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

Abstract

BACKGROUND

Chemotherapy-induced nausea and vomiting is common in patients who receive highly emetogenic chemotherapy (HEC). Olanzapine acts on multiple neurotransmitters and effectively reduces delayed-phase nausea.

AIM

To compare the safety and efficacy of olanzapine-based vs neurokinin-1 receptor antagonist-based antiemetic regimens in adults receiving HEC.

METHODS

This review followed Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 guidelines and searched various databases like PubMed, Scopus, etc., between 2020-2025. 14 studies were included in the systematic review with 11 meeting the criteria for meta-analysis. Primary outcomes were complete response (no vomiting, no rescue medication) and nausea control during acute (0-24 hours), delayed (25-120 hours), and overall (0-120 hours) phases. Data were pooled using random-effects models. Risk of bias was assessed with Cochrane risks of bias 2.0 and risk of bias in nonrandomized studies of interventions version I tools.

RESULTS

Olanzapine-based regimens showed higher nausea control, with no-nausea rates of 89% vs 76% (P < 0.001) and 96% vs 87% (P = 0.005). Acute complete response ranged from 66% to 100%, delayed complete response from 55% to 94%, and overall complete response from 63% to 91%. The pooled complete response odds ratio was 48.68 (95% confidence interval: 8.33-284.64; P < 0.0001). Sedation occurred in 10%-53% of patients and showed dose dependence, with lower rates at 5 mg. Most studies showed low risk of bias and high methodological quality, supporting reliability of pooled estimates despite high heterogeneity (I² > 95%).

CONCLUSION

Olanzapine-based regimens are at least as effective as neurokinin-1 antagonist therapy for chemotherapy-induced nausea and vomiting in HEC, particularly for delayed nausea. Low-dose (5 mg) olanzapine provides effective, well-tolerated, oral, and cost-efficient prophylaxis, supporting its use as a first-line antiemetic.

Key Words: Carboplatin; Cisplatin; Highly emetogenic chemotherapy; Neurokinin-1 antagonist; Olanzapine

Core Tip: Chemotherapy-induced nausea and vomiting commonly occur in patients receiving highly emetogenic chemotherapy, with rates over 90% without prophylaxis. Effective prevention preserves quality of life, supports treatment adherence, and reduces healthcare use. This study demonstrated that olanzapine-based regimens effectively prevent chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy, with pronounced control of delayed-phase nausea. Low dose provides predictable efficacy, manageable sedation, oral convenience, and cost-effectiveness. Clinically, olanzapine should be included in first-line antiemetic protocols to improve patient comfort, reduce the need for rescue medication, and support adherence to treatment.

INTRODUCTION

Chemotherapy-induced nausea and vomiting (CINV) commonly occur in patients receiving highly emetogenic chemotherapy (HEC), with rates over 90% without prophylaxis. Effective prevention preserves quality of life, supports treatment adherence, and reduces healthcare use[1]. Guidelines from the National Comprehensive Cancer Network and the American Society of Clinical Oncology recommend a triple antiemetic regimen of a 5-hydroxytryptamine-3 receptor antagonist, a neurokinin-1 (NK1) receptor antagonist, and dexamethasone for HEC[2-4]. Olanzapine, a second-generation atypical antipsychotic with antagonistic activity at dopamine, serotonin, histamine, and muscarinic receptors, has been incorporated into guidelines as an additional agent due to its efficacy, particularly in controlling delayed-phase nausea[5-8]. Multiple randomized controlled trials (RCTs) and meta-analyses have shown that olanzapine-based regimens, usually combined with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone, achieve complete response rates of 60%-89% for nausea and 76%-91% for vomiting in the overall phase (0-120 hours) following HEC[9-12]. Network meta-analyses rank olanzapine-containing regimens among the most effective for both acute and delayed CINV, with superior nausea control compared to NK1 receptor antagonist-based regimens alone[5,12-14]. Phase III trials evaluating low-dose olanzapine (5 mg) in combination with standard antiemetic therapy demonstrate significant reduction in nausea and vomiting in patients receiving cisplatin-based or carboplatin-based chemotherapy[9,10-12], without increasing serious adverse events[15-17]. Comparative studies indicate that olanzapine-based regimens achieve complete response rates comparable to, or exceeding, NK1 receptor antagonist-containing regimens, particularly in patients at moderate-to-high emetic risk[18,19]. Olanzapine shows particular efficacy in the delayed phase, where NK1 antagonists exhibit variable outcomes[6,8,20]. Safety profiles differ: Olanzapine is associated with dose-dependent sedation, more frequent at 10 mg than at 5 mg, whereas NK1 receptor antagonists are generally well tolerated but increase cost and potential drug interactions[9,6,11]. Studies have confirmed that constant antiemetic performance of olanzapine-based regimens across various cancer types, including thoracic, gastrointestinal, and breast malignancies[17,18,21,22]. Oral administration, and cost-effectiveness further validates olanzapine as a practical alternative to conventional triple therapy[3,23,24].

New therapies, including antibody-drug conjugates and novel chemotherapeutic agents, increase the complexity of CINV management and require adaptable prophylactic strategies[22,25-28]. Risk-based approaches using patient factors, emetic experience, and pharmacogenomic profiles have been suggested, but direct comparisons between olanzapine-based and NK1 receptor antagonist-based regimens in HEC are limited and variable[29-31]. Existing systematic reviews and network meta-analyses include heterogeneous populations, variable HEC definitions, and differing outcome measures, making direct comparisons challenging[7,13,14,32]. No recent systematic review has synthesized evidence from the growing number of phase III trials published since 2022 that directly compare these strategies in uniform HEC settings[9,11,15,18]. This meta-analysis was conducted to address this gap by evaluating the efficacy and safety of olanzapine-based vs NK1 receptor antagonist-based antiemetic regimens in adult patients receiving HEC. The primary focus is on complete response rates for nausea and vomiting across acute, delayed, and overall phases, alongside assessment of adverse event profiles, to provide evidence-based guidance for antiemetic regimen selection.

MATERIALS AND METHODS

Research question and PICO(S)

The systematic review and meta-analysis were designed to answer the research question: “In adult patients receiving HEC (population), does an olanzapine-based antiemetic regimen (intervention) compared with an NK1 receptor antagonist-based regimen (comparator) reduce the incidence of CINV (outcome); with RCTs and cohort studies study design (study type)?”

Search strategy

Literature search was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 guidelines, covering PubMed, EMBASE, Scopus, and Web of Science from 2020 to 2025; with International Prospective Register of Systematic Reviews (No. CRD42025640877). Specific terms including “olanzapine”, “NK1 receptor antagonist”, “aprepitant”, “fosaprepitant”, “netupitant”, “palonosetron”, “dexamethasone”, and chemotherapy-related terms were combined using Boolean operators (‘AND’, ‘OR’, ‘NOT’) to maximize search sensitivity and specificity.

Eligibility criteria

Studies were included if they examined adult patients receiving HEC and compared olanzapine-based antiemetic regimens with NK1 receptor antagonist-based regimens. Study designs like RCTs, cohort studies, which reported efficacy or safety outcomes, including complete response rates for nausea and vomiting were included. Exclusion criteria comprised studies with pediatric populations, moderate or low emetogenic chemotherapy, case reports, editorials, conference abstracts without full-text data, and studies without any relevant outcomes.

Data extraction, synthesis, and quality assessment

A total of 875 articles were searched through the databases and after reviewing and screening, 14 were included in the systematic review and only 11 met the criteria for meta-analysis (Figure 1). Data extraction was independently performed by three reviewers (Mv A, Babu B, Awosika A). Discrepancies were resolved through discussion among the reviewers. Data were synthesized quantitatively using meta-analytic techniques where feasible, and narrative synthesis was applied for heterogeneous data.

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-analyses flowchart for the review.

Risk of bias and quality assessment

The methodological quality and risk of bias of included RCTs were assessed using the Cochrane risk of bias 2.0 tool[33], and cohort studies risk of bias in nonrandomized studies of interventions version I[34] were evaluated using the Newcastle-Ottawa Scale[35]. Domains assessed included randomization, allocation concealment, blinding, incomplete outcome data, selective reporting, and other biases. Each study was independently assessed by the reviewers with disagreements resolved by consensus.

RESULTS

Qualitative synthesis of included studies

A total of 14 studies were included in the systematic review because they adhered to the predefined eligibility criteria for population, intervention, comparator, and outcome reporting thus allowing for comprehensive qualitative synthesis of efficacy and safety evidence prior to quantitative pooling.

Table 1 includes 14 studies with 3421 patients from Iran, India, China, Japan, Hong Kong, and the United States. Patients had solid tumors, mainly breast, lung, gastrointestinal, and head-neck cancers, and received mostly HEC, including cisplatin- or doxorubicin-based regimens[20,36,37]. Olanzapine was administered at 2.5-10 mg for 3-5 days, usually combined with 5-HT₃ receptor antagonists, dexamethasone, and occasionally NK1 antagonists[1,16,38]. Table 2 shows efficacy outcomes: Acute complete response ranged 66%-100%, delayed complete response 55%-94%, and overall complete response 63%-91%. Olanzapine regimens provided equal or better control of nausea and vomiting compared with aprepitant or netupitant-palonosetron-based therapies, with improvements in quality of life and reduced rescue medication reported[1,20,21,36,37]. Sedation or somnolence occurred in 10%-53% of patients, generally mild to moderate, and lower at 5 mg doses[11,36]. Table 3 reports Newcastle-Ottawa Scale scores ranging from 6 to 9, with a maximum possible score of 9. A total of 11 of 14 studies scored ≥ 8, indicating strong methodological rigor. Five studies achieved a score of 9, demonstrating complete fulfilment of selection criteria, appropriate control for confounding, and complete exposure or outcome assessment[11,18,21,38,39]. Four studies scored 8, losing 1 point because of limited adjustment for comparability or incomplete follow-up reporting[1,9,15,29]. Three studies scored 6-7. Wu et al[36] scored 6 due to incomplete selection documentation and exposure assessment. Sakai et al[17] and Radhakrishnan et al[38] scored 7 because of open-label or single-arm designs with partial reporting. No study scored below 6, supporting reliability of pooled analyses.

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.

Figure 2 present risks of bias 2.0 assessments for 12 RCTs. Eight of 12 trials showed low risk of bias, while 4 of 12 showed some concerns; no trial showed high risk in any domain. Issues related to the randomization process (D1) were identified in Navari et al[9], Sakai et al[17], and Ostwal et al[37], linked to incomplete reporting of allocation concealment. Deviations from intended interventions (D2) were identified in Bhargave et al[15], Radhakrishnan et al[38], and Liu et al[39], associated with open-label study designs. Missing outcome data (D3) were noted in Sakai et al[17] and Ostwal et al[37]. Issues related to outcome measurement (D4) and selective reporting (D5) were identified in Shen et al[20] and Zhao et al[29]. In each risk of bias 2.0 domain, more than 70% of trials showed low risk, supporting use of randomized trial data for quantitative synthesis. Figure 3 present risk of bias in nonrandomized studies of interventions version I assessments for the 2 cohort studies included in the review[18,36]. Low risk of bias was identified in 13 of 14 assessed domains (92.9%). A single domain showed moderate risk, limited to classification of interventions (D3), related to retrospective exposure assessment in Wu et al[36]. All remaining domains, including confounding (D1), selection of participants (D2), deviations from intended interventions (D4), missing data (D5), outcome measurement (D6), and selection of reported results (D7), showed low risk in both studies[18,36]. The overall risk of bias was low in 1 study and moderate in 1 study, with no domain showing high risk.

Figure 2 Risk of bias assessment for randomized control. A: Individual studies using the risks of bias 2.0 tool; B: Overall studies using the risks of bias 2.0 tool.

Figure 3 Risk of bias assessment for cohort. A: Individual studies using the risk of bias in nonrandomized studies of interventions version I tool; B: Overall studies using the risk of bias in nonrandomized studies of interventions version I tool.

Meta-analysis of complete response in HEC

Of the 14 studies included in the systematic review, 11 were eligible for forest plot analysis. Wu et al[36] was excluded because of its retrospective cohort design and inclusion of moderately emetogenic chemotherapy with a dual antiemetic comparator, which differed from the randomized comparison framework used in pooled analyses. Shen et al[20] was excluded because primary outcomes were reported as total control and visual analogue scale-based nausea thresholds rather than dichotomous complete response, preventing extraction of compatible odds ratios (ORs). Attili et al[21] was excluded because the comparator arm consisted of placebo plus granisetron and dexamethasone without an NK1-based or active standard antiemetic comparator, limiting compatibility with pooled control groups used in the forest plots.

Different numbers of studies appear in Figure 4 because each forest plot addresses a different analytical objective. Figure 4A evaluates overall antiemetic effectiveness using randomized studies with heterogeneous comparator regimens and mixed effect directions. Figure 4B evaluates complete response outcomes in randomized studies with comparable control arms and consistent direction of effect in favor of olanzapine, allowing focused estimation of effect magnitude.

Figure 4 Forest plot. A: Assessment comparing the effectiveness of antagonist antiemetic; B: Assessment comparing the mortality rate - antipsychotic drugs. CI: Confidence interval.

Figure 4A presents pooled analysis from 5 randomized studies comparing olanzapine-based regimens with comparator antiemetic regimens in 4340 participants[9,11,15,29,39]. The combined OR was 4.79 [95%confidence interval (CI): 1.29-17.72], with a statistically significant test for effect (Z = 2.35, P = 0.02). Between-study variability was high (τ² = 2.19; χ² = 328.80, degree of freedom = 4; P < 0.00001; I² = 99%). Individual study estimates varied widely, ranging from an OR of 0.81 (95%CI: 0.51-1.27) in Liu et al[39] to 45.12 (95%CI: 29.12-69.93) in Inui et al[11]. Intermediate effects were observed in Navari et al[9], Bhargave et al[15], and Zhao et al[29], reflecting differences in chemotherapy regimens, comparator arms, and olanzapine dosing.

Figure 4B summarizes pooled results from 6 studies with 1948 participants that directly compared olanzapine-based regimens with control regimens for complete response[16,18,21,36-38]. The pooled OR was 48.68 (95%CI: 8.33-284.64), with a statistically significant test for effect (Z = 4.31, P < 0.0001). Heterogeneity remained substantial (τ² = 4.63; χ² = 155.41, degree of freedom = 5; P < 0.00001; I² = 97%). Individual effect sizes ranged from 3.65 (95%CI: 2.40-5.54) in Bhargave et al[15] to 366.65 (95%CI: 212.14-633.71) in Ostwal et al[37]. All included studies showed ORs greater than 1, indicating higher complete response rates with olanzapine-containing regimens despite marked inter-study variability.

DISCUSSION

This systematic review and meta-analysis included 14 studies with 3421 patients and shows that olanzapine-based regimens prevent CINV in HEC more effectively, particularly delayed nausea. Recent phase III trials have reported higher rates of patients with no nausea using olanzapine quadruple therapy (89.6% vs 76.0%, P < 0.001)[11] and better complete nausea control (96% vs 87%, P < 0.001)[37]. Previous trials have also demonstrated similar advantages. A randomized trial in lung cancer patients receiving cisplatin showed improved rates of no nausea with an olanzapine-based triplet compared to standard NK1-based therapy (76.5% vs 56.4%, P = 0.036)[40]. These results confirm that olanzapine constantly reduces nausea after the first 24 hours in different patient groups and treatment modules. Olanzapine provides effective control of CINV through broad receptor antagonism, targeting dopamine D₂, serotonin 5-HT₂A/₃, histamine H₁, and muscarinic receptors involved in CINV[1,6,8]. Olanzapine’s multi-receptor activity effectively controls delayed-phase nausea, where several mediators drive emesis. Forest plot analyses showed high heterogeneity (I² > 95%) due to chemotherapy type, comparator regimens, and olanzapine dose[11,15,20], but outcomes favored olanzapine, which acts on multiple pathways[13,41]. In high-risk, multi-day cisplatin chemotherapy, acute complete response reached 100% with a quadruple regimen, higher than triple therapy without aprepitant (P = 0.045)[10]. Its effect was confirmed in lung cancer patients[42]. Olanzapine-based regimens matched the high antiemetic barrier of netupitant-palonosetron therapies[43]. Combining olanzapine with NK1 antagonists is effective for patients at high emetic risk[6]. Clinical observations reported better nausea control with olanzapine-containing triplets than dual therapy[44]. Studies that replaced NK1 antagonists with olanzapine showed similar overall complete response rates, with nausea-specific outcomes favoring olanzapine[9,15]. Its potent anti-nausea effect is supported by many other previous researches and real-world data in gastrointestinal cancers[8,37,41,45]. Olanzapine caused dose-dependent sedation, usually mild to moderate (grade 1-2), and rarely led to the cessation of the treatment. Low-dose olanzapine (5 mg) has shown to reduce sedation to 24.6% and 48.5% without decreasing the efficacy[11,15]. Chow et al[6] have reported that 5 mg provides effective nausea control with minimal sedation. Olanzapine at 10 mg caused sedation in 47%-53% of patients[9]. It does not undergo cytochrome P450 3A4 metabolism, avoiding interactions seen with NK1 antagonists like aprepitant[3,46]. Olanzapine may improve appetite[1,21]. Real-world studies confirmed its efficacy in patients unresponsive to standard antiemetics, including carboplatin-based regimens[47-50]. Reports indicate suboptimal adherence to antiemetic guidelines[41-45]; institutional protocols can improve adherence[46-50], and ensure patients receive effective olanzapine-based prophylaxis[51-53].

Olanzapine targets dopamine, serotonin, histamine, and muscarinic receptors, providing effective control of prolonged and delayed nausea caused by treatments like antibody-drug conjugates[26,28,54]. Olanzapine is available orally and has a low cost, making it practical for clinical use[49]. In moderate-emetogenic chemotherapy, it reduces nausea where NK1 antagonists have variable effects[50,55,56]. It controls nausea better than aprepitant while maintaining a manageable safety profile[57] and remains necessary even when non-pharmacologic interventions like acupoint stimulation are used[58]. Olanzapine prevents both acute and delayed nausea, providing reliable efficacy for patients receiving high-emetogenic or moderate-emetogenic chemotherapy. These features support its inclusion in treatment protocols to reduce CINV and improve patient supportive care. This meta-analysis has some limitations like clinical heterogeneity from the inclusion of moderately emetogenic chemotherapy studies and different comparator regimens, follow-up limited to ≤ 120 hours that may miss very delayed symptoms from newer chemotherapies, and dependence on the quality of original studies for pooled outcomes. Most included studies were high-quality RCTs with low risk of bias, as confirmed by risks of bias 2.0 assessment, and constantly favored olanzapine. Olanzapine-based regimens are non-inferior and often superior to NK1 antagonist-based regimens for HEC, particularly for delayed-phase nausea.

CONCLUSION

This review and meta-analysis demonstrated that olanzapine-based regimens effectively prevent CINV in patients receiving HEC, with pronounced control of delayed-phase nausea. Low dose provides predictable efficacy, manageable sedation, oral convenience, and cost-effectiveness. Clinically, olanzapine should be included in first-line antiemetic protocols to improve patient comfort, reduce the need for rescue medication, and support adherence to treatment. Future studies should evaluate its effectiveness with newer therapies, assess long-term safety in diverse populations, and explore optimized dosing schedules for specific patient subgroups. These findings support broader implementation of olanzapine in routine clinical practice for high-risk chemotherapy.