Eligible Studies and Population Characteristics
We identified 1796 records using the search strategy and included 35 studies,[17–51] including 36 trials involving 18 889 cancer patients using NK-1RA-based triple antiemetic regimens (NK-1RA+5HT3RA+dexamethasone, n = 12 051) or conventional duplex control regimen (5HT3RA+ dexamethasone, n = 6838) to control for CINV in this meta-analysis. Figure 1 shows the flow chart for the study selection procedure. There were 21, 11, and four trials that used HEC,[17–23,26–29,31,32,34,36,38,39,45,46,49] MEC,[24,33,35,40–44,48,50,51] and mixed chemotherapy regimens,[25,30,37,47] respectively. Table 1 and Supplementary Table 1 https://academic.oup.com/jnci/article/109/2/djw217/2572051/Neurokinin-1-Receptor-Antagonist-Based-Triple#supplementary-data (available online) give more detailed characteristics of all the studies included in our analyses.
Pair-wise Meta-analyses for Antiemetic Efficacy and Toxicity
NK-1RAs-based triple regimens showed statistically significantly superior antiemetic effect in overall, acute, and delayed phase CRs compared with conventional duplex regimens in overall patients, patients with HEC, and patients with MEC (Table 2). Similar results were found when "no clinically significant nausea" was the toxicity investigated (Supplementary Table 2, https://academic.oup.com/jnci/article/109/2/djw217/2572051/Neurokinin-1-Receptor-Antagonist-Based-Triple#supplementary-data available online). However, no statistically significant difference of TRAE was found between NK-1RA-based triple regimens and duplex control regimen (Table 2). We used funnel plots to assess the publication bias of the literature in this study. All the shapes of the funnels were close to symmetric, and no publication bias was found according to Begg's test and Egger's test (P > .05).
Networks for Multiple Treatment Comparisons
Network A was designed for multiple treatment comparison of different NK-1RA-based triple antiemetic regimens (NK-1RA+5HT3RA+dexamethasone) and the conventional duplex control regimen (5HT3RA+dexamethasone) (Figure 2A). Network B established the comparison of palonosetron-based triple regimen (NK-1RA+palonosetron+dexamethasone) and first-generation 5HT3RAs-based triple regimen (NK-1RA+1st generation 5HT3RAs+dexamethasone) through duplex regimens (palonosetron+dexamethasone and first-generation 5HT3RAs+dexamethasone) (Figure 2B). In addition, network C was built for multiple treatment comparison of NK-1RA-based triple antiemetic regimens and conventional duplex control regimens with various doses of dexamethasone (Figure 2C).
Network established for multiple treatment comparisons. A) For different NK-1RA-based triple antiemetic regimens (NK–1RA+5–HT3RA+D) and conventional duplex control regimens (5–HT3RA+D). B) For NK-1RA-based triple antiemetic regimens and conventional duplex control regimens including P or other 5–HT3RAs. C) For NK-1RA-based triple antiemetic regimens and conventional duplex control regimens with various doses of D (low-dose D, <20 mg; moderate-dose D, 20–39 mg; high-dose D, >39 mg). 5-HT3RA = serotonin receptor antagonist; A = aprepitant; C = casopitant; D = dexamethasone; F = fosaprepitant; N = netupitant; NK-1RA = neurokinin-1 receptor antagonist; R = rolapitant; P = palonosetron.
Network Meta-analyses for Antiemetic Efficacy and Toxicity
According to the data based on network A, various NK-1RAs-based triple regimens (aprepitant, casopitant, fosaprepitant, netupitant, and rolapitant) shared equivalent antiemetic effect in overall, acute, and delayed phase CRs without statistically significant differences in odds ratios. In all patients and patients with HEC, almost all NK-1RAs-based triple regimens showed statistically significantly higher CRs in all phases vs duplex control regimen (ORduplex/triple = 0.47–0.66), while only netupitant-based triple regimen had a statistically nonsignificant superior antiemetic efficacy compared with duplex control regimen in terms of acute phase CR. However, in patients with MEC, only aprepitant-based triple regimen showed a statistically significantly better antiemetic effect than duplex control regimen in all outcome measures of efficacy (ORduplex/triple = 0.52, 95% CI = 0.34 to 0.68). We observed no statistically significant difference in the antiemetic effect of TRAE among different NK-1RA-based triple regimens vs the duplex control regimen (Table 3).
Subgroup Analyses and Consistency Evaluation
According to the data based on network B, the antiemetic efficacy of palonosetron-based triple regimens was similar to first-generation 5HT3RAs-based triple regimens for CRs in all phases. Moreover, different doses of dexamethasone in combination with NK-1RA plus 5HT3RA showed no statistically significant difference in terms of CRs in all phases (Table 4). All the network meta-analyses in our study were used in both the consistency model and the inconsistency model. The variances of those two models were roughly equal. As a result, inconsistency did not appear to be present, and we used the consistency model to show our results.
J Natl Cancer Inst. 2016;109(2) © 2016 Oxford University Press