Gastroenterology Grand Rounds

BCM Gastroenterology Grand Rounds - Discussion

Some answers to the questions about the cancer associated anorexia-cachexia syndrome include the following:

1. What is the anorexia-cachexia syndrome?: The syndrome is characterized by host tissue wasting, anorexia, skeletal muscle atrophy, accelerated fat loss, anergy, and visceral organ atrophy. These are often found before signs and symptoms of the tumor itself are manifested. It is not a local effect of the tumor but rather arises from a distant metabolic effect and is felt to be a paraneoplastic syndrome. It resolves with effective antitumor therapy but will continue if therapy is ineffective or not initiated. It is the most common cause of death in cancer patients, usually through respiratory depression secondary to wasting of the respiratory muscles or to infection.

2. What is its pathophysiology?: Older theories suggested competition for nutrients between the tumor and the host. This however seems unlikely because some cancer patients with very large tumors show no signs of wasting, while some patients (like ours) with severe wasting have tumors representing less than 0.01% of their total body weight. Weight loss can arise from a decreased energy intake and absorption or increased energy expenditure, or a combination of both. Most studies have shown both hypercatabolism and decreased energy intake. Rouzer and Cerami identified "cachectin" to be the agent responsible for increased fat metabolism and weight loss in chronically infected rabbits. Cachetin was later found to be identical to tumor necrosis factor in humans. It is one of the major mediators of the wasting syndromes in cancer patients, together with interferon gamma, interleukin 6, and other cytokines. These factors mediate wasting by inhibition of lipoprotein lipase, preventing adipocytes from extracting fatty acids from plasma lipoproteins and by stimulating triglyceride hydrolysis in the adipocytes through the acivation of triglyceride lipase. Tumor necrosis factor has been shown to mediate muscle wasting by the activation of protein mobilizing factor in the skeletal muscle. An interesting development is the discovery of several muscle-specific ubiquitin ligases. These enzymes are situated in a pathway of proteolysis common to a variety of wasting states. They may prove to be a valuable point of intervention in muscle atrophy.; Of course, weight loss may be due to mechanical factors (for example, gastric outlet obstruction) or physiologic factors (for example, decreased fat asorption due to low levels of intestinal bile salts or pancretic enzymes). These should be addressed as in the non-cancer patient.

3. What is the role of nutritional therapy in the management of cancer patients with the anorexia-cachexia syndrome?: a. Is there a benefit to nutritional support in the cancer patient who will have surgery? The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group studied 395 patients who underwent elective laparotomy or noncardiac thoracotomy. These patients were randomly assigned to receive parenteral nutrition versus a regular diet for one to two weeks prior to surgery. Patients with mild malnutrition did not benefit from parenteral nutrition. Patients with severe malnutrition who received parenteral nutrition had a lower incidence of complications related to healing. Muller et al. showed fewer complications in patients with upper gastrointestinal cancer who received preoperative parenteral nutrition.; b. Does nutritional support (apart from preoperative support) affect the survival of cancer patients? Klein et al. showed that patients undergoing chemotherapy who are given parenteral nutrition have higher rates of pneumonia and sepsis. No benefit in survival, treatment tolerance, side effects of antineoplasic therapy, or response to treatment has been shown in cancer patients receiving nutritional support.; Nutritional support in cancer patients should be restricted to those with a prolonged life expectancy but who are unable to maintain adequate intake on their own for a long period of time. This may result in an improved quality of life.

4. What pharmacologic interventions are available for the treatment of the cancer related anorexia-cachexia syndrome?: Resting energy expenditures are elevated, and increased intermediary metabolism, proteolysis, and lipolysis occur independently of caloric intake. An interaction between catecholamines, prostaglandins, and inflammatory cytokines seems to be responsible for cachexia. Thus, pharmacologic tretment should increase appetite and decrease metabolism. The first agents used in the management of anorexic cancer patients were corticosteroids such as dexamethasone, methylprednisolone, and prednisolone. These agents stimulate the appetite. The mechanism of action is unclear but may be due to their euphorigenic effects. The duration of appetite stimulation, however, is short and frequently requires increasing doses over time. Patients experience the usual adverse effects associated with chronic steroid use. Medroxyprogesterone and megestrol acetate have also been evaluated. Their mechanism of action may be related to their anabolic effects as well as to appetite stimulation. Most patients experience increased appetite but only a small percent increase as much as 10% of their weight. Their use is not associated with improvements in body composition as measured by anthropometrics. In one study dronabinol was less effective than megestrol acetate. In view of the role that cytokines have in the pathogenesis of cancer wasting, several anticytokine modalities have been tried. Pentoxyfylline has been shown to be inhibit TNF production in lymphocytes and its use has been associated with reduced TNF levels in cancer patients. These patients reported weight gain and an increase in well being. Whether its use is associated with improved outcome has yet to be studied. Thalidomide has also been shown to inhibit TNF production. It has been associated with significant weight gain in AIDS patients. Studies in cancer patients are inconclusive. Those drugs under study include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, and melatonin--all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release.