|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2002 American Society for Clinical Oncology Dronabinol Versus Megestrol Acetate Versus Combination Therapy for Cancer-Associated Anorexia: A North Central Cancer Treatment Group StudyByFrom the Mayo Clinic and Mayo Foundation, Rochester; CentraCare Clinic, St Cloud; and Duluth Community Clinical Oncology Program, Duluth, MN; Wichita Community Clinical Oncology Program, Wichita, KS; Missouri Valley Consortium, Omah, NE; Carle Cancer Center Community Clinical Oncology Program, Urbana, IL; Ochsner Community Clinical Oncology Program, New Orleans, LA; and Scottsdale Community Clinical Oncology Program, Scottsdale, AZ. Address reprint requests to Aminah Jatoi, MD, Mayo Clinic, 200 1st St, SW, Rochester, MN 55905; email: jatoi.aminah{at}mayo.edu
PURPOSE: To determine whether dronabinol administered alone or with megestrol acetate was more, less, or equal in efficacy to single-agent megestrol acetate for palliating cancer-associated anorexia. PATIENTS AND METHODS: Four hundred sixty-nine assessable advanced cancer patients were randomized to (1) oral megestrol acetate 800 mg/d liquid suspension plus placebo, (2) oral dronabinol 2.5 mg twice a day plus placebo, or (3) both agents. Eligible patients acknowledged that loss of appetite or weight was a problem and reported the loss of 5 pounds or more during 2 months and/or a daily intake of less than 20 calories/kg of body weight.
RESULTS: Groups were comparable at baseline in age, sex, tumor type, weight loss, and performance status. A greater percentage of megestrol acetate-treated patients reported appetite improvement and weight gain compared with dronabinol-treated patients: 75% versus 49% (P = .0001) for appetite and 11% versus 3% (P = .02) for CONCLUSION: In the doses and schedules we studied, megestrol acetate provided superior anorexia palliation among advanced cancer patients compared with dronabinol alone. Combination therapy did not appear to confer additional benefit.
ANECDOTAL REPORTS and numerous small studies suggest that marijuana stimulates appetite. In one such study, Abel1 observed seven marijuana-treated individuals devour a plate of marshmallows in a controlled investigation of marijuana’s effects on memory, intellectual performance, and hunger. He concluded "marijuana increases the subjects’ desire for food." These preliminary observations led to further investigation of cannabinoids in the treatment of cancer-associated anorexia, a pervasive and devastating symptom among advanced cancer patients. More than half of patients with advanced cancer experience lack of appetite and/or weight loss.2 Moreover, when queried about symptoms faced in the setting of advanced cancer, patients consistently rank anorexia as one of the most troublesome.3 In an effort to provide palliation for these patients, Nelson et al4 conducted a phase II study in which they administered delta-9-tetrahydrocannabinol (dronabinol) to 19 cancer patients with anorexia. Patients received dronabinol at a dose of 2.5 mg orally three times a day and were assessed for appetite improvement at 2 and 4 weeks. Observing that 13 patients reported an improvement in appetite, these investigators concluded that dronabinol holds promise as an appetite stimulant in cancer patients. In addition to this trial, at least 12 clinical trials have examined dronabinol for the treatment of chemotherapy-induced nausea and vomiting, as recently reviewed by Voth and Schwartz.5 Some of these trials have suggested that dronabinol might control nausea, and four have also suggested a modest improvement in appetite. Coupled with similar information from AIDS patients,6-8 these data suggest that dronabinol may be effective in the treatment of cancer-induced anorexia. To date, no randomized trial has been undertaken to determine whether dronabinol is comparable with other orexigenic agents, such as megestrol acetate. A synthetically derived progesterone, megestrol acetate is the most extensively studied agent for treating cancer-associated anorexia and holds a well-established track record for alleviating this symptom and promoting weight gain in patients with advanced cancer.9-11 Despite this track record, however, megestrol acetate does not benefit all patients with cancer-associated anorexia. In an earlier placebo-controlled trial among 133 patients from the North Central Cancer Treatment Group, 60% of patients who completed the anorexia questionnaire thought this hormone improved their appetite, compared with 42% of placebo-treated patients who also cited improvement.9 Fewer than 15% reported weight gain in the megestrol acetate arm. Such data demonstrate that, although megestrol acetate is effective in palliating anorexia, a large proportion of patients continue to suffer from anorexia despite treatment with this hormone. We therefore undertook this double-blind, randomized trial to define the role of dronabinol in the treatment of cancer-associated anorexia. The purpose of this study was to determine whether dronabinol administered either alone or in combination with megestrol acetate was more, less, or equal in efficacy when compared with megestrol acetate in palliating cancer-associated anorexia.
Overview Conducted through the North Central Cancer Treatment Group (NCCTG), this multi-institutional, double-blind, randomized trial involved 20 institutions. All 20 institutional review boards approved the study protocol, and all patients provided informed written consent before study enrollment.
Eligibility Criteria
Exclusion Criteria
Stratification and Randomization Patients were then randomized, in a double-blind manner, to one of three treatment arms: (1) megestrol acetate liquid suspension 800 mg orally daily plus capsule placebos; (2) dronabinol capsules 2.5 mg orally twice a day plus liquid placebo; or (3) a combination of both medications in the same dosages as noted previously.
Follow-Up
Statistical Analyses
Sample Size Calculations
A total of 485 patients were recruited onto the study between December of 1996 and December of 1999, and 469 of these patients (97%) were deemed assessable. Patients were not considered assessable on the basis of withdrawal before starting study drug (n = 14) and ineligibility as determined after randomization (n = 2). Patients completed a baseline questionnaire and at least one weekly questionnaire in the first follow-up. As expected and as consistent with earlier studies from our group, 45% of patients completed both a baseline and 1-month follow-up questionnaire. Patients in all three arms were comparable at baseline with respect to weight, patients’ rating of appetite, reduction in appetite, reported perception of food intake, nausea intensity, perception of current weight, and QOL assessment. (Tables 1 and 2)
The median time on study was not statistically different between the groups that received megestrol acetate, dronabinol, or the two-drug combination: 80 days versus 57 days versus 74 days (P = .21). Reasons for patient withdrawal included patient refusal and/or toxicity (45%, 58%, and 41%, respectively) and patient death (22%, 15%, and 26%, respectively). In addition, there were no statistically significant differences in patient survival within the three treatment arms: median survival, 123 days versus 141 days versus 113 days in the megestrol acetate versus dronabinol versus the combination arms, respectively (log-rank P = .66). Within the megestrol acetate group, 75% of patients reported that this agent increased their appetite at some point during the study period, whereas only 49% of patients in the dronabinol group reported such improvement (Fisher’s exact test, P = .0001). The combination arm resulted in 66% of patients’ reporting an improvement in appetite (Fisher’s exact test, P = .17) when compared with the megestrol acetate arm. As shown in Table 3, other appetite-related questions yielded a consistently favorable orexigenic effect of megestrol acetate when compared with dronabinol alone and no statistically significant improvement with combination therapy when direct comparisons to the megestrol acetate arm were undertaken.
Eleven percent of patients in the megestrol acetate arm reported, from weights they obtained at home, a 10% or more weight gain above their baseline at some point during treatment, in contrast to 3% in the dronabinol arm (Fisher’s exact test, P = .02). The combination of megestrol acetate and dronabinol resulted in 8% of patients’ reporting a 10% increase in weight and was no different compared with the use of megestrol acetate alone (Fisher’s exact test, P = .43). Physician-reported weight gain also demonstrated results in favor of the megestrol acetate arm: 14% of megestrol acetate-treated patients gained 10% or more of their baseline weight, whereas only 5% of patients on the dronabinol arm manifested such a weight gain (Fisher’s exact test, P = .009). Likewise, by office weights, the combination of megestrol acetate and dronabinol resulted in 11% of patients manifesting a 10% increase in weight, a percentage that was not statistically different compared with the use of megestrol acetate alone (Fisher’s exact test, P = .49) (Table 4)  .
With regard to QOL, the Uniscale detected no significant differences between maximally improved QOL assessment over time in either of the three study arms. In contrast, the difference between baseline and maximum FAACT-AN scores was statistically significant between the megestrol acetate–treated and dronabinol-treated groups (median, 7.8 [range, 0 to 41] v 2.6 [range, 0 to 59]; Wilcoxon rank sum test, P = .002). Individually, the physical and the emotional constructs of the FAACT-AN questionnaire were the only ones to yield statistically significant differences between the megestrol acetate–treated and dronabinol-treated groups, and these differences illustrated that patients on the megestrol acetate arm had better QOL within these constructs. In contrast, similar analyses yielded no significant QOL differences between patients who received combination treatment and those who received megestrol acetate alone, with the exception of the emotional construct for the FAACT.In the latter construct, the megestrol acetate arm had higher scores compared with the combination arm. Results are summarized in Fig 1.
Finally, 18% of male patients reported impotence with megestrol acetate, in contrast to 4% with dronabinol (Fisher’s exact test, P = .002). Otherwise, toxicity incidence that included monitoring for nausea, vomiting, neurocortical dysfunction, edema, ascites, pleural effusion, or thromboembolic phenomena was not statistically different between treatment groups (Table 6).
This study is the first to compare megestrol acetate with dronabinol in the treatment of cancer-associated anorexia and/or weight loss. Our findings demonstrate that, in the doses and schedules mentioned above, megestrol acetate is superior to dronabinol in the treatment of cancer-associated anorexia and that the addition of dronabinol to megestrol acetate does not confer additional benefit. These results are important because they may influence oncologists’ viewpoint on the medical uses of cannabinoid derivatives. Although few oncologists prescribe dronabinol for nausea and vomiting, a recent survey completed by 1,122 American oncologists (75% reply rate) found that as many as 30% would favor rescheduling marijuana for medical purposes.15 In an earlier survey, 44% of respondents had recommended the use of marijuana to an oncology patient at some point in the past.16 Our findings that dronabinol does little to promote appetite or weight gain among advanced cancer patients compared with megestrol acetate should dampen enthusiasm for the use of cannabinoids or their derivatives. Although assessment of nausea and vomiting was not a major end point in our study, a noteworthy finding is that the severity of nausea and vomiting was not statistically different in direct comparisons between the megestrol acetate and dronabinol treatment arms. Prior data from our group and others have demonstrated that megestrol acetate has significant antiemetic potential among cancer patients9,17,18 The findings from this trial suggest that the antiemetic potential of dronabinol is comparable to that of megestrol acetate alone. Hence, these results suggest that even from an antiemetic standpoint, dronabinol appears to have little to add above and beyond megestrol acetate (Table 6). Another noteworthy aspect of this trial is the improvement in specific aspects of QOL, as measured by the FAACT-AN instrument, with the use of megestrol acetate as compared with dronabinol alone. When analyzed in aggregate, multiple placebo-controlled trials have demonstrated that megestrol acetate does not improve overall QOL in advanced cancer patients with anorexia.19 However, our study clearly demonstrates that megestrol acetate promotes symptom-specific aspects of QOL in advanced cancer patients with anorexia, as measured by the FAACT-AN instrument, compared with dronabinol alone. Because toxicity was not significantly different between the two groups, it is likely that this improvement in QOL is a direct reflection of the FAACT-AN instrument’s heavy emphasis on anorexia. In effect, this improvement in QOL as measured by the FAACT-AN further validates the NCCTG anorexia questionnaire, which demonstrated an improvement in anorexia in the present trial. One might question the dose of dronabinol that we chose in this study, and one might argue that a higher dose of this agent might have resulted in greater appetite-stimulatory effects. However, the phase II trial by Nelson and others, which suggested dronabinol at 2.5 mg three times a day resulted in improved appetite,4 found that this higher dose was also associated with notable side effects in approximately 20% of patients. Other trials have also reported that higher doses of dronabinol have had intolerable side effect profiles.20,21 On the basis of this information, we choose, in concert with the manufacturers of this drug, to study 2.5 mg twice a day orally in the current trial. In short, our study demonstrates that megestrol acetate provided superior palliation of anorexia in advanced cancer patients than dronabinol alone and that combination therapy did not confer additional benefit.
Supported in part by grant nos. CA-25224, CA-37404, CA-15083, CA-35195, CA-35272, CA-60276, CA-35269, CA-37417, CA-63849, CA-35448, CA-35101, CA-35195, CA-35415, and CA-35103 from the United States Public Health Service.
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and the Mayo Clinic. Dronabinol was provided by Roxane Laboratories, Columbus, OH; megestrol acetate was provided by Bristol-Myers Squibb, Princeton, NJ.
1. Abel EL: Effects of marihuana on the solution of anagrams, memory and appetite. Nature 231: 260–261, 1971[Medline] 2. Tchekmedyian NS, Zahyna D, Halpert C, et al: Clinical aspects of nutrition in advanced cancer. Oncology 49: 3–7, 1992 (suppl 2) 3. Walsh D, Donnelly S, Rybicki L: The symptoms of advanced cancer: Relationship to age, gender, and performance status in 1,000 patients. Support Care Cancer 8: 175–179, 2000[CrossRef][Medline] 4. 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 10: 14–18, 1994
5.
Voth EA, Schwartz RH: Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med 126: 791–798, 1997 6. Beal JE, Olson R, Lefkowitz L, et al: Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome–associated anorexia. J Pain Symptom Manage 14: 7–14, 1997[CrossRef][Medline] 7. 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 10: 89–97, 1995[CrossRef][Medline]
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. Timpone JG, Wright DJ, Li N, et al: The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome. The DATRI 004 Study Group: Division of AIDS Treatment Research Initiative. AIDS Res Hum Retroviruses 13: 305–315, 1997[Medline] 10. Loprinzi CL, Michalak JC, Schaid DJ, et al: Phase III evaluation of four doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia. J Clin Oncol 11: 762–767, 1993[Abstract]
11.
Loprinzi CL, Kugler JW, Sloan JA, et al: Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. J Clin Oncol 17: 3299–3306, 1999 12. Loprinzi CL, Sloan JA, Rowland K: Methodologic issues regarding cancer anorexia/cachexia trials, in Portenoy R (ed), Research and Palliative Care: Methodologies and Outcomes. New York, NY, Churchill Livingstone Press (in press) 13. 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] 14. Cella DF, von Roenn JH, Lloyd S, et al: The Bristol Myers anorexia/cachexia instrument: A brief assessment of patients—Subjective response to treatment for anorexia/cachexia. Qual Life Res 4: 221–231, 1995[CrossRef][Medline] 15. Schwartz RH, Voth EA, Sheridan MJ: Marijuana to prevent nausea and vomiting in cancer patients: A survey of clinical oncologists. South Med J 90: 167–172, 1997[Medline] 16. Doblin RE, Kleiman MA: Marijuana as an antiemetic medicine: A survey of oncologists’ experiences and attitudes. J Clin Oncol 9: 1314–1319, 1991[Abstract] 17. Tchekmedyian NS, Hickman M, Siau J, et al: Megestrol acetate in cancer anorexia and weight loss. Cancer 69: 1268–1274, 1992[Medline] 18. 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]
19.
Jatoi A, Kumar S, Sloan J, et al: On appetite and its loss. J Clin Oncol 18: 2930–2932, 2000 20. Frytak S, Moertel CG, O’Fallon JR, et al: Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate: A prospective, randomized evaluation. Ann Intern Med 91: 825–830, 1979 21. Sweet DL, Miller NJ, Weddington W, et al: Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy: A pilot study. J Clin Pharmacol 21: 70S–75S, 1981[Abstract] Submitted April 17, 2001; accepted August 31, 2001. This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
10% baseline weight gain. Combination treatment resulted in no significant differences in appetite or weight compared with megestrol acetate alone. The Functional Assessment of Anorexia/Cachexia Therapy questionnaire, which emphasizes anorexia-related questions, demonstrated an improvement in quality of life (QOL) among megestrol acetate–treated and combination-treated patients. The single-item Uniscale, a global QOL instrument, found comparable scores. Toxicity was also comparable, with the exception of an increased incidence of impotence among men who received megestrol acetate. 
