Tumor-induced Effects on Nutritional Status
Nutritional status can be compromised in direct response to tumor-induced alterations in metabolism. Also known as cachexia, this condition is one of advanced protein-calorie malnutrition and is characterized by involuntary weight loss, muscle wasting, and decreased quality of life.[1,2] Tumor-induced weight loss occurs frequently in patients with solid tumors of the lung, pancreas, and upper gastrointestinal tract and less often in patients with breast cancer or lower gastrointestinal cancer. Although anorexia may also be present, the energy deficit alone does not explain the pathogenesis of cachexia. Several factors have been proposed. Mediators including cytokines, neuropeptides, neurotransmitters, and tumor-derived factors are postulated to contribute to this syndrome. Products of host tissues, such as tumor necrosis factor-α, interleukin-1, interleukin-6, interferon-γ, and leukemia inhibitor factor, as well as tumor products that have a direct catabolic effect on host tissues, such as lipid-mobilizing factor and proteolysis-inducing factor (not established as definite in humans), have all been identified as mediators of this complex syndrome. Altered metabolism of fats, proteins, and carbohydrates is evident in cancer patients with cachexia. Tumors may induce impaired glucose uptake and glucose oxidation, leading to an increased glycolysis. Weight loss can occur from a decrease in energy intake, an increase in energy expenditure, or a combination of the two. Although anorexia is a common symptom of cancer patients, studies have shown that increased caloric intake either by the oral route or by supplementation with total parenteral nutrition has failed to counteract the wasting process. This supports the theory that the aberrant metabolic rate is the direct response by the tumor and the immune system to disrupt the pathways that regulate the homeostatic loop of body-weight regulation.
Current studies suggest that the basal metabolic rate serves as a possible prognostic indicator of survival. As cancer progresses, the basal metabolic rate declines and cachexia occurs, reducing long-term survival. Although alterations in overall basal metabolic rates have not been observed by some, increased basal metabolic rates have been reported in pediatric, breast, lung, malnourished, and other  cancer patient populations; however, the discrepancy may be related to the stage of cancer progression. Nutritional support therapies aimed at preserving lean muscle mass and subcutaneous adipose stores despite this altered metabolic rate may ultimately improve patients' quality of life and impact overall survival.
Although an individual’s nutritional status may be compromised initially by the diagnosis of cancer, thorough nutritional screening procedures and the timely implementation of nutritional therapies may markedly improve the patient’s outcome. Symptoms and side effects may sometimes be managed by a combination of dietary and pharmacologic interventions.
Several approaches to the treatment of cancer cachexia have been reported, and a variety of agents have been studied for their effects on appetite and weight. The decision to use pharmacological treatment to improve a patient’s appetite should be based on the patient’s desires, current medical condition, and life expectancy. Table 1 lists several medications that have been proposed to treat the symptoms of cancer cachexia. However, the management of cachexia remains a complex challenge, and integrated multimodal treatment targeting the different factors involved has been proposed. In a phase III study, patients were randomly assigned to receive megestrol acetate, eicosapentaenoic acid, L-carnitine, thalidomide, or megestrol acetate plus L-carnitine and thalidomide. Interim analysis of 125 patients suggested the most effective treatment would be a combination regimen. The optimal combination is the goal of ongoing research.Table 1. Commonly Prescribed Medications
|Drug Category||Common Drugs Used||Comments|
|EPA = eicosapentaenoic acid; TNF-alpha = tumor necrosis factor-alpha; U.S. FDA = United States Food and Drug Administration.|
|Progestational agents||megestrol acetate||Multiple investigations report appetite stimulant activity and weight gain with use. Body composition of weight gain indicates increased body fat stores instead of lean body tissue. Increased risk of thromboembolism with doses >800 mg/day is an apparent trend. Studies suggest improved effectiveness in patients with better digestive function; therefore, targeted nutritional strategies such as digestive enzymes or elemental diets may be useful.[13,15]|
|Glucocorticoids||dexamethasone||Mechanism of appetite stimulation is unknown but likely related to anti-inflammatory and euphoric actions. Studies report positive but short-lived effects on clinical outcomes such as appetite and quality of life, with minimal or no effect on weight gain. Risk of adverse effects such as muscle wasting and immunosuppression limit use for long-term use for appetite stimulation.[13,16]|
|Cannabinoids||dronabinol||Inconsistent evidence of clinical effectiveness in cancer patients. Studies of dronabinol alone or with megestrol acetate have not shown superior benefit in promoting weight gain and appetite.[13,17-20]|
|Antihistamines||cyproheptadine||Not studied well in cancer patients. A randomized placebo-controlled trial in patients with advanced cancer reported no difference in weight changes and progressive weight loss in both groups. Sedation is a frequent adverse effect that may limit usefulness in cancer patients.[13,21]|
|Antidepressants/ antipsychotics||mirtazapine||Clinical data supporting routine use in cancer patients are lacking. Further studies are needed.|
|Anti-inflammatory agents||thalidomide||All have been shown to decrease TNF-alpha. Mixed results in clinical trials regarding weight gain and appetite stimulation. One published randomized placebo-controlled trial evaluated the safety and efficacy of thalidomide, 200 mg daily, in patients with advanced pancreatic cancer and weight loss of at least 10% of premorbid weight. Thalidomide group showed a significant difference in weight loss compared with the placebo group, indicating the drug's ability to safely decrease weight loss and loss of lean body mass in the patients studied. Preliminary clinical studies and laboratory studies of the polyunsaturated fatty acid EPA have suggested a benefit to cancer patients; however, subsequent large comparative studies failed to reproduce this benefit.[23,24]|
|omega 3 fatty acids (EPA)|
|Metabolic inhibitors||hydrazine sulfate||Not approved by the U.S. FDA for marketing in the United States.|
|Anabolic agents||oxandrolone||Used in an attempt to stimulate muscle anabolism. Limited published reports of successful appetite stimulation in cancer patients.|
Weight loss associated with cancer and its treatment may be secondary to a host of symptoms and side effects. Early intervention using appropriate nutrition and pharmacologic symptom-management strategies can keep weight loss at bay. The drug categories typically used to manage these symptoms and side effects include the following:
- Prokinetic agents (e.g., metoclopramide hydrochloride).
- Antiemetic agents (e.g., phenothiazines, butyrophenones, substituted benzamides, serotonin antagonists, benzodiazepines, corticosteroids, anticholinergics, and cannabinoids).
- Antidiarrheal agents (e.g., bulk-forming agents, antimotility agents, and codeine derivatives).
- Pancreatic enzymes.
- Laxatives (e.g., stool softeners, stimulants, bulk-forming agents, hyperosmotic laxatives, and saline laxatives).
- Agents for oral care (e.g., saliva stimulants, cleansing agents, antifungal agents, topical anesthetics, mouthwashes, and healing/coating agents).
- Pain medications (e.g., nonopioid analgesics, nonsteroidal anti-inflammatory drugs, and opioids).
- Tisdale MJ: Biology of cachexia. J Natl Cancer Inst 89 (23): 1763-73, 1997. [PUBMED Abstract]
- Strasser F, Bruera ED: Update on anorexia and cachexia. Hematol Oncol Clin North Am 16 (3): 589-617, 2002. [PUBMED Abstract]
- Tisdale MJ: Pathogenesis of cancer cachexia. J Support Oncol 1 (3): 159-68, 2003 Sep-Oct. [PUBMED Abstract]
- Ramos EJ, Suzuki S, Marks D, et al.: Cancer anorexia-cachexia syndrome: cytokines and neuropeptides. Curr Opin Clin Nutr Metab Care 7 (4): 427-34, 2004. [PUBMED Abstract]
- Gambardella A, Tortoriello R, Tagliamonte MR, et al.: Metabolic changes in elderly cancer patients after glucose ingestion. The role of tumor necrosis factor-alpha. Cancer 79 (1): 177-84, 1997. [PUBMED Abstract]
- Jatoi A, Daly BD, Hughes V, et al.: The prognostic effect of increased resting energy expenditure prior to treatment for lung cancer. Lung Cancer 23 (2): 153-8, 1999. [PUBMED Abstract]
- Ottery FD: Cancer cachexia: prevention, early diagnosis, and management. Cancer Pract 2 (2): 123-31, 1994 Mar-Apr. [PUBMED Abstract]
- den Broeder E, Oeseburg B, Lippens RJ, et al.: Basal metabolic rate in children with a solid tumour. Eur J Clin Nutr 55 (8): 673-81, 2001. [PUBMED Abstract]
- Kutynec CL, McCargar L, Barr SI, et al.: Energy balance in women with breast cancer during adjuvant treatment. J Am Diet Assoc 99 (10): 1222-7, 1999. [PUBMED Abstract]
- Gambardella A, Tortoriello R, Pesce L, et al.: Intralipid infusion combined with propranolol administration has favorable metabolic effects in elderly malnourished cancer patients. Metabolism 48 (3): 291-7, 1999. [PUBMED Abstract]
- Bosaeus I, Daneryd P, Svanberg E, et al.: Dietary intake and resting energy expenditure in relation to weight loss in unselected cancer patients. Int J Cancer 93 (3): 380-3, 2001. [PUBMED Abstract]
- Pi-Sunyer FX: Overnutrition and undernutrition as modifiers of metabolic processes in disease states. Am J Clin Nutr 72 (2 Suppl): 533S-7S, 2000. [PUBMED Abstract]
- Murphy S, Von Roenn JH: Pharmacological management of anorexia and cachexia. In: McCallum PD, Polisena CG, eds.: The Clinical Guide to Oncology Nutrition. Chicago, Ill: The American Dietetic Association, 2000, pp 127-33.
- Mantovani G, Macciò A, Madeddu C, et al.: Randomized phase III clinical trial of five different arms of treatment for patients with cancer cachexia: interim results. Nutrition 24 (4): 305-13, 2008. [PUBMED Abstract]
- Deutsch J, Kolhouse JF: Assessment of gastrointestinal function and response to megesterol acetate in subjects with gastrointestinal cancers and weight loss. Support Care Cancer 12 (7): 503-10, 2004. [PUBMED Abstract]
- Mattox TW: Treatment of unintentional weight loss in patients with cancer. Nutr Clin Pract 20 (4): 400-10, 2005. [PUBMED Abstract]
- Jatoi A, Yamashita J, Sloan JA, et al.: Does megestrol acetate down-regulate interleukin-6 in patients with cancer-associated anorexia and weight loss? A North Central Cancer Treatment Group investigation. Support Care Cancer 10 (1): 71-5, 2002. [PUBMED Abstract]
- Ulutin HC, Arpaci F, Pak Y: Megestrol acetate for cachexia and anorexia in advanced non-small cell lung cancer: a randomized study comparing two different doses. Tumori 88 (4): 277-80, 2002 Jul-Aug. [PUBMED Abstract]
- Jatoi A, Windschitl HE, Loprinzi CL, et al.: Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol 20 (2): 567-73, 2002. [PUBMED Abstract]
- Strasser F, Luftner D, Possinger K, et al.: Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol 24 (21): 3394-400, 2006. [PUBMED Abstract]
- Kardinal CG, Loprinzi CL, Schaid DJ, et al.: A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer 65 (12): 2657-62, 1990. [PUBMED Abstract]
- Gordon JN, Trebble TM, Ellis RD, et al.: Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. Gut 54 (4): 540-5, 2005. [PUBMED Abstract]
- Jatoi A: Fish oil, lean tissue, and cancer: is there a role for eicosapentaenoic acid in treating the cancer anorexia/weight loss syndrome? Crit Rev Oncol Hematol 55 (1): 37-43, 2005. [PUBMED Abstract]
- Fearon KC, Barber MD, Moses AG, et al.: Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia. J Clin Oncol 24 (21): 3401-7, 2006. [PUBMED Abstract]
- Kennedy LD: Common supportive drug therapies used with oncology patients. In: McCallum PD, Polisena CG, eds.: The Clinical Guide to Oncology Nutrition. Chicago, Ill: The American Dietetic Association, 2000, pp 168-81.