Use of Dexamethasone With 5-HT3-Receptor Antagonists

Corticosteroids have not been approved by the FDA for use as antiemeticagents. However, the efficacy of these agents (primarily dexamethasone)when used as single agents for control of emesis has been extensivelydocumented. In addition, dexamethasone, when used in combinationregimens, has been shown to increase the efficacy of conventionalantiemetics, 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 combinationwith dexamethasone in patients receiving cisplatin (Platinol)chemotherapy has been confirmed in several randomized, double-blindstudies. In studies with intravenous ondansetron, complete protectionfrom emesis was achieved in 58% to 91% of patients receiving combinationtherapy, as compared with 30% to 64% of those receiving ondansetronalone (P less than 0.05) [1-5]. Smith and colleagues [6]evaluated the use of oral ondansetron with cisplatin chemotherapyand reported a complete response rate of 44% with ondansetronplus dexamethasone vs only 7% with ondansetron alone (Pless than 0.05).

Similar results demonstrating improved efficacy with dexamethasonehave been published in two randomized, double-blind studies utilizinga combination of oral or intravenous granisetron plus dexamethasone[7,8]. In these studies, complete response at 24 hours occurredin 65% of patients who received combination therapy vs 39% to56% of those who received granisetron alone.

Two published studies have evaluated the efficacy of 5-HT3 -receptorantagonists alone or in combination with dexamethasone in patientsreceiving moderately emetogenic chemotherapy [9,10]. The ItalianGroup for Antiemetic Research [10] compared granisetron alone,dexamethasone alone, and the combination of granisetron plus dexamethasonein patients receiving moderately emetogenic chemotherapy. Superiorantiemetic control (complete protection from vomiting) was demonstratedwith combination therapy, as compared with granisetron alone ordexamethasone alone (93%, 72%, 71%, respectively; P lessthan 0.001 for all comparisons).

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

The mechanisms by which dexamethasone inhibits cytotoxic-inducedemesis are not clearly understood, although several have beenproposed. These include reduction of prostanoid turnover by inhibitionof arachidonic acid release, modulation of substances derivedfrom arachidonic acid metabolism (eg, lipoxygenase products),and reduction of the amount of available serotonin by activationof tryptophan pyrrolase, thereby shunting metabolism away fromserotonergic synthetic pathways [11,12]. Further studies are warrantedto elucidate the mechanisms of emesis control of dexamethasone.

The optimal dose of dexamethasone has not been established, butmost studies to date have utilized 20 mg given intravenously priorto chemotherapy on the day of chemotherapy. However, divided orlower doses of dexamethasone (eg, 10 mg) have not been adequatelystudied.

Short courses of dexamethasone generally cause no or minimal adverseeffects; mild insomnia and epigastric discomfort may occur. Patientswith diabetes mellitus should be monitored for blood glucose elevationsfollowing dexamethasone therapy.

Based on the accumulated data, ondansetron or granisetron shouldbe administered in combination with dexa- methasone whenever eitherdrug is used for the prevention of nausea and vomiting, unlessmedical contraindications exist.

References:

1. Hesketh PJ, Harvey WH, Harker WG, et al: A randomized, double-blindcomparison of intravenous ondansetron alone and in combinationwith intravenous dexamethasone in the prevention of high-dosecisplatin-induced emesis. J Clin Oncol 12:596-600, 1994.

2. Joss RA, Bacchi M, Buser K, et al: Ondansetron plus dexamethasoneis superior to ondansetron alone in the prevention of emesis inchemotherapy-naive and previously treated patients. Ann Oncol5:253-258, 1994.

3. Roila F, Tonato M, Cognetti F, et al: Prevention of cisplatin-inducedemesis: A double-blind multicenter randomized crossover studycomparing ondansetron and ondansetron plus dexamethasone. J ClinOncol 9:675-678, 1991.

4. Smyth JF, Coleman RE, Nicolson M, et al: Does dexamethasoneenhance 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 ClinicalResearch: Ondansetron plus dexamethasone. Eur J Cancer 27(suppl1):S12-14, 1991.

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

7. Heron JF, Goedhals L, Jordaan JP, et al, on behalf of the GranisetronStudy 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 hoursfollowing 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 granisetronalone and granisetron plus dexamethasone in the prophylaxis ofcytotoxic-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 vomitingduring chemotherapy for cancer. N Engl J Med 332:1-5, 1995.

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

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