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Use of Dexamethasone With 5-HT3-Receptor Antagonists

Use of Dexamethasone With 5-HT3-Receptor Antagonists

Corticosteroids have not been approved by the FDA for use as antiemetic agents. However, the efficacy of these agents (primarily dexamethasone) when used as single agents for control of emesis has been extensively documented. In addition, dexamethasone, when used in combination regimens, has been shown to increase the efficacy of conventional antiemetics, such as metoclopramide and, recently, the 5-hydroxytryptamine (5-HT3)-receptor antagonists ondansetron (Zofran) and granisetron (Kytril), in preventing chemotherapy-induced acute emesis.

The improved efficacy of ondansetron when administered in combination with dexamethasone in patients receiving cisplatin (Platinol) chemotherapy has been confirmed in several randomized, double-blind studies. In studies with intravenous ondansetron, complete protection from emesis was achieved in 58% to 91% of patients receiving combination therapy, as compared with 30% to 64% of those receiving ondansetron alone (P less than 0.05) [1-5]. Smith and colleagues [6] evaluated the use of oral ondansetron with cisplatin chemotherapy and reported a complete response rate of 44% with ondansetron plus dexamethasone vs only 7% with ondansetron alone (P less than 0.05).

Similar results demonstrating improved efficacy with dexamethasone have been published in two randomized, double-blind studies utilizing a combination of oral or intravenous granisetron plus dexamethasone [7,8]. In these studies, complete response at 24 hours occurred in 65% of patients who received combination therapy vs 39% to 56% of those who received granisetron alone.

Two published studies have evaluated the efficacy of 5-HT3 -receptor antagonists alone or in combination with dexamethasone in patients receiving moderately emetogenic chemotherapy [9,10]. The Italian Group for Antiemetic Research [10] compared granisetron alone, dexamethasone alone, and the combination of granisetron plus dexamethasone in patients receiving moderately emetogenic chemotherapy. Superior antiemetic control (complete protection from vomiting) was demonstrated with combination therapy, as compared with granisetron alone or dexamethasone alone (93%, 72%, 71%, respectively; P less than 0.001 for all comparisons).

Similarly, in the other study, granisetron plus dexamethasone provided complete protection in 85% of patients vs 76% of patients treated with granisetron alone (P = 0.053) [9]. No prospective, randomized studies are available to compare the efficacy of ondansetron alone or in combination with dexamethasone in patients treated with moderately emetogenic chemotherapy.

The mechanisms by which dexamethasone inhibits cytotoxic-induced emesis are not clearly understood, although several have been proposed. These include reduction of prostanoid turnover by inhibition of arachidonic acid release, modulation of substances derived from arachidonic acid metabolism (eg, lipoxygenase products), and reduction of the amount of available serotonin by activation of tryptophan pyrrolase, thereby shunting metabolism away from serotonergic synthetic pathways [11,12]. Further studies are warranted to elucidate the mechanisms of emesis control of dexamethasone.

The optimal dose of dexamethasone has not been established, but most studies to date have utilized 20 mg given intravenously prior to chemotherapy on the day of chemotherapy. However, divided or lower doses of dexamethasone (eg, 10 mg) have not been adequately studied.

Short courses of dexamethasone generally cause no or minimal adverse effects; mild insomnia and epigastric discomfort may occur. Patients with diabetes mellitus should be monitored for blood glucose elevations following dexamethasone therapy.

Based on the accumulated data, ondansetron or granisetron should be administered in combination with dexa- methasone whenever either drug is used for the prevention of nausea and vomiting, unless medical contraindications exist.

References

1. Hesketh PJ, Harvey WH, Harker WG, et al: A randomized, double-blind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of high-dose cisplatin-induced emesis. J Clin Oncol 12:596-600, 1994.

2. Joss RA, Bacchi M, Buser K, et al: Ondansetron plus dexamethasone is superior to ondansetron alone in the prevention of emesis in chemotherapy-naive and previously treated patients. Ann Oncol 5:253-258, 1994.

3. Roila F, Tonato M, Cognetti F, et al: Prevention of cisplatin-induced emesis: A double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol 9:675-678, 1991.

4. Smyth JF, Coleman RE, Nicolson M, et al: Does dexamethasone enhance control of acute cisplatin-induced emesis by ondansetron? Br Med J 303:1423-1426, 1991.

5. Tonato M, on behalf of the Italian Oncology Group for Clinical Research: Ondansetron plus dexamethasone. Eur J Cancer 27(suppl 1):S12-14, 1991.

6. Smith DB, Newlands ES, Rustin GJS, et al: Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatin-containing chemotherapy. Lancet 338:487-490, 1991.

7. Heron JF, Goedhals L, Jordaan JP, et al, on behalf of the Granisetron Study Group: Oral granisetron alone and in combination with dexamethasone. Ann Oncol 5:579-584, 1994.

8. Latreille J, Stewart D, Laberge F, et al: Dexamethasone (DEX) improves the efficacy of granisetron (GRAN) in the first 24 hours following high-dose cisplatin (HDCP) chemotherapy (abstract). Proc Am Soc Clin Oncol 12:133, 1993.

9. Carmichael J, Bessell EM, Harris AL, et al: Comparison of granisetron alone and granisetron plus dexamethasone in the prophylaxis of cytotoxic-induced emesis. Br J Cancer 70:1161-1164, 1994.

10. The Italian Group for Antiemetic Research: Dexamethasone, granisetron, or both for the prevention of nausea and vomiting during chemotherapy for cancer. N Engl J Med 332:1-5, 1995.

11. Andrews PLR, Davis CJ: The mechanism of emesis induced by anti-cancer therapies, in Andrews PLR, Sanger GJ (eds): Emesis in Anti-Cancer Therapy: Mechanisms and Treatment, pp 113-161. London, Chapman & Hall Medical, 1993.

12. Woods AJ, Andrews PLR: Cisplatin acutely reduces 5-hydroxytryptamine-induced vagal depolarization in the rat: Protective action of dexamethasone. Eur J Pharmacol 278:275-278, 1995.

 
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