Correspondence
Antiemetic Properties of Granisetron
N Engl J Med 1995; 332:1653-1654June 15, 1995
- Article
To the Editor:
The article on the use of granisetron and dexamethasone to prevent chemotherapy-induced nausea and vomiting (Jan. 5 issue)1 does not appear to be relevant to current practice in the United States. The study group used 3 mg of granisetron, which is triple the dose recommended to provide an effect equivalent to that of 32 mg of ondansetron. Furthermore, a simple economic analysis makes it clear that this dose would be exceedingly unappealing to any purchaser of health care. At a rock-bottom cost of $135 per milligram of granisetron, each treatment would cost approximately $400. Since the study found that granisetron reduced the number of patients who vomited by 20 percent, one would need to treat 100 patients, at a cost of $40,000, to prevent 20 patients from vomiting, or $2,000 per patient saved from vomiting.
I know your job is not to design clinical trials. Your publication of the report on this trial, however, suggests that it has relevance for American oncologists, though it does not. A more useful trial for this cost-conscious era would be one in which a reduced dose of granisetron is compared with metoclopramide, which sells for $4 per 100 mg.
1 ReferencesHerman Kattlove, M.D., M.P.H.
SalickNet, Inc., Los Angeles, CA 90048-45201
The Italian Group for Antiemetic Research
Full Text | Web of Science | Medline
To the Editor:
Dr. Roila and his colleagues should be congratulated for contributing, through a carefully conducted multicenter trial, yet another set of important observations to our knowledge of antiemetic therapy in patients with cancer. As the authors indicate, their results raise some key issues. One is the discrepancy between their results and those of studies like ours,1 which showed granisetron to be superior, not equivalent, to dexamethasone in patients receiving moderately emetogenic chemotherapy. The Italian group implies that the difference lies in the use of a higher dose and repeated administration of dexamethasone. The results from another of our studies, however, suggest that this explanation should not be accepted too readily. First, in an early trial,2 we found that the administration of a long-acting depot corticosteroid did not prolong the previously demonstrated antiemetic effect of a single dose of methylprednisolone, suggesting that repeated administration may not have been the important factor. Second, in a trial involving patients who received less emetogenic chemotherapy, we too found an equivalence between an antagonist to serotonin (5-hydroxytryptamine3 [5-HT3]) and dexamethasone.3 Since it appears that the relative effectiveness of 5-HT3 antagonists, as compared with corticosteroids, is dependent on the type of chemotherapy administered,4 it is possible that the discrepancy between the Italian group's results and ours1 can be explained as well by differences in the populations studied as by differences in the dose of corticosteroids and the frequency of their administration. If the explanation we propose is correct, it suggests that the Italian group's demonstration of the superiority of combination therapy could apply to less emetogenic regimens; that is, although 5-HT3 antagonists do not appear to be superior to corticosteroids in this context, their addition to corticosteroids might improve the results. This effect would, of course, have to be shown in a prospective trial.
4 ReferencesJoseph L. Pater, M.D.
National Cancer Institute of Canada, Kingston, ON K7L 3N6, CanadaDavid Warr, M.D.
Princess Margaret Hospital, Toronto, ON M4X 1K9, Canada1
Warr D ,Willan A ,Fine S , et al. Superiority of granisetron to dexamethasone plus prochlorperazine in the prevention of chemotherapy-induced emesis. J Natl Cancer Inst 1991;83:1169-1173
CrossRef | Web of Science | Medline2
Osoba D ,Erlichman C ,Willan AR , et al. Failure of methylprednisolone acetate to prolong the antinauseant effect of intravenous methylprednisolone sodium succinate in patients receiving chemotherapy. Clin Invest Med 1988;11:377-379
Web of Science | Medline3
Levitt M ,Warr D ,Yelle L , et al. Ondansetron compared with dexamethasone and metoclopramide as antiemetics in the chemotherapy of breast cancer with cyclophosphamide, methotrexate, and fluorouracil. N Engl J Med 1993;328:1081-1084
Full Text | Web of Science | Medline4
Pater J ,Slamet L ,Zee B ,Osoba D ,Warr D ,Rusthoven J . Inconsistency of prognostic factors for post-chemotherapy nausea and vomiting. Support Care Cancer 1994;2:161-166
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We disagree with Dr. Kattlove's comments. First, our study is of relevance for all oncologists, including those in the United States, since it provides evidence that the best protection from moderately emetogenic chemotherapy is a combination of granisetron and dexamethasone. Moreover, the study suggests that, for this indication, granisetron should not be used alone, except when corticosteroids are contraindicated.
Second, we used the 3-mg dose of granisetron because when the study was planned, the available data suggested that it was the optimal dose. Furthermore, the only two studies of dose ranges, which show an insignificant difference in efficacy between 10 μg per kilogram of body weight (1 mg) and 40 μg per kilogram (3 mg), are far from definitive.1,2 These small studies can demonstrate only very large differences between doses; in one of the studies, a dose of 40 μg per kilogram was superior to a dose of 10 μg per kilogram.
Third, Dr. Kattlove's statement that 1 mg of granisetron provides “an effect equivalent to that of 32 mg of ondansetron” is not supported by any published data.
Fourth, the rationale for comparing metoclopramide with 1 mg of granisetron is highly questionable, because metoclopramide has consistently been shown to be less effective or more toxic than corticosteroids or ondansetron in patients receiving moderately emetogenic chemotherapy.3
Finally, in our article, we also suggest that “an economic evaluation of the two options [granisetron plus dexamethasone and dexamethasone alone] would be interesting.” In Italian hospitals, the cost of 3 mg of granisetron is about $21. According to Dr. Kattlove's calculation, this means a cost of $105 for each patient saved from vomiting.
Drs. Pater and Warr correctly note the problem of the optimal dose of corticosteroids and schedule of administration, which are still matters of controversy. We are not convinced that the discrepancy between the results obtained with repeated high doses and those obtained with a single dose of dexamethasone before chemotherapy4 is due mainly to differences in the populations studied. In fact, in these studies the rate of complete protection from vomiting with granisetron was similar with the two approaches (70 percent). A more likely explanation may be the efficacy of the single dose of dexamethasone used by Warr et al.4 in protecting patients against the late onset of emesis induced by cyclophosphamide and carboplatin.
4 ReferencesFausto Roila, M.D.
Policlinico Monteluce, 06122 Perugia, ItalyEnzo Ballatori, Ph.D.
University of L'Aquila, 67100 L'Aquila, ItalyAlbano Del Favero, M.D.
University of Perugia, 06100 Perugia, Italyfor the Italian Group for Antiemetic Research
1
Riviere A . Dose finding study of granisetron in patients receiving high-dose cisplatin chemotherapy. Br J Cancer 1994;69:967-971
CrossRef | Web of Science | Medline2
Navari RM ,Kaplan HG ,Gralla RJ ,Grunberg SM ,Palmer R ,Fitts D . Efficacy and safety of granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and vomiting induced by high-dose cisplatin. J Clin Oncol 1994;12:2204-2210
Web of Science | Medline3
Del Favero A ,Roila F ,Tonato M . Reducing chemotherapy-induced nausea and vomiting: current perspectives and future possibilities. Drug Saf 1993;9:410-428
CrossRef | Web of Science | Medline4
Warr D ,Willan A ,Fine S , et al. Superiority of granisetron to dexamethasone plus prochlorperazine in the prevention of chemotherapy-induced emesis. J Natl Cancer Inst 1991;83:1169-1173
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Gary D. Cieslak, Mehernoor F. Watcha, Michael B. Phillips, John H. Pennant. (1996) The Dose-Response Relation and Cost-effectiveness of Granisetron for the Prophylaxis of Pediatric Postoperative Emesis. Anesthesiology 85:5, 1076-1085
CrossRef
