Cyberounds CME

Course Authors

David R. Thomas, M.D., and John E. Morley, M.D.

Release Date: 07/16/2002

Upon completion of this Cyberounds^®, you should be able to:

Discuss the high prevalence of malnutrition in older persons
List the effects and side effects of different orexigenics
Discuss the rationale for treating malnutrition in older persons.

The drive to find food, designated by the term hunger, is essential to animal survival. Over a lifetime, considerable effort is expended seeking food. Hunger is controlled by chemical mediators, signaling when to stop eating (satiation), and when to resume searching for food (satiety), which defines the interval between meals. Appetite, defined here as the enjoyment of food for itself rather than for physiologic need, is conditioned by a number of social, cultural, and psychological factors, as well as by disease states.

Accumulating evidence points toward anorexia, or the decline in appetite, as a contributor to weight loss and undernutrition of older persons.(1) The chief causes of anorexia in older persons are shown in Table 1.

Older persons consume less food than younger persons. On average, persons over the age of 70 years consume one-third fewer calories compared with younger persons, with energy intakes of older men (40-74 years old) in a range of 2100 to 2300 calories/day compared with younger men (24-34 years old) at 2700 calories/day.(2) In dietary intake studies, 10% of men and 20% of women have protein intakes below the U.S. Recommended Daily Allowance (RDA), and one-third consume fewer calories than the RDA. Fifty percent of older adults have mineral and vitamin intakes less than the RDA and 10% to 30% have subnormal levels of minerals and vitamins.(3) Sixteen to 18% of community-dwelling elderly persons consume fewer than 1000 calories/day.(4) Lower food intake by older adults seems to result from smaller meals eaten at a slower rate.(5)

Regulation of Appetite

Appetite is regulated by combination of a peripheral satiation system and a central feeding drive. The interplay of these two systems is modulated by a hormonal feedback system that provides information on the nutrient status of the organism. The central feeding drive is modulated by factors including dynorphin, nitric oxide, neuropeptide Y, and corticotrophin-releasing factor. Gastrointestinal hormones, including cholecystokinin, gastrin-releasing peptide, amylin, somatostatin, and bombesin also regulate satiety in humans to varying degrees.(6)

The physiologic regulation of appetite differs fundamentally in older adults compared with younger persons. Neurotransmitter regulators of appetite have been implicated in decreased intake associated with aging. Impaired appetite contributes to undernutrition frequently found in older persons. Moreover, when older persons decrease their food intake, they appear to reset their ìappetostatî and then find it difficult to increase their food intake appropriately in response to a period of anorexia.(7) The changes in these regulatory hormones and their effect on undernutrition is poorly understood. The major regulators of appetite have been extensively reviewed(8),(9) and are delineated in Table 2.(10)

Pathological Causes of Anorexia

Anorexia may result from either pathological or physiologic causes in older persons. Acute illness results in a decline in nutrient intake in most species. This response seems paradoxical in the face of a need for increased nutrients during healing.(11) Several disease states induce cachexia, the cytokine-induced wasting of protein and energy stores. Cytokines are related to a number of disease conditions, including cancer,(12) end-stage renal disease,(13) chronic obstructive pulmonary disease,(14) congestive heart failure,(15) rheumatoid arthritis,(16) and AIDS.(17) Cytokines directly result in feeding suppression and lower intake of nutrients. Interleukin-1 beta and tumor necrosis factor (TNF) act on the glucose-sensitive neurons in the ventromedial hypothalamic nucleus (a ìsatietyî site) and the lateral hypothalamic area (a ìhungerî site). This response is the most common cause of anorexia observed in the acute care setting.(8) In ambulatory clinic patients, one or more pathological causes of undernutrition can be identified in 93% of older persons and 90% of younger persons. Most of these patients (89%) will have potentially treatable causes for their undernutrition.(21)

The common causes of undernutrition in older persons are shown in Table 3.

Using a series of questions for the differential diagnosis, the etiology of most causes of undernutrition can be determined.(22),(23) Recently, a structured algorithm to assist in evaluating causes of undernutrition was published by the Council for Nutritional Clinical Strategies in Long-Term Care.(24)

Sociological, Psychological & Physiologic Causes of Anorexia

In addition to the pathological causes of anorexia, appetite is greatly influenced by sociological, psychological, and physiologic factors (Table IV).

Sociological factors include food preferences, chiefly determined by cultural circumstances.

Studies have shown that consideration of food preferences, consistency, and temperature may increase food intake.(25),(26) Older persons modulate food intake by time of day, number of people present, premeal stomach contents, and their subjective state of hunger in a way similar to that of younger persons. Women eat more (13%) when men are present, and both genders eat more (23%) with family present. Meals eaten in groups tend to be up to 44% larger than those eaten alone. Larger meals (10%) are eaten on weekends rather than weekdays, and larger meals are eaten later in the day.(5) Provision of pleasant, well-lighted, unhurried mealtimes in a social environment may increase the intake.(27) During meals-on-wheels deliveries, if the person delivering the meal stays while the older person eats, nutritional risk is reduced.(9) These data suggest that intake may be improved in older persons by paying attention to these sociologic factors.

Psychological factors have a tremendous impact on appetite. Depression is one of the most common reversible causes of weight loss in elderly persons, accounting for up to 30% of undernutrition in medical outpatients.(21) Depression is a cause of undernutrition in up to 36% of residents who lose weight in nursing homes.(28),(29) In nursing home residents, ìfailure to thriveî has been closely correlated with depression.(30)

Tricyclic antidepressants and monoamine oxidase inhibitors are more likely to produce weight gain thanthe selective serotonin reuptake inhibitors or the newer antidepressants. Mirtazapine appears to be particularly useful in stimulating appetite.(31) Clinical trials report weight gain as the most common side effect of this agent.(32),(33),(34) Whether this effect can be translated into long-term care settings for the treatment of depression in older adults with weight loss has not been studied.

Physiologic changes in the hedonic qualities of food occur universally with aging. These are due particularly to a decline in olfaction(35) and to taste(36) that occur with aging. These changes in taste and smell are extremely important in nursing home residents. Residents often complain about the quality of food in nursing homes. Much of this is due to the physiologic alterations in taste and smell, which makes food appear less ìtastyî as people age. The alterations in the ability to appreciate the taste of food (most of this is due to decreased olfaction) means that in the nursing home, food presentation and food choice can play a more important role than does the actual taste of the food.

While the ability to smell declines in all individuals, the changes in taste are more variable. Persons who have smoked are more likely to have declines in taste. The major change in taste results in an increase in the threshold at which one can recognize a taste. However, the most common alteration in taste in older persons stems from the effects of drugs and diseases, rather than the physiologic changes of aging. Drugs that have an effect on taste and appetite are listed in Table 5.

Flavor amplification may enhance food palatability and acceptance, stimulate salivary flow, and reduce complaints concerning the oral cavity. Flavor enhancers have been shown to produce a tendency for ingestion of greater quantities of food and improved food preference.(37)

The presence of fat in the diet contributes much of the taste of food. Restriction of salt may make food unpalatable. Unpalatability due to overly restricted diets may cause decreased intake.(38) Special or restrictive diets (low cholesterol, low salt, no concentrated sweets) often reduce food intake without significantly helping the clinical status of the resident. For example, a regular diet does not affect glucose control in nursing home residents with diabetes.(39)

Management Considerations in Anorexia

In addition to sociological, psychological, and physiologic approaches to improving appetite, pharmacologic appetite stimulants should be useful in overcoming the physiologic anorexia of aging. Orexigenic drugs should be considered if all standard environmental and nutritional interventions fail. These drugs may help to prevent further morbidity and enteral feeding. No drug has received U.S. Food and Drug Administration approval for geriatric anorexia (Table 6).

Cannabinoids have shown promise in improving mood and appetite in cancer patients(40),(41) and in AIDS-related cachexia.(42) Jatoi et al(43) found a 49% improvement in appetite in advanced cancer patients receiving dronabinol. Dronabinol is a promising novel therapeutic agent that may be useful not only for treatment of anorexia, but also to improve disturbed behavior in patients with Alzheimer's disease. Body weight increased more during the dronabinol treatment than during the placebo periods.(44) In addition, somewhat less agitation was seen in treated patients. Because of the risk of delirium, dronabinol should be started at 2.5 mg before bed for one week, then given at 2.5 mg before dinner. If no response is seen, 2.5 mg can also be administered before lunch. Dronabinol has also been used to treat intractable nausea and vomiting.(45)

In randomized, placebo-controlled trials, corticosteroids have been shown to improve appetite, but have not demonstrated body weight gain.(46),(47),(48),(49),(50) Cyproheptadine has been shown to increase appetite in cancer patients, but also without weight gain.(51) Thalidomide, a TNF inhibitor, has produced body weight gain in a small number (n = 28) of patients with HIV-associated wasting syndrome.(52) Recombinant human growth hormone (GH) has produced weight gain (mean 1.6 kg vs 0.1 kg in the placebo group) in patients with AIDS, but at substantially higher than physiologic doses.(53) GH also improved nitrogen retention in older persons,(54) but in a study in malnourished critically ill patients, there was an increase in mortality.(55)

Sex steroids have shown promise in producing weight gain in ill subjects. An anabolic-androgenic steroid, oxymetholone, has produced body weight gain in advanced HIV-1 infection,(56) but not in cachectic cancer patients.(57) The weight gain has usually occurred only in patients who were hypogonadal. Medroxyprogesterone acetate has been observed to produce body weight gain when used as a chemotherapeutic agent, independent of tumor response.(58)

The male anabolic hormone, testosterone, declines with age.(59) This decline is associated with a loss of muscle mass and strength.(60) Testosterone levels are even lower in ill and malnourished persons.(61),(62) Testosterone replacement leads to an increase in muscle mass(63) and muscle strength.(64),(65) Testosterone has been shown to improve function in a rehabilitation center.(66) For these reasons, testosterone may be an ideal drug to use for hypogonadal malnourished men. The combination of testosterone and megestrol acetate offers an attractive hypothesis for treating anorectic, sarcopenic older men. In a study comparing megestrol acetate in cancer and AIDS patients randomized to recieve either resistance exercise training or no training, with or without testosterone injections, mean body weight increased by 3.8 kilograms. There was no difference between groups. Thigh muscle cross-sectional area decreased in the placebo group recieving megestrol acetate alone. This reduction in cross-sectional area was prevented by resistance exercise training, but not by testosterone without excercise training. The combination of megestrol acetate, testosterone, and resistance exercise training had an anabolic effect on muscle mass.(67) Testosterone replacement may also have a place at lower doses in older malnourished women.

Megestrol acetate has been the most widely studied agent used in cachexia.(68),(69) An increase in body weight has been shown in 54% (7 of 13) clinical trials.(70),(71),(72),(73),(74),(75),(76) Other trials with megestrol acetate have shown improvement in appetite, but have not shown an increase in body weight.(76),(77),(78),(79),(80),(81)

Assessment of changes in appetite are essential to intervene in older persons. The Council for Nutritional Clinical Strategies in Long-Term Care has developed an appetite assessment instrument (Table 7).

This simple eight-question tool can identify problems with anorexia in older adults. When appetite changes are identified, a search for reversible causes should be instituted. If weight loss continues, use of an orexigenic drug should be considered.

Summary

Profound differences occur in older persons. First, appetite correlates poorly with body weight in older persons, leading to failure to increase ingestion of nutrients in response to weight loss. Older persons exhibit less hunger and earlier satiety. Dramatic and poorly understood alterations occur in the physiologic regulation of appetite. Despite the changes in appetite regulation in older persons, the response to social and psychological stimulants is similar to younger adults. Pharmacologic stimulants of appetite suggest a promising intervention for anorexia.

1	Morley JE. Decreased food intake with aging J Gerontol A Biol Sci Med Sci 2001;56:81-88.
2	McGandy RB, Barrows CH Jr, Spanias A, et al. Nutrient intakes and energy expenditure in men of different ages. J Gerontol 1966;21:581-587.
3	Ritchie CR, Thomas DR. Aging. In: Heimburger DC, Weinsier RL, eds. Handbook of Clinical Nutrition. Third Edition. St. Louis, MO: Mosby-Yearbook, Inc; 1997: 154-168.
4	Abraham S, Carroll MD, Dresser CM, et al. Dietary Intake of Persons 1-74 Years of Age in the United States. Rockville, MD: National Center for Health Statistics; 1977. Advance Data from Vital and Health Statistics of the National Center for Health Statistics, No. G. 5.
5	De Castro JM. How can eating behavior be regulated in the complex environments of free-living humans? Neurosci Biobehav Rev 1996;20:119-131.
6	Morley JE, Silver AJ. Anorexia in the elderly. Neurobiol Aging 1988;9:9-16.
7	Roberts SB, Fuss P, Heyman MB, et al. Control of food intake in older men. JAMA 1994;272:1601-1606.
8	Morley JE, Thomas DR. Anorexia and aging: Pathophysiology. Nutrition 1999;15:499-503.
9	Morley JE. Anorexia, sarcopenia, and aging. Nutrition 2001;17:660-663.
10	Morley JE. Anorexia in older persons: Epidemiology and optimal treatment. Drugs Aging 1996:8:134.
11	Plata-Salaman CR. Anorexia during acute and chronic disease. Nutrition 1996;12:69-76.
12	Shike M, Russell DM, Detsky AS, et al. Changes in body composition in patients with small-cell cancer: The effect of total parenteral nutrition as an adjunct to chemotherapy. Ann Intern Med 1984;101:303-309.
13	Mitch WE. Robert H. Herman Memorial Award in Clinical Nutrition Lecture, 1997. Mechanisms causing loss of lean body mass in kidney disease. Am J Clin Nutr 1998;67:359-366.
14	Hedlund J, Hansson LO, Ortqvist A. Short- and long-term prognosis for middle-aged and elderly patients hospitalized with community-acquired pneumonia: Impact of nutritional and inflammatory factors. Scand J Infect Dis 1995;27:32-37.
15	Toth MJ, Gottlieb SS, Goran MI, et al. Daily energy expenditure in free-living heart failure patients. Am J Physiol 1997;272:469-475.
16	Roubenoff R, Roubenoff RA, Cannon JG, et al. Rheumatoid cachexia: Cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. J Clin Invest 1994;93:2379-2386.
17	Kotler DP, Wang J, Pierson RN. Body composition studies in patients with the acquired immunodeficiency syndrome. Am J Clin Nutr 1985;42:1255-1265.
21	Wilson MM, Vaswani S, Liu D, et al. Prevalence and causes of undernutrition in medical outpatients. Am J Med 1998;104:56-63.
22	Morley JE, Kraenzie D. Causes of weight loss in a community nursing home. J Am Geriatr Soc 1994;42:583-585.
23	Thomas DR. Causes of protein-energy malnutrition. In: Seiler OO, Stahelin HB, eds. Malnutrition in the Elderly. Steinhopff, Dietrich: Germany; 1999: 59-68.
24	Thomas DR, Ashmen W, Morley JE, Evans WJ. Nutritional management in long-term care: Development of a clinical guideline. J Gerontol A Biol Sci Med Sci 2000;55:M725-M734.
25	Hotaling DL. Nutritional considerations for the pureed diet texture in dysphagic elderly. Dysphagia 1992;7:81-85.
26	Johnson RM, Smiciklas-Wright H, Soucy IM, Rizzo JA. Nutrient intake of nursing home residents receiving pureed foods or a regular diet. J Am Geriatr Soc 1995;43:344-348.
27	Kayser-Jones J. Mealtime in nursing homes: The importance of individualized care. J Gerontol Nurs 1996;22:26-31.
28	Fitten LJ, Morley JE, Gross PI, et al. Depression. J Am Geriatr Soc 1989;37:459-472.
29	Blaum CS, Fries BE, Fiatarone MA. Factors associated with low body mass index and weight loss in nursing home residents. J Gerontol A Biol Sci Med Sci 1995;50:M162-168.
30	Katz IR, Beaston-Wimmer P, Parmetee P, et al. Failure to thrive in the elderly: Exploration of the concept and delineation of psychiatric components. J Geriatr Psychiatry Neurol 1993;6:151-169.
31	Fava M. Weight gain and antidepressants. J Clin Psychiatry 2000;11S:37-41.
32	Gelenberg AJ, Laukes C, McGahuey C, et al. Mirtazapine substitution in SSRI-induced sexual dysfunction. J Clin Psychiatry 2000;61:356-360.
33	Carpenter LL, Leon Z, Yasmin S, Price LH. Clinical experience with mirtazapine in the treatment of panic disorder. Ann Clin Psychiatry 1999;11:81-86.
34	Carpenter LL, Jocic Z, Hall JM, et al. Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry 1999;60:45-49.
35	Doty RL, Shaman P, Applebaum SL, et al. Smell identification ability: Changes with age. Science 1984;226:1441-1443.
36	Schiffman S. Food recognition by the elderly. J Gerontol 1977;32:586-592.
37	Schiffman SS, Warwick ZS. Effect of flavor enhancement of foods for the elderly on nutritional status: Food intake, biochemical indices, and anthropometric measures. Physiol Behav 1993;53:395-402.
38	Buckler DA, Kelber ST, Goodwin JS. The use of dietary restrictions in malnourished nursing home patients. J Am Geriatr Soc 1994;42:1100-1102.
39	Tariq S, Karcic E, Thomas DR, et al. The use of a no-concentrated-sweets diet in the management of type 2 diabetes in nursing home patients. J Am Diet Assoc 2001;101(12):1463-1466.
40	Plasse TF, Gorter RW, Krasnow SH, et al. Recent clinical experience with dronabinol. Pharmacology, Biochemistry and Behavior 1991;40:695-700.
41	Nelson K, Walsh D, Deeter P, et al. A phase II study of delta-9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia. J Palliat Care 1994;10:14-18.
42	Beal JE, Olson R, Laubenstein L, et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 1995;10:89-97.
43	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 2002;20:567-573.
44	Volicer L, Stelly M, Morris J, et al. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimerís disease. Int J Geriatr Psychiatry 1997;12:913-919.
45	Gonzalez-Rosales F, Walsh D. Intractable nausea and vomiting due to gastrointestinal mucosal metastases relieved by tetrahydrocannabinol (dronabinol). J Pain Symptom Manage 1997:14:311-314.
46	Moertel C, Schutt AG, Reiteneier RJ, et al. Corticosteroid therapy of pre-terminal gastrointestinal cancer. Cancer 1974;33:1607-1609.
47	Willox J, Corr J, Shaw J, et al. Prednisolone as an appetite stimulant in patients with cancer. Br Med J (Clin Res Ed) 1984;288:200-227.
48	Bruera E. Roca E, Cedaro L, et al. Action of oral methylprednisolone in terminal cancer patients: a prospective randomized double blind study. Cancer Treat Rep 1985;69:751-754.
49	Robusteli Della Cuna G, Pellegrini A, Piazzi M. Effect of methylprednisolone sodium succinate on quality of life in pre-terminal cancer patients: A placebo-controlled multicenter study. Eur J Cancer Clin Oncol 1989;25:1817-1821.
50	Popiela T, Lucchi R, Giongo F. Methylprednisolone as palliative therapy for female terminal cancer patients. Eur J Cancer Clin Oncol 1989;25:1823-1829.
51	Kardinal C. Loprinzi CL, Schaid DJ, et al. A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer 1990;65:2657-2662.
52	Reyes-Teran G, Sierra-Madero JG, Martinez del Cerro V, et al. Effects of thalidomide on HIV-associated wasting syndrome: A randomized, double-blind, placebo-controlled clinical trial. AIDS 1996;10:1501-1507.
53	Schambelan M, Mulligan K, Grunfeld C, et al. Recombinant human growth hormone in patients with HIV-associated wasting: A randomized, placebo-controlled trial. Serostim Study Group. Ann Intern Med 1996;125:873-872.
54	Kaiser FE, Silver AJ, Morley JE. The effect of recombinant human growth hormone on malnourished older individuals. J Am Geriatr Soc 1991;39:235-240.
55	Takala J, Ruokonen E, Webster NR, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999;341:785-792.
56	Hengge UR, Baumann M, Maleba R, et al. Oxymetholone promotes weight gain in patients with advance human immunodeficiency virus (HIV-1) infection. Br J Nutr 1996;75:129-138.
57	Pengelly CD. Oxymetholone in the chemotherapy of malignant disease. Curr Med Res Opin 1973;1(7):401-406.
58	Desport JC, Blanc-Vincent MP, Gory-Delabaere G, et al. Standards, Options and Recommendations (SOR) for the use of appetite stimulants in oncology. Work group. Federation of the French Cancer Centres (FNCLCC). Bull Cancer 2000;87:315-328.
59	Morley JE, Kaiser FE, Perry HM 3rd, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 1997;46:410-413.
60	Baumgartner RN, Waters DL, Gallagher D, et al. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 1999;107:123-136.
61	Morley JE, Distiller LA, Lissoos I, et al. Testicular function in patients with spinal cord damage. Horm Metab Res 1979;11:679-682.
62	Rudman D, Mattson DE, Nagraj HS, et al. Plasma testosterone in nursing home men. J Clin Epidemiol 1988;41:231-236.
63	Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 2000;85:2670-2677.
64	Morley JE, Perry HM 3rd, Kaiser FE, et al. Effects of testosterone replacement therapy in old hypogonadal males: A preliminary study. J Am Geriatr Soc 1993;41:149-152.
65	Sih R, Morley JE, Kaiser FE, et al. Testosterone replacement in older hypogonadal men: A 12-month randomized controlled trial. J Clin Endocrinol Metab 1997;82:1661-1667.
66	Bakhshi V, Elliott M, Gentili A, et al. Testosterone improves rehabilitation outcomes in ill older men. J Am Geriatr Soc 2000;48:550-553.
67	Lambert CP, Sullivan DH, Freeling SA, et al.. Effects of testosterone replacement and/or resistance exercise on the composition of megestrol acetate stimulated weight gain in elderly men. A randomized controlled trial. J Clin Endocrinol Metab 2002;87:2100-2106.
68	Tchekmedyian S, Tait N, Moody M, et al. High dose megestrol acetate: A possible treatment of cachexia. JAMA 1987;257:1195-1199.
69	Cruz JM, Muss HB, Brockschmidt JK, Evans GW. Weight changes in women with metastatic breast cancer treated with megestrol acetate: A comparison of standard versus high-dose therapy. Semin Oncol 1990;17(6 suppl 9):63-67.
70	Bruerra E, Macmillan K, Hanson J, et al. A controlled trial of megestrol acetate on appetite, caloric intake, nutritional status, and other symptoms in patients with advance cancer. Cancer 1990;66:1279-1282.
71	Loprinzi CL, Ellison NM, Schaid DJ, et al. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst 1990;82:1127-1132.
72	Schmoll E, Wilke H, Thole R. Megestrol acetate in cancer cachexia. Semin Oncol 1991;1(suppl)2:32-34.
73	Heckmayr M, Gatzenneier U. Treatment of cancer weight loss in patients with advanced lung cancer. Oncology 1992;49(suppl)2:32-34.
74	Feliu J, Gonzalez-Baron M, Berrocal A. Usefulness of megestrol acetate in cancer cachexia and anorexia. Am J Clin Oncol 1992;15:436-440.
75	Azona C, Castro L, Crespo E, et al. Megestrol acetate therapy for anorexia and weight loss in children with malignant solid tumors. Alimentary Pharmacology & Therapy 1996;10:577-586.76.
76	Mantovani G, Maccio A, Bianchi A, et al. Megestrol acetate in neoplastic anorexia/cachexia: Clinical evaluation and comparison with cytokine levels in patients with head and neck carcinoma treated with neoadjuvant chemotherapy. Int J Clin Lab Res 1995;25:135-141.
77	Tchekmedyian S, Hakman M, Siau J, et al. Megestrol acetate in cancer anorexia and weight loss. Cancer 1992;69:1268-1274.
78	Beller E, Tattersail M, Lumley T, et al. Improved quality of life with megestrol acetate in patients with endocrine-insensitive advanced cancer: A randomized placebo-control trial. Ann Oncol 1997;8:277-283.
79	Bruera E, Ernst S, Hagen N, et al. Symptomatic effects of megestrol acetate (MA): A double-blind, crossover study (abstract). Proc Am Soc Clin Oncol 1996;1716:531.
80	Fietkau R, Riepl M, Kettner H, et al. Supportive use of megestrol acetate in patients with head and neck cancer during radio(chemo)therapy. Eur J Cancer 1997;33:75-79.
81	McMillan DC, Wigmore SJ, Fearon KC, et al. A prospective randomized study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss. Br J Cancer 1999;79:495-500.