Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT₃ receptor antagonists

Abstract

Purpose: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT₃ receptor antagonists to assess its translational validity.

Methods: A systematic review identified available evidence and was used to perform meta-analyses.

Results: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg⁻¹ dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg⁻¹, which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT₃ receptor antagonists reduced cisplatin (5 mg kg⁻¹) emesis by 68% (45-91%) during the acute phase (day 1) and by 67% (48-86%) and 53% (38-68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin.

Conclusion: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT₃ receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret.

Fig. 1

Flow chart of identified studies. Reproduced and adapted from the QUOROM statement flow diagram [97]

Fig. 2

Latency to the onset of emesis (first retch, vomit or vomiting episode) induced by various doses of cisplatin. Data collected from 64 studies involving 702 animals and plotted on the graph as weighted mean ± SD. Differences between the doses were assessed by one-way ANOVA followed by Bonferroni post-tests, ***p < 0.0001 compared with all other doses in the post-tests. The exact latency values, the number of ferrets from which those values were calculated (n) and the number of studies from which this data was extracted (S) are given above each column

Fig. 3

Profile of emesis induced by 10 mg kg⁻¹ (a) and 5 mg kg⁻¹ (b) cisplatin in the ferret. a Data plotted as mean vomits ± SD per 30 min periods, collected from 6 studies involving 34 animals and mean retches ± SD, collected from 4 of those studies involving 20 out of the 34 animals. b Data plotted as weighted mean R+V ± SD per 4-h periods collected from 9 studies involving 92 animals

Fig. 4

Efficacy of ondansetron number of retches + vomits during the acute phase of emesis induced by cisplatin 5 or 10 mg kg⁻¹. Point estimates and 95% confidence intervals for each of the ondansetron versus control comparisons ranked by dose. The effect estimate was computed as the weighted mean difference (WMD) and expressed as the proportion of retches and vomits in the control group. An effect estimate of −1 indicates that emesis was abolished in the treatment group, 0 indicates that the treatment had no effect on the R + V response and an effect estimate >0 indicates that the treatment increased the number of R + V. The size of each square represents the weight of the comparison in the WMD calculation

Fig. 5

Efficacy of ondansetron on the number of animals developing an acute phase of emesis following cisplatin 5 or 10 mg kg⁻¹. Point estimates and 95% confidence intervals for each of the ondansetron versus control comparisons ranked by dose. The effect estimate was computed as the risk difference (RD) and represents the proportion of animals with emesis during the duration of the observation period. An effect estimate of 0 indicates that the treatment had no effect on the number of animals with emesis, −1 indicates maximal effect. The size of each square represents the weight of the comparison in the total RD calculation

Fig. 6

Efficacy of ondansetron on the latency to emesis induced by cisplatin (5 or 10 mg kg⁻¹). Point estimates and 95% confidence intervals for each of the ondansetron versus control comparisons ranked by dose. The effect estimate is the impact of the treatment on the latency expressed as a proportion of the latency in the control group. An effect estimate <0 indicates that the latency was shorter in the control group than in the treatment group, 0 indicates that the treatment had no effect on the latency and an effect estimate of 1 indicates that the treatment increased the latency by 100%. The size of each square represents the weight of the comparison in the WMD calculation. Note that in 3 comparisons, the effect estimate was not estimable as only one animal developed emesis in the group treated with ondansetron

Fig. 7

Funnel plots for the effect of ondansetron on the number of retches + vomits (a), number of animals with emesis (b) and latency (c). For each comparison, the effect estimates are plotted on the x-axis and corresponding standard errors are plotted on the y-axis

Fig. 8

Efficacy of 5-HT₃ receptor antagonists on the daily number of retches + vomits (R + V) induced by 5 mg kg⁻¹ i.p. cisplatin during the acute (day 1) and delayed (days 2, 3) phases of emesis. Point estimates and 95% confidence intervals for each of the 5-HT₃ receptor antagonist versus control comparisons ranked by dose. The effect estimate was computed as the weighted mean difference (WMD) and expressed as the proportion of retches and vomits in the control group. An effect estimate of −1 indicates that emesis was abolished in the treatment group, 0 indicates that the treatment had no effect on the R + V response and an effect estimate >0 indicates that the treatment increased the number of R + V. The size of each square represents the weight of the comparison in the WMD calculation