 lists the potential etiologic factors in the development of malnutrition and cancer anorexia. The development of malnutrition in the individual patient is usually the result of a combination of these mechanisms (11).

Several factors, including changes in the central nervous system, changes in taste perception due to tumor, depression, and its associated reduced physical activity, have been implicated as causes of cancer anorexia. The regulation of appetite is complex and is mediated by blood nutrient levels, host nutrient resources, liver function, GI capacity or toxicity, medications, and environmental cues (7, 8, 11, 12). When weight loss is encountered despite adequate caloric intake, it is termed the anorexia-cachexia syndrome. Recently, considerable attention has been directed to the role of various cytokines and tumor byproducts as mediators of this syndrome which are discussed in detail later in this chapter under mediators of cancer cachexia.

The site, magnitude, and duration of radiation therapy all influence the severity of nutritional compromise. This injury may be associated with both acute and long-term effects of radiation therapy (13, 14).

After radiotherapy of the oral cavity and pharynx, patients can experience either heightened or suppressed taste sensation. Loss of taste is severe and rapid after oropharyngeal irradiation, as measured by quantitative tests of sensitivity to sour, sweet, and bitter substances. Fortunately, patients often regain preradiation taste sensitivity 60 to 120 days after therapy is completed.

Radiation to the head and neck may inhibit adequate salivation, leading to changes in eating habits. Also, patients may experience increased sensitivity of their teeth to extreme temperature and sweetness. In a study of weight loss during a 6- to 8-week course of external beam radiation therapy to the head and neck regions, 93% of 114 patients lost an average of 3.7 kg. In addition, approximately 9% of individuals lost more than one tenth of their body weight during their 6- to 8-week course of radiation (14).

Radiation to the gastric area and small and large intestine is associated with various complications that may influence nutritional status. Low doses of gastric irradiation reduce gastric acidity whereas higher doses may induce ulcer formation. Nausea, vomiting, and diarrhea are common in individuals undergoing radiation to the small and large bowel. In addition, chronic diarrhea or bowel obstruction may develop due to radiation-induced enteritis following high-dose GI irradiation.

Upper abdominal radiation may produce radiation-induced hepatitis, characterized by anorexia, nausea, vomiting, and abdominal distention. This disorder is usually temporary. Radiation to the pancreas may similarly result in acute anorexia, nausea, and vomiting.

Chemotherapy can affect host tissue in addition to the targeted neoplasm and thereby cause short-term nutritional defects. Many chemotherapies and immunotherapy products can produce nausea, vomiting, and diarrhea. This can lead to anorexia, electrolyte imbalance, and malnutrition.

Mucosal toxicity, manifested as oral ulcerations, cheilosis, glossitis, and pharyngitis, may be inevitable with the use of some chemotherapeutic agents. This often leads to odynophagia and anorexia. Specific agents, such as actinomycin D, cytarabine, 5-fluorouracil, hydroxyurea, and methotrexate, can produce ulcerations of the entire GI epithelium (15). Therapy itself does not induce malabsorption but, because of its side effects, can aggravate the effect of tumor-related malabsorption syndromes (15). With either a single agent or combination chemotherapy, small intestinal absorptive function remains well preserved in most instances. Nutrition support is usually unnecessary in the initially well-nourished patient if the ill effects of chemotherapy are significantly limited in time and intensity.

Multiple major organ systems are affected by chemotherapeutic agents which results in decreased efficiency of metabolism. The liver is especially vulnerable, and hepatic injury is commonly associated with anorexia. Diffuse hepatocellular damage often results in hypoalbuminemia. Several additional agents affect other organ systems. Hydroxyurea may cause renal impairment. Doxorubicin may cause cardiac toxicity leading to congestive heart failure, water retention, and electrolyte imbalance. Carter (16) provides extensive discussions of the nutritional consequences of chemotherapy and immunotherapy.

Nutritional depletion can be attributed to surgical intervention in many cancer patients. Nutrition support can be a beneficial tool, as a patient with good nutritional status develops fewer postoperative complications. Poor nutritional status can affect wound healing immune function and several studies have shown that when patients with severe malnutrition receive nutritional support the complication rate improves (4, 5, 6).

Certain surgical procedures may require nutritional intervention. Surgery of the upper GI tract can compromise a patient’s ability to take oral feedings. Conditions associated with esophagectomy and esophageal reconstruction may include delayed gastric emptying secondary to vagotomy, malabsorption, and the development of a fistula or stenosis. Gastric surgery may result in dumping syndrome, malabsorption, and/or hypoglycemia.

The site and extent of intestinal resection can result in a variety of nutritional complications. Jejunal resection can decrease the efficiency of absorption of carbohydrates, protein, fat, water, and electrolytes. Ileum resection commonly results in vitamin B₁₂ deficiency and bile salt losses. With extensive small bowel resection, malabsorption can result. Abnormalities in sodium and water balance are commonly associated with ileostomy and colostomy formation. In addition, gastric and intestinal bypass surgery to relieve obstruction can result in a blind loop syndrome with specific nutritional deficiencies.

Individuals with pancreatic cancer should be nutritionally assessed because they frequently lose weight before their diagnosis and surgical intervention. After pancreatectomy, malabsorption as well as endocrine and exocrine insufficiency are common problems that may require insulin and pancreatic enzyme replacement. Patients with cancer undergoing uretero-sigmoidostomy may experience hyperchloremic acidosis and hypokalemia in addition to other more common postoperative problems.

If it is anticipated that nutritional intervention will be required postoperatively, a nasoenteric feeding tube can be placed intraoperatively. With patients in whom a longer recuperative course is anticipated, surgical placement of a gastrostomy tube or jejunostomy tube may be more appropriate.

The anorexia-cachexia syndrome incorporates a group of symptoms and signs such as inanition, severe anorexia, weakness, skeletal muscle wasting, organ dysfunction, and progressive weight loss. Physiologically it is characterized by dramatic loss of triglycerides from adipose tissue and loss of visceral and skeletal protein mass (28). Potential etiologies of cancer anorexia are listed in Table 67.2. Cachexia was previously thought to be the result of increased energy demanded by the growing tumor mass. Recent research has demonstrated that it is primarily due to immune mediators [e.g., tumor necrosis factor (TNF), interluekin-6, and eicosanoids], and tumor byproducts (e.g., proteolysis—inducing factor, lipolytic hormone) causing abnormalities in carbohydrate, protein, and lipid metabolism (11). This means that anorexia, an almost universal characteristic of cachexia, should be interpreted as the result of metabolic abnormalities rather than the main cause of cachexia, and that the weight loss seen is not simply a result of decreased caloric intake. In addition to risks that worsening nutritional status has on complication rates of surgery, radiation therapy, and chemotherapy, the cachexia and anorexia are also a source of psychological distress for patients and their families (12).

There has been much interest in the possible role of cytokines in cancer anorexia. Prominent cytokines include TNF, interleukin-1α, and β (IL-1), interleukin-6 (IL-6), interferon-α (IFN-α), and differentiation factor, also known as leukemia inhibitory factor (29, 30). The peptides are pyrogens, and their administration, with the exception of IL-6, can produce many of the systemic vascular effects seen in sepsis and shock. For example, IL-1 and TNF-α share the capacity to up-regulate gene transcription of endothelial cell adhesion molecules, increase procoagulant activity, promote the transendothelial migration of leukocytes out of the vascular component into the pulmonary epithelium, and activate the release of toxic superoxide and other enzyme products from neutrophils (31).

Features of cancer cachexia can also be reproduced by cytokine administration. For example, IL-1 (32) and, to a lesser extent, TNF-α (33) and IFN-α (34) are potent anorexia-producing agents. Some cytokine effects are mediated through the hypothalamus (32), and others act directly on the GI tract, causing decreased gastric emptying (33). Other cytokines may promote cachexia by increasing resting energy expenditure. Warren et al. (35). reported that patients with cancer receiving cytokines as antineoplastic therapy had a dose-dependent increase in resting energy expenditure.

A mechanism proposed by Kern and Norton (2) to explain the anorexia and metabolic derangements of the anorexia-cachexia syndrome is shown in Figure 67.1. Some cancers incite a paracrine-induced systemic host response with production of cytokines such as interleukins or cachectin/TNF. These are secreted by immune cells and may be part of the host defense in an attempt to destroy the tumor. However, cytokines have negative secondary effects on host organs, resulting in anorexia and abnormalities in carbohydrate, protein, and lipid metabolism. Mobilization of nutrients from fat and skeletal muscle during the acute phase of sepsis or in patients with trauma rapidly provides a physiologic source of nutrients to the liver so that it can synthesize acute injury proteins. In a patient with cancer, the low-grade release of cytokines persists because of the metabolic activity of the tumor and eventually causes severe depletion of host cell mass, skeletal muscle wasting, and abnormal lipolysis. The anorexia of chemotherapy, radiotherapy, or surgery only exacerbates this process, adding to the net effect of host depletion. The “at-risk” patient with cancer can be identified by a rapid weight loss of greater than 10% of usual body weight.

There are other prominent mediators aside from cytokines that appear to play a prominent role in skeletal muscle wasting. A 24-kilodalton proteoglycan, called proteolysis-inducing factor (PIF), was identified in the murine MAC16 colonic adenocarcinoma model of anorexia. This factor was subsequently identified in the urine of weight-losing patients with cancer but not in the urine of weight-stable patients with cancer or weight-losing controls with benign disease (29, 36, 37). There is also some evidence that eicosanoids play a role in the metabolic affects PIF and affect protein and fat metabolism (38, 39).

Although the murine MAC16 model demonstrates muscle wasting to PIF and not to certain cytokines, there are other models that show similar metabolic activity with cytokine production but do not demonstrate activity of PIF. One final pathway of these multiple mediators of skeletal muscle
catabolism could be the ATP-ubiquitin-proteasome pathway. In fact, animal studies have shown that both TNF and PIF can increase proteasome activity (38, 40, 41). This suggests that these multiple mediators may share a common downstream affect on catabolism (11).

Fordy et al. reported that patients with significant weight loss from colorectal liver metastases required a large tumor volume (42). This weight loss was not explained by changes in diet, quality of life, or hormones, but activation of the innate immune systems and incomplete activation of the acquired immune systems were likely to be involved. Agents that attenuate either the acute-phase inflammatory response or T lymphocyte IL-2 receptor up-regulation might reduce weight loss in patients with metastatic disease (42). Some studies have looked at targeting other inflammatory mediators like eicosanoids with NSAIDs or COX2 inhibitors as a means of preventing weight loss (43). The final role anticatabolic medications will play in reversing the weight loss seen in cancer cachexia has yet to be determined.

Preventing malnutrition is easier than reversing it. Reversing malnutrition in a patient with advanced cancer is nearly impossible. Patients with cancer often lose weight and become malnourished at a time when they most need nutrition support (44). Current pharmacologic therapies as well as complementary and alternative methods may be recommended for patients with cancer cachexia (45). In recent years, anabolic medications, such as corticosteroids and progestational drugs, have proven effective in relieving symptoms of cancer cachexia. Corticosteroids have a limited effect (lasting up to 4 weeks) on symptoms such as appetite, food intake, sense of well-being and performance status, but none of the studies proved that patients had weight gain (12). Recent studies involving terminally ill patients have shown that progestational drugs improved the symptoms of fatigue and anorexia even in the absence of weight gain. If abruptly discontinued, both megestrol and medroxyprogesterone could induce thromboembolic phenomena, breakthrough vaginal bleeding, peripheral edema, hyperglycemia, hypertension, Cushing’s syndrome, alopecia, adrenal suppression, and adrenal insufficiency. However, in most clinical trials, the adverse effects rarely led patients to discontinue these drugs. There has also been much interest in appetite stimulants (Cannaboids) and anticatabolic medications (eicosapentaenoic acid, pentoxifylline), but the most consistent data so far has been for megestrol and medroxyprogesterone (12, 46).