Neurokinin-1 Receptor Antagonist-Based Triple Regimens in Preventing Chemotherapy-Induced Nausea and Vomiting: A Network Meta-analysis

Yaxiong Zhang; Yunpeng Yang; Zhonghan Zhang; Wenfeng Fang; Shiyang Kang; Youli Luo; Jin Sheng; Jianhua Zhan; Shaodong Hong; Yan Huang; Ningning Zhou; Hongyun Zhao; Li Zhang


J Natl Cancer Inst. 2016;109(2) 

In This Article

Abstract and Introduction


Background: Neurokinin-1 receptor antagonists (NK-1RAs) are widely used for chemotherapy-induced nausea and vomiting (CINV) control in patients with highly emetogenic chemotherapy (HEC) and/or moderately emetogenic chemotherapy (MEC). Whether the efficacy and toxicity of antiemesis are different among various NK-1RA-based triple regimens is unknown.

Methods: Data of complete responses (CRs) in the acute, delayed, and overall phases and treatment-related adverse events (TRAEs) were extracted from electronic databases. Efficacy and toxicity were integrated by pairwise and network meta-analyses.

Results: Thirty-six trials involving 18 889 patients using triple regimens (NK-1RA+serotonin receptor antagonists [5HT3RA] + dexamethasone) or duplex regimen (5HT3RA+dexamethasone) to control CINV were included in the analysis. Different NK-1RA-based triple regimens shared equivalent effect on CRs. In patients with HEC, almost all triple regimens showed statistically significantly higher CRs than duplex regimen (odds ratio [OR]duplex/triple = 0.47–0.66). However, in patients with MEC, only aprepitant-based triple regimen showed better effect than duplex regimen statistically significantly in CRs (ORduplex/triple = 0.52, 95% confidence interval [CI] = 0.34 to 0.68). No statistically significant difference of TRAEs was found among different triple regimens. Palonosetron-based triple regimens were equivalent to first-generation 5HT3RAs-based triple regimens for CRs. Moreover, different doses of dexamethasone plus NK-1RA and 5HT3RA showed no statistically significant difference in CRs.

Conclusions: Different NK-1RAs-based triple regimens shared equivalent effect on CINV control. Various triple regimens had superior antiemetic effect than duplex regimen in patients with HEC. Only aprepitant-based triple regimen showed better CINV control compared with duplex regimen in patients receiving MEC. Palonosetron and first-generation 5HT3RAs might share equivalent CINV control in the combination of NK-1RAs and dexamethasone. Lower doses of dexamethasone might be applied when used with NK-1RAs and 5HT3RAs.


Chemotherapy-induced nausea and vomiting (CINV) are common adverse effects that often affect patients' compliance with treatment and impact health-related quality of life.[1,2] Patients receiving highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) are major populations suffering nausea and vomiting.[3] Corticosteroids, most commonly dexamethasone, were first used for the treatment of CINV in the early 1990s.[4] Thereafter, the addition of serotonin receptor antagonists (5HT3RAs) showed additional improvement in acute CINV, which act via peripheral nervous pathways of gastrointestinal tracts.[5] Furthermore, recent studies found that dexamethasone plus 5HT3RA and neurokinin-1 receptor antagonists (NK-1RAs) made greater advances in controlling CINV because NK-1RA could play a role in both acute and delayed CINV through blocking the actions of substance P (SP) in the vomiting center of the brain.[5] As a result, combination antiemetic therapy is the standard regimen for patients receiving HEC or MEC to prevent CINV.[6–8] Recent clinical practice guidelines recommend a 5HT3RA plus an NK-1RA and a corticosteroid for HEC, and a 5HT3RA plus a corticosteroid, with or without an NK-1 RA, for MEC.[6–8]

Because there are various NK-1RAs (aprepitant, casopitant, fosaprepitant, netupitant, and rolapitant) and 5HT3RAs (first generation: ondansetron and granisetron; second generation: palonosetron) for oncologists to choose from, according to sufficient clinical data, a large-scale analysis is needed to answer whether the efficacy and toxicity of antiemesis are different among those NK-1RA-based triple antiemetic regimens. Besides, it is still unclear whether the antiemetic efficacy in palonosetron-based triple regimens is better compared with first-generation 5HT3RAs-based triple regimens. Moreover, whether the doses of dexamethasone in combination with NK-1RA plus 5HT3RA will impact the antiemetic effect is also unknown. Therefore, a network meta-analysis is an optimal method to compare different regimens because of its good agreement in the real-world situation.[9,10]