Initial high anti-emetic efficacy of granisetron with dexamethasone is not maintained over repeated cycles

Abstract

Initial high antimemetic efficacy of granisetron with dexamethasone is not maintained over repeated cycles R de Wit', H van den Berg', J Burghouts2, J Nortier3, P Slee4, C Rodenburg5, J Keizer6, M Fonteyn7, J Verweij1 and J Wils7 Summary We have reported previously that the anti-emetic efficacy of single agent 5HT3 antagonists is not maintained when analysed with the measurement of cumulative probabilities. Presently, the most effective anti-emetic regimen is a combination of a 5HT3 antagonist plus dexamethasone. We, therefore, assessed the sustainment of efficacy of such a combination in 125 patients, scheduled to receive cisplatin 2 70 mg m-2 either alone or in combination with other cytotoxic drugs. Anti-emetic therapy was initiated with 10 mg of dexamethasone and 3 mg of granisetron intravenously, before cisplatin. On days 1-6, patients received 8 mg of dexamethasone and 1 mg of granisetron twice daily by oral administration. Protection was assessed during all cycles and calculated based on cumulative probability analyses using the method of Kaplan-Meier and a model for transitional probabilities. Irrespective of the type of analysis used, the anti-emetic efficacy of granisetron/dexamethasone decreased over cycles. The initial complete acute emesis protection rate of 66% decreased to 30% according to the method of Kaplan-Meier and to 39% using the model for transitional probabilities. For delayed emesis, the initial complete protection rate of 52% decreased to 21% (Kaplan-Meier) and to 43% (transitional probabilities). In addition, we observed that protection failure in the delayed emesis period adversely influenced the acute emesis protection in the next cycle. We conclude that the anti-emetic efficacy of a 5HT3 antagonist plus dexamethasone is not maintained over multiple cycles of highly emetogenic chemotherapy, and that the acute emesis protection is adversely influenced by protection failure in the delayed emesis phase.

Chemotherapy-Induced Nausea and Vomiting: The Importance of Acute Antiemetic Control

“…Conversely, failure during the acute period has a high negative predictive value for delayed 190 emesis in the same cycle [12]. Furthermore, patients who experience delayed symptoms during their initial cycle of chemotherapy are more likely to suffer recurrent delayed symptoms during subsequent cycles [13] as well as reduced acute antiemetic protection in the next cycle [30]. Thus, any patient characteristic that predisposes an individual to acute symptoms (such as female sex, low prior alcohol intake history, and emesis with prior cycles of chemotherapy) should also be considered as a predictive factor for delayed nausea and vomiting [11].…”

Multicenter, phase II, placebo‐controlled, double‐blind, randomized study of aprepitant in Japanese patients receiving high‐dose cisplatin

“…(6,7) In several clinical studies of a 5-HT 3 receptor antagonist with dexamethasone, no efficacy was demonstrated for CINV in the delayed phase. (3,8) Aprepitant is a neurokinin-1 (NK 1 ) receptor antagonist developed as a treatment for CINV.…”

Current position of 5HT3 antagonists and the additional value of NK1 antagonists; a new class of antiemetics

“…In the largest study in 125 patients receiving six cycles of cisplatin-based chemotherapy, despite dual therapy with granisetron and dexamethasone both in the acute and the delayed period, the initial complete acute emesis protection decreased from 66 to 39%, and for delayed emesis, the initial complete protection of 52% decreased to 43, or 21% in the sixth cycle, depending on the type of statistical analysis. In this study, it was also found that unsuccessful delayed emesis protection adversely influenced acute emesis protection in subsequent cycles of chemotherapy (de Wit et al, 1998). If delayed emesis protection is not improved, most patients will develop emesis, and in due course both in the acute and in the delayed phase.…”

“…Several studies have demonstrated that indeed, and despite the use of 5HT 3 antagonist plus dexamethasone, with each subsequent cycle of chemotherapy, emesis protection decreases (de Wit et al, , 1998. In the largest study in 125 patients receiving six cycles of cisplatin-based chemotherapy, despite dual therapy with granisetron and dexamethasone both in the acute and the delayed period, the initial complete acute emesis protection decreased from 66 to 39%, and for delayed emesis, the initial complete protection of 52% decreased to 43, or 21% in the sixth cycle, depending on the type of statistical analysis.…”

“…In view of the discontinuation of group I, the efficacy evaluations focused on the aprepitant 125/80 mg dose (group II) compared with standard therapy (group III). A cumulative probability analysis using the model for transitional probabilities was used to analyse the data, as was also applied in the previous multiple cycle studies with 5HT 3 antagonists (de Wit et al, , 1998. In the first cycle, the percentages of patients with complete response (0 -120 h) were 64% in the aprepitant 125/80 mg (plus standard therapy) group and 49% in the standard therapy alone group, Po0.05.…”