Comparative efficacy of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists with or without dexamethasone for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy (HEC): a network meta-analysis

Objective This network meta-analysis evaluated the efficacy of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, with or without Dexamethasone (D), for preventing chemotherapy-induced nausea and vomiting (CINV) in patients undergoing highly emetogenic chemotherapy (HEC) who were limited to these regimens. Methods Randomized controlled studies (RCTs) were searched in PubMed, Embase, Cochrane and Web of Science from their inception up to January 28, 2026 (a supplementary search was conducted from April 1, 2025, to January 28, 2026), to identify studies on patients who used 5-HT3 receptor antagonists (with or without Dexamethasone) to prevent nausea and vomiting caused by highly emetogenic chemotherapy. A total of 36 randomized controlled trials (reported in 37 articles) enrolling 11,131 patients were included in this analysis. The outcome measures included acute nausea, acute vomiting, acute complete control, delayed nausea, delayed vomiting and delayed complete control. Results Palonosetron (P) is generally more effective than first-generation 5-HT3 receptor antagonists (1 st 5-HT3 antagonists), with a significantly greater advantage over Ondansetron in the delayed phase (such as in delayed vomiting (20 trials/6,347 patients) (RR 1.47, 95% CI [1.03–2.08]). In all phases, adding Dexamethasone to 1 st 5-HT3 antagonists significantly improved efficacy compared to using them alone. However, combining Dexamethasone with palonosetron showed no significant advantage over Palonosetron alone in any outcome measure in indirect comparisons. In the delayed phase [such as in delayed vomiting (20 trials/6,347 patients)), Palonosetron + Dexamethasone (P+D) demonstrated statistically significant superiority over both Ondansetron + Dexamethasone (O+D) (RR 1.35, 95% CI [1.14–1.60]) and Granisetron + Dexamethasone (G+D) (RR 1.52, 95% CI [1.22–1.91]). However, in the acute phase, Palonosetron + Dexamethasone showed statistically significant superiority over Ondansetron + Dexamethasone (RR 0.81, 95% CI [0.69–0.96]) only in preventing acute vomiting (23 trials/9096 patients). In contrast, no significant efficacy differences were observed between Palonosetron + Dexamethasone and Tropisetron + Dexamethasone (T+D), or Ramosetron + Dexamethasone (R+D). No significant differences were observed between Palonosetron and 1 st 5-HT3 antagonists + Dexamethasone. Conclusions Dexamethasone may enhance the efficacy of first-generation 5-HT 3 receptor antagonists, but may not provide a similar benefit for Palonosetron. Palonosetron is generally more effective than first-generation 5-HT3 antagonists. Palonosetron + Dexamethasone demonstrates superior efficacy over Ondansetron + Dexamethasone or Granisetron + Dexamethasone, particularly in the delayed phase. Further studies are needed between Palonosetron + Dexamethasone and Tropisetron + Dexamethasone or Ramosetron + Dexamethasone, as well as between Palonosetron monotherapy and 1 st 5-HT3 antagonists + Dexamethasone.