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© 2000 American Society for Clinical Oncology
On Appetite and Its LossFrom the Division of Medical Oncology and Department of Biostatistics, Mayo Clinic, Rochester; and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN. Address reprint requests to Aminah Jatoi, MD, Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. WHAT FOLLOWS IS AN exchange between a medical oncology fellow and an attending oncologist: "One thing I forgot to mention. In addition to the new findings on her chest x-ray, Ms Jones was telling me that she’s lost 12 pounds since we last saw her and doesn’t feel like eating anymore. I’m going to prescribe megestrol acetate." "Why?" "To help with appetite." "Why?" "Because it might help her." "Yes, but how will it help Ms Jones?" "Well, I know that most randomized, placebo-controlled studies haven’t really shown that it improves overall quality of life—you reviewed those data with me last week on another patient. But appetite is important. When I talked with Ms Jones about appetite and told her about side effects of megestrol acetate and lack of data on improved quality of life, she still really wanted to give it a try." "Sounds reasonable." But is it reasonable? In 1999, nearly 1 million prescriptions were written for Megace Oral Suspension (Bristol-Myers Squibb Co, Princeton, NJ). This medication is the best studied and probably most widely prescribed appetite stimulant. Although not all of these prescriptions were written for anorectic cancer patients, it is estimated that 50% were. Similarly, other orexigenic agents, such as dexamethasone, megestrol acetate tablets, medroxyprogesterone acetate, and cyproheptadine, are less easily tracked but also prescribed in this setting. In short, oncologists and other health care providers devote substantial effort to boost appetite among advanced cancer patients. Underlying this effort is a compilation of 15 published studies, which in aggregate demonstrate that megestrol acetate improves appetite (Table 1). Only one of these studies, however, reported a significant improvement in global quality of life.6 A second demonstrated partial improvement.5 Yet a third reported that global quality of life actually declined with the use of megestrol acetate.3 Of parenthetical note, none of these studies reported a survival advantage in patients receiving megestrol acetate.
How do we reconcile data that clearly demonstrate that megestrol acetate improves appetite in patients with cancer but at the same time do not suggest that it improves global quality-of-life scores? At a time when health care providers are asked to justify why they do what they do, addressing this question becomes timely and relevant. One factor that may explain the discordance between the improvement in appetite and the lack of improvement in quality of life involves methodologic issues that are relevant to measuring the latter. The study by Parnes et al4 illustrates one such issue. These investigators used very extensive testing to assess global quality of life. The difficulty of administering this testing, however, ultimately led to inconclusive quality-of-life findings, with only 8% of patients completing all questionnaires at the end of an 8-week period. The researchers explain, "Compliance with the quality of life survey was adversely affected by the advanced state of the patients’ cancer as well as by the research interviewers’ own reluctance to contact patients... . " Subsequent data have cross-validated simpler global quality-of-life instruments,16 but the onus of completing any quality-of-life measurement may pose a challenge for advanced cancer patients and compromise study results. Couple this methodologic issue with the admission that quality of life is multifaceted, and the challenge of measurement becomes even greater. Appetite is complex and modified by reduced hunger, possible altered taste, dysphagia, depression, and fear of eating. Global quality of life subsumes appetite, is far more intricate and intangible, and poses a greater challenge with respect to measurement. In effect, we cannot totally discount the possibility that megestrol acetate does improve global quality of life but that our measurement tools are not detecting it. Another explanation for the discordance between an improvement in appetite and no improvement in global quality of life might be that appetite stimulants concurrently cause undesirable side effects that detract from the latter. Perhaps toxic effects counterbalance the modest benefits conferred by appetite stimulants. Overall, however, most side effects of megestrol acetate (for example, thrombophlebitis and edema) affect only a minority of patients. Although several studies demonstrate subtle biochemical evidence of adrenal insufficiency in many patients who receive megestrol acetate, direct clinical evidence of such insufficiency is not apparent among most cancer patients treated with this hormone. Only during times of stress, such as with severe infection or perioperatively, are compensatory corticosteroids appropriate for patients who receive megestrol acetate. It is also noteworthy that one of the so-called side effects of megestrol acetate is in fact a favorable one: its antiemetic effect.8 Thus although it may be tempting to invoke undesirable side effects attributable to megestrol acetate to explain its lack of favorable impact on quality of life, such an argument does not seem plausible. Yet a third consideration when reviewing these studies focuses on our recognition of their primary objective. We must acknowledge that these studies did not address the question of whether appetite stimulation improves quality of life. Those that examined global quality of life addressed whether megestrol acetate improves quality of life, not whether improvement in appetite does so. Only a small subset of advanced cancer patients, less than 30%, derives a substantial enhancement of appetite with megestrol acetate. This proportion may be too small to impact on the global quality of life of the entire group receiving megestrol acetate. Were we to find an agent that provides a more sweeping improvement in appetite, we might also have detected an improvement in global quality of life. Finally and importantly, another factor that may explain the discordance between appetite and global quality of life centers on the fact that multiple symptoms converge among advanced cancer patients. Recognizing that advanced cancer patients are polysymptomatic, Donnelly et al17 evaluated symptom prevalence in 1,000 such patients and found that although anorexia was highly prevalent, it was not an isolated symptom. Nausea, fatigue, dry mouth, pain, and a variety of other symptoms accompany anorexia. It might not be surprising that successful treatment of anorexia does little to influence favorably overall quality of life, if other symptoms are viewed as stepping forward as the severity of anorexia takes a step back. One of our colleagues has described this stepping forward of symptoms as a variant of the "sore-tooth-tight-shoe" phenomenon. Walking around with tight shoes is a good way to ameliorate a sore tooth: when tight shoes cause sore feet, the tooth pain seems to get better. Consistent with this analogy, overall quality of life might not improve with megestrol acetate because relief of anorexia would amount to nothing more than a shifting of symptomatology in the setting of advanced cancer. Hence, patients benefit from appetite improvement, but global quality of life remains unchanged. To summarize, the above arguments point to one conclusion: no clear explanation reconciles the discrepancy between improvement in appetite and lack of improvement in global quality of life. The foregoing arguments also illustrate another point: this discrepancy should not necessarily be accepted at face value. Given the lack of data that megestrol acetate improves global quality of life, however, the question re-emerges, "Why do we prescribe appetite stimulants?" Or, as prompted by the exchange between the medical oncology fellow and attending oncologist, "Is it reasonable to prescribe them?" To answer this question, we must look beyond data provided by randomized placebo-controlled trials and into our common humanity. There is immense anguish with the loss of appetite. In an interview of 14 patients and their respective caregivers, Holden18 quotes a husband’s fear and guilt as he watches his wife’s appetite regress in the face of cancer progression: "It is so frightening for me to see her lose weight. I knew something was drastically wrong. I blamed myself for not feeding her the right things." In yet another study, Meares19 interviewed 12 women who had cared for patients with cancer toward the end of their lives. Interviews occurred within the first year of bereavement and underscored the importance of food, especially during illness. One caregiver explained why eating was so important at the end of life, despite a fleeting appetite: "Food, from time immemorial, is part of the nurturing process, and ‘Bread the Staff of Life,’ all that stuff... so when you think of food, you think, well, if you can eat, you can get healthy." The descriptive studies of Holden18 and of Meares,19 as well as the compilation of 15 randomized, placebo-controlled trials, which in aggregate demonstrate that megestrol acetate improves appetite, finally explain why physicians and other health care providers prescribe appetite stimulants to patients with advanced cancer. Oncologists prescribe them because appetite is important. It is important in its own right—independent of global quality of life, independent of survival, and independent of any other clinical end point. Is it reasonable to prescribe them? Yes, it is.
NOTES A.J. is the recipient of a Clinical Associate Physician Award (RR00585-S). REFERENCES 1. Fietkau R, Riepl M, Kettner H, et al: Supportive use of megestrol acetate in patients with head and neck cancer during radiotherapy. Eur J Cancer 33:75-79, 1997 2. Vadell C, Segui MA, Gimeez-Arnau JM, et al: Anticachectic efficacy of megestrol acetate at different doses and versus placebo in patients with neoplastic cachexia. Am J Clin Oncol 21:347-351, 1998[Medline] 3. Westman G, Berman B, Albertsson M, et al: Megestrol acetate in advanced, progressive hormone-insensitive cancer: Effects in the quality of life—A placebo-controlled, randomized, multicentre trial. Eur J Cancer 35:586-595, 1999 4. Parnes HL, Conaway M, Aisner J, et al: Megestrol acetate for the treatment of cachexia in patients with advanced lung or colorectal cancer. Cancer Ther 2:75-82, 1999 5. Bruera E, Ernst S, Hagen N, et al: Effectiveness of megestrol acetate in patients with advanced cancer: A randomized, double-blind crossover study. Cancer Prev Control 2:74-78, 1998[Medline]
6.
Beller E, Tattersall M, Lumley T, et al: Improved quality of life with megestrol acetate in patients with endocrine-insensitive advanced cancer: A randomized placebo-controlled trial. Ann Oncol 8:277-283, 1997 7. DeConno F, Martini C, Zecca E, et al: Megestrol acetate for anorexia in patients with far-advanced cancer: A double-blind controlled clinical trial. Eur J Cancer 34:1705-1709, 1998
8.
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 82:1127-1132, 1990 9. Bruera E, Macmillan K, Kuehan N, et al: A controlled trial of megestrol acetate on appetite, caloric intake, nutritional status, and other symptoms in patients with advanced cancer. Cancer 66:1279-1282, 1990[Medline] 10. Tchekmedyian NS, Hickman M, Siau J, et al: Megestrol acetate in cancer anorexia and weight loss. Cancer 69:1268-1274, 1992[Medline] 11. Rowland KM, Loprinzi CL, Shaw EG, et al: Randomized double-blind placebo-controlled trial of cisplatinum and etoposide plus megestrol acetate/placebo in extensive-stage small-cell lung cancer: A North Central Cancer Treatment Group study. J Clin Oncol 14:135-141, 1996[Abstract] 12. Feliu J, Gonzales-Baron M, Berrocal A, et al: Usefulness of megestrol acetate in cancer cachexia and anorexia. Am J Clin Oncol 15:436-440, 1992[Medline] 13. Lai Y-L, Fang F-M, Yeh C-Y, et al: Management of anorexic patients in radiotherapy: A prospective randomized comparison of megestrol and prednisolone. J Pain Symptom Manage 9:265-268, 1994[Medline] 14. Schmoll E, Wilke H, Thole R, et al: Megestrol acetate in cancer cachexia. Semin Oncol 18:32-34, 1991[Medline] 15. Chen H-C, Leung SW, Wang C-J, et al: Effect of megestrol acetate and prepulsid on nutritional improvement in patients with head and neck cancers undergoing radiotherapy. Radiother Oncol 43:75-79, 1997[Medline] 16. Sloan JA, Loprinzi CL, Kuross SA, et al: Randomized comparison of four tools measuring overall quality of life in patients with advanced cancer. J Clin Oncol 16:3662-3673, 1998[Abstract] 17. Donnelly S, Walsh D, Rybicki L: The symptoms of advanced cancer: Identification of clinical and research priorities by assessment of prevalence and severity. J Palliat Care 22:27-32, 1995 18. Holden CM: Anorexia in the terminally ill cancer patient: The emotional impact on the patient and the family. Hosp J 7:73-84, 1991[Medline] 19. Meares CJ: Primary caregiver perceptions of intake cessation in patients who are terminally ill. Oncol Nurs Forum 24:1751-1757, 1997[Medline]
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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