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

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1 JNCI J Natl Cancer Inst (2017) 109(2): djw217 doi: /jnci/djw217 First published online October 30, 2016 Article 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 Affiliations of authors: Department of Medical Oncology (YZ, YY, ZZ, WF, JS, JZ, SH, YH, NZ, HZ, LZ) and Department of Anesthesiology (SK), Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangzhou, China (YZ, YY, ZZ, WF, SK, JS, JZ, SH, YH, NZ, HZ, LZ); Collaborative Innovation Center for Cancer Medicine, Guangzhou, China (YZ, YY, ZZ, WF, SK, JS, JZ, SH, YH, NZ, HZ, LZ); Department of Medical Oncology, the Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China (YL) *Authors contributed equally to this work. Correspondence to: Li Zhang, MD, Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong , P. R. China ( zhangli6@mail.sysu.edu.cn). Abstract 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 s 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 patients using triple regimens (NK-1RAþserotonin receptor antagonists [5HT3RA] þ dexamethasone) or duplex regimen (5HT3RAþdexamethasone) 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 ¼ ). However, in patients with MEC, only aprepitant-based triple regimen showed better effect than duplex regimen statistically significantly in CRs (OR duplex/triple ¼ 0.52, 95% confidence interval [CI] ¼ 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 Received: May 20, 2016; Revised: July 18, 2016; Accepted: August 26, 2016 The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com 1of11

2 Y. Zhang et al. 2of11 Figure 1. Profile summarizing the trial flow. 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). Methods Search Strategy and Selection Criteria We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases using a combination of the terms neurokinin-1 receptor antagonist, aprepitant, casopitant, fosaprepitant, netupitant, and rolapitant to find relevant articles published up to February A manual search through reference lists of relevant reviews was additionally performed. Three authors carried out the literature retrieval independently (YZ, YY, ZZ). Eligible studies met the following criteria: 1) they were randomized control trials (RCTs) or prospective studies that evaluated NK-1RAbased triple antiemetic regimens in the prophylaxis of CINV; 2) efficacy and/or toxicity measures were available; 3) NK-1RA was used at the standard dose. Studies failing to meet these inclusion criteria were excluded. Outcomes Measures, Data Extraction,and Quality Assessment The outcomes of antiemetic efficacy were the proportions of patients with complete responses (CRs) and no clinically significant nausea in the acute (0 24 hours after chemotherapy), delayed (> hours after chemotherapy), and overall (0 120 hours) s. The toxic outcome was defined as treatment-related adverse events (TRAEs). The assessment of efficacy and toxicity occurred during the first cycle of chemotherapy. The data on trial name, therapeutic and antiemetic regimens, and clinical outcomes were extracted by two investigators independently (YZ and ZZ). HEC, such as anthracycline plus cyclophosphamide (AC) or cisplatin, and MEC, such as carboplatin or oxaliplatin, were defined according to the National Comprehensive Cancer Network Antiemesis Guideline Version 2, 2016 (11). Cochrane risk of bias was used to assess the quality of all included studies by another two reviewers (YL and YY) (12). Discrepancies were discussed by all investigators to reach a consensus. More details on this can be found in Supplementary Figure 1 (available online). Statistical Analyses First, we conducted pair-wise meta-analyses using a randomeffects model to synthesize studies comparing the same pair of antiemetic treatments. The results were reported as pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Statistical heterogeneity across studies was assessed with a forest plot and the inconsistency statistic (I 2 ). Statistical significance was set at a P value of.05. All calculations were

3 3of11 JNCI J Natl Cancer Inst, 2017, Vol. 109, No. 2 Table 1. Characteristics of included studies for network meta-analyses (data of complete response and treatment-related adverse events) Complete response Trial Emetogenic potential Chemotherapy regimens No. Regimens* Total (each day) dose (mg) of D Overall Acute Delayed TRAE 2003 Chawla High Cisplatin-based chemotherapy 131 AþDþO 52 (20, 8, 8, 8, 8) 93/ /131 95/132 58/ DþO 52 (20, 8, 8, 8, 8) 55/126 89/126 56/126 55/ de Wit High Cisplatin-based chemotherapy 80 AþDþO 52 (20, 8, 8, 8, 8) 51/80 NA NA 21/62 84 DþO 52 (20, 8, 8, 8, 8) 41/84 NA NA 15/ Hesketh High Cisplatin-based chemotherapy 260 AþDþO 36 (12, 8, 8, 8) 118/ / /260 38/ DþO 68 (20, 16, 16, 16) 104/ / /260 29/ Poli-Bigelli High Cisplatin-based chemotherapy 261 AþDþO 36 (12, 8, 8, 8) 114/ / /260 55/ DþO 68 (20, 16, 16, 16) 84/ /263 89/263 41/ Warr High AC 433 AþDþO 12 (12) 220/ / /433 94/ DþO 20 (20) 178/ / /424 84/ Schmoll High Cisplatin-based chemotherapy 243 AþDþO 36 (12, 8, 8, 8) 174/ / /243 57/ DþO 68 (20, 16, 16, 16) 146/ / /241 59/ Herrington High Cisplatin-based chemotherapy or AC 27 AþDþP 36 (12, 8, 8, 8) 14/27 19/27 16/27 NA 16 DþP 42 (18, 8, 8, 8) 4/16 8/16 4/16 NA 2009 Arpornwirat Moderate Carboplatin-based chemotherapy 602 CþDþO 8 (8) i.v. 489/ / /602 NA 121 DþO 8 (8) i.v. 84/ /121 84/121 NA 2009 Gore Mixed Mixed 28 AþDþO 20 (8, 4, 4, 4) 8/28 17/28 10/28 7/32 18 DþO 40 (16, 8, 8, 8) 1/18 7/18 1/18 1/ Grunberg High Cisplatin-based chemotherapy 535 CþDþO 36 (12, 8, 8, 8) or 60 (12, 16, 16, 16) 442/ /535 NA 59/ DþO 68 (20, 16, 16, 16) 175/ /265 NA 29/ Herrstedt High AC 1438 CþDþO 8 (8) i.v. 1053/ / /1438 NA 479 DþO 8 (8) i.v. 282/ / /479 NA 2009 Roila High Cisplatin-based chemotherapy 327 CþDþO 36 (12, 8, 8, 8) or 60 (12, 16, 16, 16) 256/ / /327 NA 82 AþDþO 36 (12, 8, 8, 8) 59/82 74/82 59/82 NA 2009 Yeo High AC 62 AþOþD 12 (12) 29/62 45/62 40/62 NA 62 OþD 20 (20) 26/62 45/62 36/62 NA 2010 Rapoport Mixed AC or non-ac 430 AþOþD 12 (12) 292/ / /430 31/ OþD 20 (20) 229/ / /418 39/ Takahashi High Cisplatin-based chemotherapy 146 AþGþD 14 (6, 4, 4) i.v. 103/ / /146 35/ GþD 28 (12, 8, 8) i.v. 75/ /150 77/149 30/ Grunberg High Cisplatin-based chemotherapy 1109 FþOþD 52 (12, 8, 16, 16) 797/ / /1109 NA 1138 AþOþD 36 (12, 8, 8, 8) 823/ / /1138 NA 2012 Hesketh Moderate Oxaliplatin-based chemotherapy 355 CþOþD 8 (8) i.v. 305/ / /355 34/ OþD 8 (8) i.v. 298/ / /352 33/ Saito High Cisplatin-based chemotherapy 173 FþGþD 22 (10, 4, 8) i.v. 111/ / /173 45/ GþD 36 (20, 8, 8) i.v. 79/ /167 81/166 48/ Tanioka Moderate Carboplatin-based chemotherapy 45 AþGþD 20 (12, 4, 4) i.v. 28/45 44/45 28/45 NA 46 GþD 36 (20, 8, 8) i.v. 24/46 44/46 24/46 NA 2014 Aapro High AC 724 NþPþD 12 (12) 538/ / /724 59/ PþD 20 (20) 483/ / /725 52/725 (continued)

4 Y. Zhang et al. 4of11 Table 1. (continued) Complete response Trial Emetogenic potential Chemotherapy regimens No. Regimens* Total (each day) dose (mg) of D Overall Acute Delayed TRAE 2014 Gralla Mixed Mixed 309 NþPþD 36 (12, 8, 8, 8) or 12 (12) 103 AþPþD 36 (12, 8, 8, 8) or 12 (12) 250/309 NA NA 16/308 78/103 NA NA 3/ Hesketh High Cisplatin-based chemotherapy 135 NþPþD 36 (12, 8, 8, 8) 121/ / /135 21/ AþOþD 36 (12, 8, 8, 8) 116/ / /134 26/ Hu High Cisplatin-based chemotherapy 204 AþGþD (6, 3.75, 3.75, 3.75) 142/ / /204 24/ GþD 33 (10.5, 7.5, 7.5, 7.5) 119/ / /207 28/ Ito Moderate Carboplatin-based chemotherapy 66 A þ 5-HT3RAþD 36 (20, 8, 8) 53/66 NA NA NA 67 5-HT3RAþD 36 (20, 8, 8) 45/67 NA NA NA 2014 Schmitt Moderate High-dose melphalan 181 AþGþD 8 (4, 2, 2) 105/ / /181 NA 181 GþD 16 (8, 4, 4) 72/ /181 83/181 NA 2015 Kitayama Moderate Oxaliplatin-based chemotherapy or others 35 FþDþG 4.95 (4.95) i.v. 24/35 35/35 24/35 NA 35 DþP 9.9 (9.9) i.v. 26/35 33/35 26/35 NA 2015 Maehara Moderate Carboplatin-based chemotherapy 11 AþDþ5-HT3RA 16 (8, 4, 4) i.v. D1 11/11 11/11 11/11 NA 12 D þ 5-HT3RA 32 (16, 8, 8) i.v. D1 5/12 6/12 8/12 NA 2015 Nishimura Moderate Oxaliplatin-based chemotherapy 187 AþDþ5-HT3RA 14.6 (6.6, 4, 4) i.v. D1 159/ / /187 NA 183 D þ 5-HT3RA 25.9 (9.9, 8, 8) i.v. D1 136/ / /183 NA 2015 Schwartzberg Mixed AC or non-ac 666 RþGþD 20 (20) 457/ / /666 64/ GþD 20 (20) 385/ / /666 52/ Yahata Moderate Carboplatin-based chemotherapy 151 AþDþG/O 20 (20) i.v. 93/ /151 96/151 NA 146 DþG/O 20 (20) i.v. 69/ /146 72/146 NA 2015 Rapoport (HEC) High Cisplatin-based chemotherapy 90 RþDþO 68 (20, 16, 16, 16) 56/90 79/90 57/90 9/90 91 DþO 68 (20, 16, 16, 16) 42/91 61/91 44/91 8/ Rapoport (HEC1) High Cisplatin-based chemotherapy 264 RþGþD 68 (20, 16, 16, 16) 185/ / /264 2/ GþD 68 (20, 16, 16, 16) 148/ / /262 10/ Rapoport (HEC2) High Cisplatin-based chemotherapy 271 RþGþD 68 (20, 16, 16, 16) 183/ / /271 15/ GþD 68 (20, 16, 16, 16) 165/ / /273 12/ Ando High Cisplatin-based chemotherapy 48 AþDþP/G/AZ ( , , , ) 41/48 47/48 42/48 NA 45 FþDþP/G/AZ ( , , , ) 37/45 44/45 38/45 NA 2016 Micha Moderate Carboplatin-based chemotherapy 10 AþDþP NA 6/10 8/10 6/10 NA 10 FþDþP NA 6/10 7/10 6/10 NA 2016 Weinstein Moderate Non-AC 502 FþDþO NA 387/ / /502 43/ DþO NA 333/ / /498 45/497 *Regimens of neurokinin-1 receptor antagonists: A) p.o. 125 mg D1, 80 mg D2 D3/80 mg D2 D5; C) p.o. 50/100/150 mg D1 D3 or p.o. 150 mg D1þ 50 mg D2 D3 or p.o. 150 mg D1 or i.v. 90 mg D1þp.o. 50 mg D2 D3 or i.v. 90 mg D1; F) i.v. 150 mg D1; N) p.o. 300 mg D1; R) p.o. 180 mg D1. 5-HT3RA ¼ serotonin receptor antagonist; A ¼ aprepitant; AC ¼ anthracycline and cyclophosphamide; AZ ¼ azasetron; C ¼ casopitant; D ¼ dexamethasone; F ¼ fosaprepitant; G ¼ granisetron; N ¼ netupitant; NA ¼ not available; O ¼ ondansetron; P ¼ palonosetron; R ¼ rolapitant; TRAE ¼ treatment-related adverse event.

5 5of11 JNCI J Natl Cancer Inst, 2017, Vol. 109, No. 2 Table 2. Binary comparison of NK-1RA-based triple regimens vs conventional duplex regimens for antiemetic efficacy and toxicity measured as complete response and treatment-related adverse events Outcome No. of trials (No. of participants) References OR* (95% CI) in random model Effect size Heterogeneity Z P P I 2,% Overall CR (Total) 30 (15 427) (17 27,29 31,33 36,39 48,51) 1.70 (1.56 to 1.85) < Acute CR (Total) 28 (15 142) (17,19 27,29 31,33 36,39,41 48,51) 1.53 (1.36 to 1.71) 7.32 < Delayed CR (Total) 27 (14 340) (17,19 25,27,29 31,33 36,39,41 48,51) 1.68 (1.53 to 1.84) < Overall CR (HEC) 17 (9425) (17 23,26 27,29,31,34,36,39,45,46) 1.72 (1.53 to 1.93) 9.21 < Acute CR (HEC) 16 (9273) (17,19 23,26,27,29,31,34,36,39,45,46) 1.52 (1.32 to 1.75) 5.74 < Delayed CR (HEC) 15 (8471) (17,19 23,27,29,31,34,36,39,45,46) 1.73 (1.53 to 1.96) 8.54 < Overall CR (MEC) 10 (3776) (24,33,35,40 44,48,51) 1.68 (1.39 to 2.03) 5.38 < Acute CR (MEC) 9 (3643) (24,33,35,41 44,48,51) 1.54 (1.16 to 2.03) Delayed CR (MEC) 9 (3643) (24,33,35,41 44,48,51) 1.62 (1.37 to 1.93) 5.59 < TRAE 19 (11 507) (17 22,25,26,30,31,33,34,36,39,45 47,51) 1.09 (0.97 to 1.22) *Represents OR triple/duplex in cancer patients using NK-1RA-based triple regimens or conventional duplex regimens in preventing chemotherapy-induced nausea and vomiting. CI ¼ confidence interval; CR ¼ complete response; HEC ¼ highly emetogenic chemotherapy; MEC ¼ moderately emetogenic chemotherapy; OR ¼ odds ratio; TRAE ¼ treatment-related adverse event; NK-1RA ¼ neurokinin-1 receptor antagonist. Two-sided test for pooled analysis (Z test). Two-sided test for heterogeneity (I 2 ). performed using REVIEW MANAGER (version 5.2 for Windows; the Cochrane Collaboration, Oxford, UK). The statistical methods to detect funnel plot asymmetry were the rank correlation test of Begg and Mazumdar and the regression asymmetry test of Egger (13,14). Secondly, a random-effects network within a Bayesian framework using the Markov chain Monte Carlo methods was built using ADDIS 1.15 (15, 16). We networked binary clinical outcomes within studies and specified the relations among the ORs across studies to make comparisons of different antiemetic treatments in terms of efficacy and/or toxicity. P values of less than.05 and 95% confidence intervals were used to assess statistical significance. The inconsistency within this multiple treatment comparison was evaluated by a variance calculation as previously described (16). All statistical tests were two-sided. Results Eligible Studies and Population Characteristics We identified 1796 records using the search strategy and included 35 studies (17 51), including 36 trials involving cancer patients using NK-1RA-based triple antiemetic regimens (NK-1RAþ5HT3RAþdexamethasone, n ¼ ) or conventional duplex control regimen (5HT3RAþ dexamethasone, n ¼ 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 (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 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, 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- 1RAþ5HT3RAþdexamethasone) and the conventional duplex control regimen (5HT3RAþdexamethasone) (Figure 2A). Network B established the comparison of palonosetron-based triple regimen (NK-1RAþpalonosetronþdexamethasone) and first-generation 5HT3RAs-based triple regimen (NK-1RAþ1st generation 5HT3RAsþdexamethasone) through duplex regimens (palonosetronþdexamethasone and first-generation 5HT3RAsþdexamethasone) (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 Meta-Analyses for Antiemetic Efficacy and Toxicity According to the data based on network A, various NK-1RAsbased triple regimens (aprepitant, casopitant, fosaprepitant, netupitant, and rolapitant) shared equivalent antiemetic effect in overall, acute, and delayed 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 s vs duplex control regimen (OR duplex/triple ¼ ), while only netupitantbased triple regimen had a statistically nonsignificant superior

6 Y. Zhang et al. 6of11 Figure 2. Network established for multiple treatment comparisons. A) For different NK-1RA-based triple antiemetic regimens (NK 1RAþ5 HT3RAþD) and conventional duplex control regimens (5 HT3RAþD). 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, <20mg; moderate-dose D, 20 39mg; high-dose D, >39 mg). 5-HT3RA ¼ serotonin receptor antagonist; A ¼ aprepitant; C ¼ casopitant; D ¼ dexamethasone; F ¼ fosaprepitant; N ¼ netupitant; NK-1RA ¼ neurokinin-1 receptor antagonist; R ¼ rolapitant; P ¼ palonosetron. antiemetic efficacy compared with duplex control regimen in terms of acute 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 (OR duplex/triple ¼ 0.52, 95% CI ¼ 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 firstgeneration 5HT3RAs-based triple regimens for CRs in all s. Moreover, different doses of dexamethasone in combination with NK-1RA plus 5HT3RA showed no statistically significant difference in terms of CRs in all s (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. Discussion To our knowledge, this is the first meta-analysis to compare the antiemesis efficacy among various NK-1RAs-based triple regimens. Our study showed that different NK-1RAs-based triple regimens had an equivalent effect on CINV control in the overall, acute, and delayed s after chemotherapy. Almost all the NK-1RAs-based triple regimens showed statistically significant higher CRs in all s compared with duplex control regimen in patients with HEC. However, only aprepitant-based triple regimen provided statistically significantly better CINV prevention vs duplex control regimen in patients receiving MEC. Our study also found that palonosetron and first-generation 5HT3RAs had similar effectiveness for CINV control in all s when used with NK-1RAs. Moreover, there was no difference between different doses of dexamethasone in the prevention of CINV in all s when combined with NK-1RAs and 5HT3RAs. Consistent with the results of individual RCTs, our study confirmed that NK1RAs-based triple regimen had higher efficacy of CINV control than duplex control regimen in patients receiving HEC. As expected, we also found that various NK-1RAsbased triple regimens showed a similar effect on CINV control in all s. Thus any NK-1RAs-based triple regimen could be used for patients receiving HEC. To date, guidelines only recommend NK1RAs-based triple regimens for patients who receive HEC or anthracycline-cyclophosphamide treatment. Our study demonstrated that patients who receive MEC could also derive clinically significant benefit from applying NK-1RAs-based triple regimens that are of a similar magnitude as patients receiving HEC. Our findings suggest the application of NK-1RAs-based triple regimens for patients receiving MEC. However, subgroup analyses indicated that only aprepitant, rather than other NK- 1RAs, was associated with statistically significantly increased CINV control compared with duplex control regimen in patients receiving MEC. Therefore, aprepitant might be the preferred choice when applying triple regimens to patients receiving MEC. Palonosetron is a second-generation 5-HT3 receptor antagonist with higher binding affinity against 5-HT3 receptor and longer half-time than first-generation 5-HT3 receptor antagonists (granisetron, dolasetron, and ondansetron) (52,53). The high affinity and long half-life of palonosetron might explain its better antiemetic effect throughout the delayed emesis risk period compared with first-generation 5-HT3 receptor antagonists. Several large randomized III studies and meta-analyses assessed the effectiveness of palonosetron compared with first-generation 5-HT3 receptor antagonists in controlling vomiting emesis induced by both HEC and MEC. These studies demonstrated that palonosetron was superior to first-generation 5-HT3 receptor antagonists in preventing CINV in both the delayed and overall

7 7of11 JNCI J Natl Cancer Inst, 2017, Vol. 109, No. 2 Table 3. Odds ratios and 95% confidence intervals for antiemetic efficacy and toxicity measured as complete response and treatment-related adverse events according to multiple treatment comparisons based on network A* Overall CR (total), No. of trials ¼ 36 (17 51) (n ¼ 6838) 0.58 (0.51 to 0.65) A þ 5 HT3RAþD (n ¼ 4461) 0.53 (0.44 to 0.64) 0.91 (0.73 to 1.14) C þ 5 HT3RAþD (n ¼ 3257) 0.61 (0.48 to 0.74) 1.04 (0.84 to 1.28) 1.15 (0.84 to 1.51) F þ 5 HT3RAþD (n ¼ 1874) 0.60 (0.44 to 0.77) 1.02 (0.77 to 1.33) 1.14 (0.78 to 1.55) 0.99 (0.69 to 1.36) N þ 5 HT3RAþD (n ¼ 1168) 0.62 (0.50 to 0.76) 1.07 (0.85 to 1.35) 1.18 (0.88 to 1.56) 1.03 (0.77 to 1.38) 1.04 (0.77 to 1.49) R þ 5 HT3RAþD (n ¼ 1291) Acute CR (total), No. of trials ¼ 33 (17,19 36,38,39,41 51) (n ¼ 6687) 0.64 (0.53 to 0.76) A þ 5 HT3RAþD (n ¼ 4212) 0.67 (0.48 to 0.91) 1.05 (0.73 to 1.50) C þ 5 HT3RAþD (n ¼ 3257) 0.55 (0.38 to 0.77) 0.86 (0.59 to 1.20) 0.82 (0.51 to 1.30) F þ 5 HT3RAþD (n ¼ 1874) 0.64 (0.36 to 1.02) 1.00 (0.57 to 1.64) 0.95 (0.52 to 1.71) 1.16 (0.61 to 2.10) N þ 5 HT3RAþD (n ¼ 859) 0.64 (0.46 to 0.86) 0.99 (0.69 to 1.40) 0.95 (0.61 to 1.44) 1.16 (0.73 to 1.84) 1.00 (0.56 to 1.82) R þ 5 HT3RAþD (n ¼ 1291) Delayed CR (total), No. of trials ¼ 32 (17,19 25,27 36,38,39,41 51) (n ¼ 6422) 0.57 (0.50 to 0.65) A þ 5 HT3RAþD (n ¼ 4212) 0.57 (0.45 to 0.74) 1.00 (0.78 to 1.33) C þ 5 HT3RAþD (n ¼ 2722) 0.64 (0.50 to 0.80) 1.11 (0.89 to 1.43) 1.12 (0.80 to 1.55) F þ 5 HT3RAþD (n ¼ 1874) 0.65 (0.45 to 0.90) 1.13 (0.78 to 1.61) 1.13 (0.73 to 1.71) 1.02 (0.66 to 1.52) N þ 5 HT3RAþD (n ¼ 859) 0.61 (0.49 to 0.77) 1.07 (0.83 to 1.39) 1.08 (0.76 to 1.49) 0.96 (0.70 to 1.33) 0.95 (0.64 to 1.45) R þ 5 HT3RAþD (n ¼ 1291) Overall CR (HEC), No. of trials ¼ 21 (17 23,26 29,31,32,34,36,38,39,45,46,49) (n ¼ 4095) 0.60 (0.51 to 0.70) A þ 5 HT3RAþD (n ¼ 3249) 0.47 (0.36 to 0.60) 0.77 (0.60 to 1.04) C þ 5 HT3RAþD (n ¼ 2300) 0.58 (0.44 to 0.78) 0.97 (0.75 to 1.30) 1.24 (0.86 to 1.84) F þ 5 HT3RAþD (n ¼ 1327) 0.66 (0.45 to 0.88) 1.10 (0.75 to 1.51) 1.39 (0.89 to 2.07) 1.12 (0.70 to 1.67) N þ 5 HT3RAþD (n ¼ 859) 0.62 (0.46 to 0.81) 1.04 (0.74 to 1.43) 1.32 (0.88 to 1.93) 1.06 (0.69 to 1.58) 0.93 (0.62 to 1.50) R þ 5 HT3RAþD (n ¼ 625) Acute CR (HEC), No. of trials ¼ 20 (17,19 23,26 29,31,32,34,36,38,39,45,46,49) (n ¼ 4011) 0.71 (0.56 to 0.88) A þ 5 HT3RAþD (n ¼ 3169) 0.65 (0.41 to 0.93) 0.91 (0.55 to 1.37) C þ 5 HT3RAþD (n ¼ 2300) 0.53 (0.30 to 0.84) 0.75 (0.43 to 1.13) 0.82 (0.43 to 1.51) F þ 5 HT3RAþD (n ¼ 1327) 0.64 (0.34 to 1.03) 0.91 (0.46 to 1.52) 1.00 (0.48 to 1.91) 1.21 (0.57 to 2.50) N þ 5 HT3RAþD (n ¼ 859) 0.55 (0.35 to 0.82) 0.78 (0.47 to 1.22) 0.86 (0.48 to 1.56) 1.04 (0.57 to 2.03) 0.86 (0.46 to 1.81) R þ 5 HT3RAþD (n ¼ 625) (continued)

8 Y. Zhang et al. 8of11 Delayed CR (HEC), No. of trials ¼ 19 (17,19 23,27 29,31,32,34,36,38,39,45,46,49) (n ¼ 3746) 0.57 (0.46 to 0.68) A þ 5 HT3RAþD (n ¼ 3169) 0.50 (0.32 to 0.72) 0.86 (0.56 to 1.29) C þ 5 HT3RAþD (n ¼ 1765) 0.64 (0.43 to 0.91) 1.11 (0.76 to 1.59) 1.29 (0.76 to 2.19) F þ 5 HT3RAþD (n ¼ 1327) 0.65 (0.41 to 0.95) 1.15 (0.71 to 1.73) 1.33 (0.73 to 2.31) 1.03 (0.58 to 1.75) N þ 5 HT3RAþD (n ¼ 859) 0.59 (0.42 to 0.83) 1.02 (0.71 to 1.56) 1.18 (0.72 to 2.09) 0.92 (0.57 to 1.57) 0.90 (0.55 to 1.64) R þ 5 HT3RAþD (n ¼ 625) Overall CR (MEC), No. of trials ¼ 11 (24,33,35,40 44,48,50,51) (n ¼ 1641) 0.52 (0.34 to 0.68) A þ 5 HT3RAþD (n ¼ 651) 0.65 (0.42 to 1.13) 1.25 (0.78 to 2.59) C þ 5 HT3RAþD (n ¼ 957) 0.66 (0.42 to 1.19) 1.28 (0.78 to 2.73) 1.02 (0.50 to 2.07) F þ 5 HT3RAþD (n ¼ 547) Acute CR (MEC), No. of trials ¼ 10 (24,33,35,41 44,48,50,51) (n ¼ 1574) 0.39 (0.14 to 0.77) A þ 5 HT3RAþD (n ¼ 585) 0.83 (0.24 to 2.55) 2.05 (0.58 to 9.76) C þ 5 HT3RAþD (n ¼ 957) 0.63 (0.14 to 1.62) 1.61 (0.38 to 5.47) 0.78 (0.11 to 3.14) F þ 5 HT3RAþD (n ¼ 547) Delayed CR (MEC), No. of trials ¼ 10 (24,33,35,41 44,48,50,51) (n ¼ 1574) 0.54 (0.35 to 0.80) A þ 5 HT3RAþD (n ¼ 585) 0.71 (0.40 to 1.24) 1.30 (0.66 to 2.68) C þ 5 HT3RAþD (n ¼ 957) 0.65 (0.39 to 1.28) 1.20 (0.67 to 2.70) 0.92 (0.45 to 2.31) F þ 5 HT3RAþD (n ¼ 547) Treatment related adverse event, No. of trials ¼ 21 (17 22,25,26,30,31,33,34,36 39,45 47,51) (n ¼ 5490) 0.89 (0.74 to 1.06) A þ 5 HT3RAþD (n ¼ 2453) 0.95 (0.63 to 1.41) 1.06 (0.69 to 1.64) C þ 5 HT3RAþD (n ¼ 890) 1.12 (0.75 to 1.61) 1.26 (0.82 to 1.89) 1.20 (0.68 to 2.00) F þ 5 HT3RAþD (n ¼ 675) 0.89 (0.60 to 1.29) 1.01 (0.66 to 1.45) 0.95 (0.54 to 1.62) 0.79 (0.46 to 1.36) N þ 5 HT3RAþD (n ¼ 1168) 0.91 (0.64 to 1.31) 1.02 (0.69 to 1.60) 0.96 (0.59 to 1.69) 0.81 (0.49 to 1.39) 1.01 (0.61 to 1.76) R þ 5 HT3RAþD (n ¼ 1291) *5 HT3RA ¼ serotonin receptor antagonist; A ¼ aprepitant; C ¼ casopitant; CR ¼ complete response; D ¼ dexamethasone; F ¼ fosaprepitant; HEC ¼ highly emetogenic chemotherapy; MEC ¼ moderately emetogenic chemotherapy; N ¼ netupitant; R ¼ rolapitant. (54 57). However, in these studies, palonosetron or first-generation 5-HT3 receptor antagonists were used without the presence of NK-1RAs. Thus it is still unclear if palonosetron would be more effective than first-generation 5-HT3 receptor antagonists in CINV control when NK-1RAs were used. Our study found that palonosetron and first-generation 5HT3RAs showed an equivalent effect on CINV control in all s in the presence of NK-1RAs. Therefore, because of its higher cost, palonosetron may not be recommended as the preferred 5-HT3 receptor antagonist. Further clinical trials comparing the effectiveness of palonosetron and first-generation 5HT3RAs when combined with NK-1RAs are warranted to verify our findings. Because of a lack of other effective antiemetics, high doses of dexamethasone were used to improve CINV control.

9 9of11 JNCI J Natl Cancer Inst, 2017, Vol. 109, No. 2 Table 4. Odds ratios and confidence intervals for antiemetic efficacy measured as complete response according to multiple treatment comparison based on network B and network C* Overall CR (total), No. of trials ¼ 28 (17 27,29 31,33 36,38,39,41,42,45 48,51) NK-1RA-based triple regimen (palonosetron) (n ¼ 886) 1.65 (0.85 to 3.09) NK-1RA -based triple regimen (nonpalonosetron ) (n ¼ 7720) Acute CR (total), No. of trials ¼ 27 (17,19 27,29 31,33 36,38,39,41,42,45 48,51) NK-1RA-based triple regimen (palonosetron) (n ¼ 886) 2.12 (0.59 to 10.09) NK-1RA-based triple regimen (nonpalonosetron ) (n ¼ 7640) Delayed CR (total), No. of trials ¼ 26 (17,19 25,27,29 31,33 36,38,39,41,42,45 48,51) NK-1RA-based triple regimen (palonosetron) (n ¼ 886) 1.55 (0.71 to 2.74) NK-1RA-based triple regimen (nonpalonosetron ) (n ¼ 7105) Overall CR (total), No. of trials ¼ 29 (17 25,27,29 36,39 48) NK-1RA-based triple regimen (high-dose D) (n ¼ 1945) 1.06 (0.84 to 1.36) NK-1RA-based triple regimen (moderate-dose D) (n ¼ 3050) 1.13 (0.78 to 1.65) 1.06 (0.80 to 1.41) NK-1RA-based triple regimen (low-dose D) (n ¼ 4808) Acute CR (total), No. of trials ¼ 27 (17,19 25,27,29 36,39,41 48) NK-1RA-based triple regimen (high-dose D) (n ¼ 1865) 1.16 (0.82 to 1.66) NK-1RA-based triple regimen (moderate-dose D) (n ¼ 2984) 1.34 (0.78 to 2.48) 1.15 (0.76 to 1.89) NK-1RA-based triple regimen (low-dose D) (n ¼ 4808) Delayed CR (total), No. of trials ¼ 27 (17,19 25,27,29 36,39,41 48) NK-1RA-based triple regimen (high-dose D) (n ¼ 1865) 0.96 (0.73 to 1.30) NK-1RA-based triple regimen (moderate-dose D) (n ¼ 2984) 1.03 (0.67 to 1.61) 1.07 (0.76 to 1.49) NK-1RA-based triple regimen (low-dose D) (n ¼ 4808) *Dexamethasone: low-dose D, <20mg; moderate-dose D, 20 39mg; high-dose D, >39 mg. CR ¼ complete response; D ¼ dexamethasone; NK-1RA ¼ neurokinin-1 receptor antagonist. According to a meta-analysis of 32 studies published from 1966 to 1999, the mean total dose of dexamethasone was 56 mg (58). A high dose of dexamethasone was associated with several side effects, such as hypertension, hyperglycemia, and insomnia. However, there was no strong evidence to support the relationship between the higher dose of dexamethasone and better efficacy in CINV control (59,60). In addition, several NK-1RAs such as aprepitant, fosaprepitant, and netupitant were CYP3A4 inhibitors. Thus the dose of dexamethasone should be decreased when used with these NK-1RAs because of CYP3A4 inhibition. Moreover, data from clinical trials suggested that in combination with NK-1RAs and 5HT3RAs, low dose of dexamethasone also showed clear efficacy (31,36,39). Therefore, the optimal dose of dexamethasone in NK-1RAs-based triple regimens remains unknown. According to our study, there was no difference between different doses of dexamethasone in the prevention of CINV in all s when combined with NK-1RAs and 5HT3RAs. To minimize the adverse events related to dexamethasone, a lower dose of dexamethasone might be used with NK-1RAs and 5HT3RAs. However, dose-finding studies for dexamethasone should be conducted in combination with NK-1RAs and 5HT3RAs to confirm these findings. Olanzapine is an atypical antipsychotic drug that blocks multiple neuronal receptors involved in the nausea and vomiting pathways (61). It has been studied for CINV control, especially in patients presenting with nausea and vomiting refractory to standard antiemetics (61). A previous study showed that olanzapine had similar antiemetic effect compared with aprepitant in patients with HEC in combination with dexamethasone and 5HT3RAs (62). Recently, a single-arm trial reported that preventive use of olanzapine combined with triplet therapy (NK-1RA, 5HT3RA, and dexamethasone) showed better antiemetic effect than those from previously reported studies of triplet therapy (63). However, our study did not cover the evidence of olanzapine in CINV control because of limited data, which was not enough for multiple treatment comparisons. Future analyses are warranted to compare olanzapine-based regimens with NK-1RAs-based regimens in CINV control. According to our results, we found that the odds ratios for both the delayed and overall appeared to be very similar in most end points. It seemed that the overall results didn t add substantially to the current knowledge. Acute and delayed results might represent all of the useful information from this analysis. Further research about whether

10 Y. Zhang et al. 10of11 the overall result should be excluded in future study design, statistical analysis, and regulatory review is needed. Our study is not without limitations. First, the lack of connections in the networks made the results dependent on only a few studies so that some of the presented estimates were based exclusively on indirect evidence. Second, we were not able to extract specific patients data on HEC or MEC in some of the included studies that enrolled mixed patients. Third, we could not compare netupitant-based triple regimen and rolapitant-based triple regimen with other NK-1RAs-based triple regimens. Future studies were warranted to confirm our results. Despite the above limitations, our study confirmed that different NK-1RAs-based triple regimens were associated with an equivalent effect on CINV control in all the s. Various NK- 1RAs-based triple regimens had superior antiemetic effect than duplex control regimen in patients with HEC. Only aprepitantbased triple regimen showed better CINV control compared with duplex control regimen in patients receiving MEC. Moreover, palonosetron and first-generation 5HT3RAs might share equivalent effect on CINV control in the combination of NK-1RAs and dexamethasone. A lower dose of dexamethasone might be applied when used with NK-1RAs and 5HT3RAs. 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