Olanzapine-based vs neurokinin-1 receptor antagonist antiemetic regimens in highly emetogenic chemotherapy: Systematic review and meta-analysis of efficacy and safety

Table 1 Characteristics of included studies

Ref.	Country	Design	n	Cancer type	Chemo (HEC/MEC)	Intervention (olanzapine regimen)	Comparator	Olanzapine dose and duration	Follow-up	Key findings
Maleki et al[1], 2020	The Islamic Republic of Iran	Phase III, RCT, DB	60	Early breast (I-III)	AC (doxorubicin ≥ 50 + cyclophosphamide ≥ 500 mg/m2)	OLA 10 mg + aprepitant + dex + granisetron	Mirtazapine 15 mg + aprepitant + dex + granisetron	10 mg D1-4 (5 mg ≥ 60 years)	0-120 hours × 2 cycles	CR similar (acute 766% vs 83.3%); ↑somnolence/fatigue with OLA; better QoL (cycle 2) with mirtazapine
Radhakrishnan et al[38], 2020	India	Phase III, open-label RCT	80	Pediatric solid tumors	Mostly HEC (cisplatin/ifosfamide/cyclophosphamide/doxorubicin)	OLA (2.5-5 mg daily)	Metoclopramide (no NK1)	2.5-5 mg ≥ 72 hours	72 hours + AE 7 days	CR vomiting 72% vs 39%, nausea 59% vs 34%; sedation 25% vs 0%; OLA superior for breakthrough CINV
Wu et al[36], 2020	China	Retrospective cohort	93	GI (CRC 78.5%, gastric 21.5%)	MEC (mFOLFOX6/XELOX/FOLFIRI)	OLA 5 mg + tropisetron + dex	Tropisetron + dex	5 mg D1-3	0-120 hours	Overall CR 70% vs 47%; delayed CR 75% vs 55%; ↑QoL (75% vs 49% no impact); somnolence 47% vs 15%
Sakai et al[17], 2021	Japan	Phase II, single-arm	50	Thoracic (NSCLC 66%, SCLC 22%)	Carboplatin ± other drugs (HEC)	OLA 5 mg + granisetron + dex	None	5 mg D1-4 pm	0-120 hours	CR 100% acute, 94% delayed; no ≥ G3 AEs; nausea peaked D3-4
Gao et al[10], 2022	China	RCT	120	Lung (52%) + others	Cisplatin × 3 days (HEC)	Quadruple: OLA 5 mg + aprepitant + tropisetron + dex	Triplet: OLA 5 mg + tropisetron + dex	5 mg D1-3	0-120 hours (5 days)	Acute CR↑ (100% vs 93%, P = 0.045); overall CR NS; longer TTE with aprepitant; well-tolerated
Liu et al[39], 2022	China	RCT	210	Mixed solid tumors	Cisplatin × 3 days	OLA 5 mg + tropisetron + dex 10 mg	Aprepitant + tropisetron + dex 5 mg	5 mg D1-4	0-120 hours	Similar efficacy (all endpoints); somnolence (OLA) vs constipation (aprepitant)
Yip et al[18], 2023	Mainland	Post hoc (2 prospective)	120	Early breast	AC (HEC)	OLA 10 mg + aprepitant + ondansetron + dex	NEPA + dex	10 mg D1-5	0-120 hours × 4 cycles	C1: ↑“No rescue” and “no nausea”; CR similar (approximately 65%-70%); later cycles favored NEPA; QoL NS
Navari et al[9], 2023	United States	Phase III, RCT, DB, PC	690	Breast 77% + others	HEC (AC 77%, cisplatin 23%)	OLA + 5-HT3 RA + dex + placebo	Same + NK1 (fosaprepitant/aprepitant)	10 mg D1-4	0-120 hours × 4 cycles	Overall CR 47% vs 55%; NK1 arm better nausea control; OLA alone non-inferior not met; ↑sedation day 1
Zhao et al[29], 2023	China	Phase III, RCT, DB	720	Solid tumors	Cisplatin ≥ 50 mg/m2 (HEC)		Fosaprepitant vs aprepitant (+ palonosetron + dex)		0-120 hours	Fosaprepitant non-inferior for overall CR (78% vs 78%); similar nausea QoL; AEs mild
Inui et al[11], 2024	Japan	Phase III, RCT, DB, PC	355	Thoracic	Carboplatin ± ICI (HEC)	OLA 5 mg + aprepitant + 5-HT3 RA + dex	Placebo + same	5 mg D1-4 pm	0-120 hours	Overall CR 87% vs 81% (NS); no nausea↑ (89% vs 76% P < 0.001); somnolence 24%; no serious AEs
Ostwal et al[37], 2024	India	Phase III, open-label	544	Solid tumors (GI > lung)	MEC (oxaliplatin 61%, carbo 29%)	OLA 10 mg + aprepitant + palonosetron + dex	Aprepitant + palonosetron + dex	10 mg D1-3 hs	0-120 hours	Overall CR 91% vs 82% (P = 0.005); nausea 96% vs 87%; better QoL; somnolence 10% (G1)
Shen et al[20], 2024	China	RCT, open-label	102	GI (rectal 55%, gastric 28%)	MEC (XELOX/SOX/FOLFOX)	OLA 5 mg + palonosetron + dex	Palonosetron + dex	5 mg D1-5 hs	0-120 hours	TP 66.7% vs 37% (P = 0.003); QoL↑ (84% vs 59%); ↑drowsiness (53% vs 31%); ↑appetite
Bhargave et al[15], 2025	India	Phase III, DB, DD, PC	195	Head-neck 38%, Gyn 29% + others	Carboplatin AUC ≥ 4	OOD: OLA 5 mg + ondansetron + dex + placebo	Fosaprepitant + ondansetron + dex + placebo	5 mg D1-4	0-120 hours	Overall CR 66% vs 67% (NS); no nausea 44% vs 34%; sedation 49% vs 29%; cost-effective alternative
Attili et al[21], 2025	India	Phase III, RCT, DB, PC	82	Mixed carcinomas	Cisplatin-based HEC	OLA 10 mg + granisetron + dex	Placebo + granisetron + dex	10 mg D1 to D3	0-120 hours	CR↑ (acute 87% vs 55%, delayed 72% vs 47%, overall, 67% vs 34%); mild sedation 31%

Complete response (no vomiting and no rescue medication); total control (no vomiting + no rescue + nausea ≤ 25 mm). RCT: Randomized controlled trial; DB: Double-blind; PC: Placebo-controlled; DD: Double-dummy; GI: Gastrointestinal; CRC: Colorectal cancer; NSCLC: Non-small cell lung cancer; SCLC: Small cell lung cancer; Gyn: Gynecology; HEC: Highly emetogenic chemotherapy; MEC: Moderately emetogenic chemotherapy; AC: Doxorubicin, cyclophosphamide; mFOLFOX6: Modified fluorouracil, leucovorin, oxaliplatin 6-day regimen; XELOX: Capecitabine, oxaliplatin; FOLFIRI: Fluorouracil, leucovorin, irinotecan; ICI: Immune checkpoint inhibitor; XELOX: Capecitabine, oxaliplatin; SOX: S-1, oxaliplatin; FOLFOX: Fluorouracil, leucovorin, oxaliplatin; AUC: Area under the curve; OLA: Olanzapine; dex: Dexamethasone; 5-HT₃ RA: 5-hydroxytryptamine 3 receptor antagonist; NK1: Neurokinin-1; pm: Post meridiem; hs: Hora somni; AE: Adverse events; CR: Complete response; OLA: Olanzapine; QoL: Quality of life; CINV: Chemotherapy-induced nausea and vomiting; NS: Not significant; TTE: Time to emesis; C1: Cycle 1; NEPA: Netupitant-palonosetron; TP: Total control (no vomiting + no rescue + nausea ≤ 25 mm).

Table 2 Efficacy and safety outcomes

Ref.	Comparator regimen	Primary outcome (CR) definition	Acute CR (%)	Delayed CR (%)	Overall CR (%)	Nausea control (%)	Vomiting control (%)	Sedation/somnolence (%)	Other AEs (≥ 10%)	Statistical significance (P value/ 95%CI)	Relative risk/OR (95%CI)
Maleki et al[1], 2020	Mirtazapine + aprepitant + dexamethasone + granisetron (both arms NK1)	No vomiting + no rescue (0-120 hours)	76.6	86.6	63.3	70.0	86.6	53.3 (G1-3)	Fatigue 667; dry mouth 33.3; constipation 26.7; appetite loss 43.3	CR: P = 0.51-0.78; Somnolence P = 0.04; fatigue P = 0.02; FLIE P = 0.044
Radhakrishnan et al[38], 2020	Metoclopramide (no NK1)	No vomiting or nausea within 72 hours post rescue	70	100	72	59	72	25 (G1-3)	Anorexia 30 vs 27; abdominal pain 30 vs 24; headache 17 vs 10	Vomiting CR P = 0.003; nausea CR P = 0.026; sedation P = 0.0004	OR vomiting 4.0 (1.6-10.0); OR nausea 27 (1.1-6.6)
Wu et al[36], 2020	Tropisetron + dexamethasone (dual; no NK1)	No vomiting + no rescue (0-120 hours)	85.0	75.0	70.0	No nausea < 5 mm: 55		47.5	Constipation 62.5; anorexia 575; insomnia 15; dizziness 30	Delayed CR P = 0.044; overall CR P = 0.028; somnolence P = 0.001	OR overall CR ≈ 2.6; OR delayed ≈ 2.5
Sakai et al[17], 2021	None (single arm)	No emesis + no rescue (0-120 hours)	100	94	94	Total control 86	94	76 (mostly G1)	Constipation 72; dry mouth 64; insomnia 56; hiccups 50	P < 0.0001 vs historical 65% CR
Gao et al[10], 2022	Olanzapine + tropisetron + dexamethasone	No vomiting + no rescue (0-120 hours)	100	76	76	28.8	93.2	57.6	Fatigue 542; constipation 22	Acute CR P = 0.045; no vomiting P = 0.038	RR ≈ 1.13 (ns)
Liu et al[39], 2022	Aprepitant + tropisetron + dexamethasone	No vomiting + no rescue; TP primary	96.15 vs 97.17	75 vs 79.25	75 vs 79.25	TP 54.8 vs 54.7; TC 31.7 vs 27.3		88.46 vs 50.8	Constipation 53 vs 62	CR P = 0.46; somnolence P = 0.00; constipation P = 0.02
Yip et al[18], 2023	NEPA + dexamethasone	No vomiting + no rescue (0-120 hours)	70.0	92.9	65.0	91.7	68.3		Neutropenia ≥ G2↑ in olanzapine arm	Overall CR P = 0.5716; no nausea P = 0.0408
Navari et al[9], 2023	Olanzapine + 5-HT3 RA + dex + NK1 vs placebo	No emesis + no rescue (0-120 hours)		55 vs 47	55 vs 47	38 vs 30		Higher in NK1 arm (P = 0.017)	Appetite↑ (no difference)	Overall CR P = 0.0497; no nausea P = 0.2443	Risk difference +8% (both CR and nausea)
Zhao et al[29], 2023	Aprepitant + palonosetron + dexamethasone	No emesis + no rescue (0-120 hours)	88.9 vs 88.4	80.1 vs 79.9	78.1 vs 77.7	No nausea < 5 mm: 52 vs 50.6			None ≥ 10%	CR P = 0.765; 95%CI: -5.7 to 6.6	Risk difference +0.4%
Inui et al[11], 2024	Placebo + aprepitant + 5-5-HT3 RA + dex	No vomiting + no rescue	98.9 vs 97.8	87.4 vs 80.6	86.9 vs 80.6	No nausea 886		24.6 vs 22.9	Constipation 44; hepatotoxicity 55; cytopenias > 60	CR P = 0.116; nausea P < 0.001	Risk difference CR +6.3%; nausea +13.6%
Ostwal et al[37], 2024	Aprepitant + palonosetron + dex (NK1 triplet)	No vomiting + no nausea < 5 mm + no rescue (0-120 hours)	96	92	91	96	95	10 (G1)	None ≥ 10%	Overall CR P = 0.005; somnolence P < 0.001	OR CR 2.04 (1.24-3.36); OR nausea 3.57 (1.94-6.57)
Shen et al[20], 2024	Palonosetron + dexamethasone (dual; no NK1)	CR: No vomiting + no rescue; TP ≤ 25 mm; TC ≤ 5 mm	84.3	80.3	76.5	TP 66.7; TC 31.4		52.9	Appetite loss 56.9; weakness 78.4; dizziness 43.1	TP P = 0.003; drowsiness P = 0.027; FLIE P = 0.003	OR overall TP ≈ 3.3
Bhargave et al[15], 2025	Fosaprepitant + ondansetron + dex	CR: No vomiting + no rescue; primary: No nausea	87.3 vs 92.5	67.7	65.7 vs 66.7	No nausea 441		48.5 vs 29.0	Fatigue 28; muscle pain 19; constipation 15	No nausea P = 0.19; CR P > 0.99	OR no nausea 151 (0.84-2.69); CR 0.96 (0.53-1.73)
Attili et al[21], 2025	Placebo + granisetron + dex (no NK1)	No vomiting + no rescue	87.1	71.8	66.6	No nausea: 76.9 (acute), 46.1 (overall)		30.7 (mild)	Appetite↑ 10.2	Acute CR P = 0.001; overall CR P = 0.004	RR CR ≈ 1.95; RR Nausea ≈ 2.51

Complete response (no vomiting and no rescue medication). NK1: Neurokinin-1; NEPA: Netupitant-palonosetron; 5-HT₃ RA: 5-hydroxytryptamine 3 receptor antagonist; dex: Dexamethasone; CR: Complete response; TP: Total control (no vomiting + no rescue + nausea ≤ 25 mm); TC: Total control (nausea ≤ 5 mm); AE: Adverse events; FLIE: Functional Living Index-Emesis; CI: Confidence interval; OR: Odds ratio; RR: Relative risk; ns: Not significant.

Table 3 Quality assessment for randomized controlled trial, cohort and cross-sectional studies using the Newcastle Ottawa Scale

No.	Ref.	S1	S2	S3	S4	Comparability	E1/O1	E2/O2	E3/O3	Total
1	Maleki et al[1], 2020	1	1	1	1	1	1	1	1	8
2	Radhakrishnan et al[38], 2020	1	0	1	1	1	1	1	1	7
3	Wu et al[36], 2020	1	1	0	0	1	1	1	1	6
4	Sakai et al[17], 2021	1	1	1	1	1	1	1	0	7
5	Gao et al[10], 2022	1	1	1	1	1	1	0	1	7
6	Liu et al[39], 2022	1	1	1	1	2	1	1	1	9
7	Yip et al[18], 2023	1	1	1	1	2	1	1	1	9
8	Navari et al[9], 2023	1	1	1	1	1	1	1	1	8
9	Zhao et al[29], 2023	1	1	1	1	1	1	1	1	8
10	Inui et al[11], 2024	1	1	1	1	2	1	1	1	9
11	Ostwal et al[37], 2024	1	1	1	1	2	1	1	1	9
12	Shen et al[20], 2024	1	1	1	1	2	1	1	1	9
13	Bhargave et al[15], 2025	1	1	1	1	1	1	1	1	8
14	Attili et al[21], 2025	1	1	1	1	2	1	1	1	9

1: Denote the award of one point for the corresponding Newcastle-Ottawa Scale domain, while two asterisks. 2: Indicate two points awarded under the comparability domain, as per standard Newcastle-Ottawa Scale scoring guidelines. S: Selection; E: Exposure; O: Outcome.