Netupitant-palonosetron combined with dexamethasone for preventing chemotherapy-induced nausea and vomiting in high-risk patients with colorectal cancer receiving moderately emetogenic chemotherapy: A retrospective study

Abstract

Although netupitant-palonosetron (NEPA) is an established option for preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy, its efficacy in patients with high-risk features undergoing moderately emetogenic chemotherapy (MEC) remains insufficiently investigated. Therefore, the present study evaluated the efficacy of NEPA combined with dexamethasone for preventing CINV in high-risk patients with colorectal cancer (CRC) receiving MEC. This retrospective analysis included 182 patients with CRC receiving MEC who had at least one high-risk factor for CINV, including no alcohol consumption, a history of CINV and female sex. All patients received prophylaxis with a single dose of NEPA combined with dexamethasone. The primary outcome was complete remission (CR), defined as no vomiting and no rescue medication use. Secondary outcomes included complete control (CC), defined as no significant nausea, no vomiting and no rescue medication use, and complete protection (CP), defined as no nausea, no vomiting and no rescue medication use, assessed during the acute (0–24 h), delayed (24–120 h) and overall (0–120 h) phases. Extended efficacy during the 120–168 h period and safety outcomes were also evaluated. The median age was 58.7 years (range: 32–75 years). The most frequent high-risk factors were no alcohol consumption (72.0%, 131/182) and a history of CINV (22.0%, 40/182). CR rates during the acute, delayed and overall phases were 98.9, 95.6 and 94.5%, respectively. CC rates were 98.9, 92.3 and 91.2% in the acute, delayed, and overall phases, respectively, while CP rates were 98.9, 78.0 and 76.3% in the corresponding phases. Although CR rates >95% in the acute and delayed phases and only 1.1% of patients required rescue therapy, the CP rate markedly declined from 98.9% in the acute phase to 78.0% in the delayed phase, indicating that nausea control remains a major clinical challenge during the delayed period despite effective prevention of vomiting. In a subset of 120 patients, the overall CR, CC and CP rates during the 120–168 h post-chemotherapy period remained high at 96.6, 91.6 and 84.2%, respectively. The combination of NEPA and dexamethasone was well tolerated; constipation was the most frequently reported adverse event (11.0%), predominantly grade 1 (9.3%), with no grade 3 or 4 events observed. In this single-arm retrospective study, the combination of NEPA and dexamethasone demonstrated promising efficacy and a favorable safety profile in high-risk patients with CRC receiving MEC, with sustained antiemetic protection beyond 120 h post-chemotherapy. Nevertheless, these findings should be considered preliminary and require confirmation in prospective randomized controlled trials.

Introduction

Colorectal cancer (CRC) is among the most common malignant tumors worldwide, and chemotherapy remains a cornerstone in its management. In the United States alone, an estimated 158,850 new cases and 55,230 deaths are projected for 2026 (1). However, 60 to 80% of patients receiving chemotherapy experience varying degrees of nausea and vomiting, a condition defined as chemotherapy-induced nausea and vomiting (CINV) (2). CINV substantially impairs the quality of life of patients and may result in dose reductions, treatment delays or even treatment discontinuation, thereby adversely affecting prognosis (3).

Oxaliplatin and irinotecan, the two commonly used chemotherapeutic agents in treating CRC, are classified as moderately emetogenic chemotherapy (MEC). In the TRIBE2 trial, the incidence of vomiting among patients receiving bevacizumab combined with FOLFIRI or FOLFIRI alone was 24 and 31%, respectively, with grade ≥3 vomiting reported in 2.0 and 3.0% of patients (4). These historical control data, derived from older antiemetic standards without routine use of neurokinin-1 (NK-1) receptor antagonists (RAs), indicate that a substantial proportion of patients still experience CINV despite conventional prophylaxis, underscoring the urgent need for more effective and simplified antiemetic strategies in contemporary clinical practice. For patients with high-risk features receiving MEC, the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) guidelines recommend a triple antiemetic regimen comprising a 5-hydroxytryptamine-3 (5-HT₃) RA, an NK-1 RA, and dexamethasone (5). Nevertheless, several important gaps in clinical practice remain. First, although MEC is generally associated with a lower emetogenic risk than highly emetogenic chemotherapy (HEC), high-risk subgroups, including younger patients, female patients, those with no alcohol consumption and those with a history of CINV, may experience CINV rates comparable to HEC-treated populations, yet remain underrepresented in studies and often receive suboptimal prophylaxis. Second, in clinical practice, only 23% of patients receive guideline-concordant prophylaxis during the acute and delayed phases, partially due to the complexity of multidrug regimens (6). Simplified antiemetic strategies with reduced dosing complexity have been demonstrated to improve adherence and subsequently enhance antiemetic control (7).

Netupitant-palonosetron (NEPA) is the first and only oral fixed-dose combination administered as a single dose that simultaneously blocks the 5-HT₃ and NK-1 receptor pathways. This fixed-dose formulation may simplify antiemetic prophylaxis, improve patient adherence and enhance the overall care consistency. According to the 2023 MASCC/ESMO guidelines, triple therapy consisting of a 5-HT₃ RA, an NK-1 RA, and dexamethasone is recommended for high-risk patients receiving MEC (8). In this context, NEPA combined with a single dose of dexamethasone provides the full triple prophylactic regimen in a single oral capsule, thereby considerably simplifying the treatment schedule and improving patient adherence. NEPA is currently approved for preventing acute and delayed CINV associated with HEC (9). However, its efficacy in MEC, particularly among high-risk patients with CRC who are highly susceptible to CINV, has not been systematically evaluated. Given that simplified regimens improve adherence and that high-risk patients receiving MEC may benefit more from NK-1 receptor antagonism, there is a strong rationale to assess NEPA combined with dexamethasone in this population. A small-scale clinical study reported that NEPA combined with dexamethasone effectively reduced the incidence of CINV in patients with pancreatic cancer or CRC receiving FOLFIRINOX (10). Nevertheless, dedicated evidence in high-risk patients with CRC receiving standard MEC regimens, such as oxaliplatin- or irinotecan-based chemotherapy, remains limited.

Therefore, the present study evaluated the effectiveness and safety profile of NEPA combined with dexamethasone for preventing CINV during the key 120-h post-chemotherapy period in high-risk patients with CRC receiving MEC. In contrast to the majority of previous NEPA trials, which have focused on mixed tumor populations or HEC settings, the present study specifically targets patients with CRC treated with oxaliplatin- or irinotecan-based regimens, includes patients with at least one CINV risk factor such as no alcohol consumption or a history of CINV and extends efficacy assessment up to 168 h post-chemotherapy. These design features address important evidence gaps in this underrepresented high-risk population. Moreover, particular emphasis is placed on patient subgroups with identifiable risk factors for increased susceptibility to CINV.

Materials and methods

Study design and patient selection

This single-center retrospective cohort study retrospectively accessed and analyzed data from patients with CRC who received chemotherapy at Peking University Shenzhen Hospital (Shenzhen, China) between January 2023 and September 2024; data retrieval and analysis were performed from November 2024 to February 2025. The present study was approved by the Institutional Review Board of Peking University Shenzhen Hospital (Shenzhen, China) and was conducted in accordance with the Declaration of Helsinki.

The inclusion criteria were as follows: Age 18–75 years, histopathological diagnosis of CRC, Eastern Cooperative Oncology Group Performance Status of 0–1, no severe pre-existing hematological, hepatic or renal disease prior to CRC diagnosis, and receipt of first-line chemotherapy with oxaliplatin or irinotecan. Additionally, patients were classified as high risk for CINV if they presented with at least one of the following factors: Female, age <50 years, no alcohol consumption, history of anxiety, history of pregnancy-related vomiting, history of motion sickness, history of CINV, anticipatory nausea and vomiting, and medication use, such as opioid analgesics.

Treatment

All included patients received MEC. Although patients received various chemotherapy regimens (as detailed below), all regimens were classified as moderately emetogenic according to MASCC/ESMO guidelines, except mFOLFOXIRI, which is classified as HEC in some guidelines. To account for potential confounding associated with regimen heterogeneity, a sensitivity analysis excluding patients treated with mFOLFOXIRI was conducted, as reported in the Results section. All patients, irrespective of chemotherapy regimen, received identical antiemetic prophylaxis consisting of NEPA combined with dexamethasone. The chemotherapy regimens were as follows: i) mFOLFOX6: Oxaliplatin 85 mg/m² administered as an intravenous infusion over 2 h on day 1; leucovorin 400 mg/m² administered as an intravenous infusion over 2 h on day 1; 5-fluorouracil 400 mg/m² administered as an intravenous bolus on day 1, followed by a continuous infusion of 2,400 mg/m² 5-fluorouracil administered over 46 h. Each cycle was 14 days. ii) FOLFIRI: Irinotecan 180 mg/m² administered as an intravenous infusion over 90 min on day 1; leucovorin and 5-fluorouracil were administered as described for mFOLFOX6. Each cycle was 14 days. iii) mFOLFOXIRI: Irinotecan 150 mg/m² administered as an intravenous infusion over 90 min on day 1; oxaliplatin 85 mg/m² administered as an intravenous infusion over 2 h on day 1; leucovorin 400 mg/m² administered as an intravenous infusion over 2 h on day 1; and 5-fluorouracil 2,800 mg/m² administered as an infusion over 48 h. Each cycle was 14 days. iv) XELOX: Oxaliplatin 130 mg/m² administered as an intravenous infusion over 2 h on day 1; and capecitabine 1,000 mg/m² administered orally twice daily from days 1 to 14. Each cycle was 3 weeks. In addition to chemotherapy, bevacizumab or cetuximab was administered based on RAS/BRAF mutation status and tumor location.

All patients received a single oral dose of NEPA (300 mg netupitant and 0.5 mg palonosetron) 1 h prior to the initiation of chemotherapy on day 1. Dexamethasone was administered as a single 12 mg intravenous bolus immediately before chemotherapy on day 1. No additional dexamethasone was administered on days 2–4, in accordance with the NEPA prescribing information. Netupitant is a moderate cytochrome P450 3A4 inhibitor that increases and prolongs dexamethasone exposure by ~2-fold, thereby supporting the adequacy of a single-day dosing strategy. In contrast to traditional aprepitant-based regimens, which require dexamethasone administration over 3 days, this approach further simplifies the antiemetic regimen. For breakthrough CINV, oral olanzapine was administered as rescue therapy.

Assessments

From day 1 of chemotherapy initiation to day 7 (0–168 h) post-treatment, patients were instructed to complete daily diaries documenting vomiting episodes, nausea severity using the visual analog scale (VAS), rescue medication use and adverse events. Research nurses conducted daily telephone follow-ups to ensure data completeness and resolve any ambiguities. The primary outcome was complete remission (CR), defined as the absence of vomiting and no rescue medication use during the acute (0–24 h), delayed (24–120 h) and overall (0–120 h) phases following chemotherapy. Secondary outcomes included complete control (CC) and complete protection (CP). CC was defined as no significant nausea (VAS score <2), no vomiting and no rescue medication use ≤120 h after chemotherapy. CP was defined as no nausea, no vomiting, and no rescue medication use within ≤120 h after chemotherapy. Nausea severity was assessed daily using a VAS ranging from 0 to 10, with higher scores indicating greater severity. Nausea was classified as none (VAS 0), mild (VAS 1–3), moderate (VAS 4–6) and severe (VAS 7–10). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0) (11).

Daily records were collected from days 1 to 7 post-chemotherapy (0–168 h). Owing to the study's retrospective design, complete 7-day diary data were available for 120 of 182 patients (66.0%). Missing data for days 6 to 7 were primarily due to incomplete documentation rather than patient withdrawal or adverse events.

Statistical analysis

Statistical analyses were performed using the Statistical Package for the Social Sciences software (version 26.0; IBM Corp.). Normally distributed continuous variables are expressed as mean ± standard deviation, whereas non-normally distributed variables are presented as median with interquartile range. Categorical variables are reported as frequencies and percentages (N, %). Descriptive statistics were applied to baseline demographic and clinical characteristics to define the study population profile. Missing data were addressed using complete-case analysis because the proportion of missing values for each variable remained below 5%, which was considered negligible. For the primary (CR) and secondary outcomes (CC and CP), any missing daily record was conservatively classified as treatment failure, defined as the absence of remission. Subgroup analyses were conducted according to prespecified high-risk factors, including sex, age (<50 vs. ≥50 years), alcohol consumption status and history of CINV, to explore potential heterogeneity in treatment response. Given the exploratory nature of these subgroup analyses, results were reported descriptively without formal statistical comparison. All statistical tests were two-tailed, and a P<0.05 was considered to indicate a statistically significant difference.

Results

Patient characteristics

Data were collected for 182 patients with CRC during the study period (Fig. 1). The median age of the study population was 58.7 years (range: 32–75 years) and 72 patients (39.6%) were women. Colon cancer was diagnosed in the majority of patients (61.5%, 112/182), whereas the majority of participants presented with stage III disease (59.3%, 108/182). Among the identified high-risk factors for CINV, no alcohol consumption was most prevalent (72%, 131/182), followed by a history of CINV (22.0%, 40/182). Regarding treatment, oxaliplatin-based regimens were the most frequently administered chemotherapy protocols (90.1%, 164/182), followed by capecitabine-based regimens (48.9%, 89/182). Detailed baseline characteristics are presented in Table I.

Figure 1.

Flowchart illustrating the patient enrollment process.

Table I.

Baseline demographics and clinical characteristics of the patients of the present study (n=182).

Characteristics	Patients (n, %)
Age, (years) median (range)	58.7 (32–75)
<50	50 (27.5)
≥50	132 (72.5)
Sex
Man	110 (60.4)
Woman	72 (39.6)
Type of cancer
Colon	112 (61.5)
Rectal	70 (38.5)
Clinical stage
II	5 (2.80)
III	108 (59.3)
IV	69 (37.9)
ECOG PS
0	162 (89.0)
1	20 (11.0)
Treatment
XELOX	83 (45.6)
mFOLFOX6	63 (34.6)
mFOLFOXIRI	18 (9.9)
FOLFIRI	12 (6.60)
XELIRI	6 (3.3)
High-risk factors
No alcohol consumption status	131 (72.0)
History of CINV	40 (22.0)
Concomitant medication	25 (13.7)
History of pregnant-related vomiting	24 (13.2)
Expected CINV	20 (11.0)
Anxiety disorder	9 (5.0)
Motion sickness	6 (3.3)

CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status; CINV, Chemotherapy-induced Nausea and Vomiting; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Concomitant medication, mainly opioid analgesics, which are known risk factors for CINV.

Efficacy

CR rates were 98.9% (180/182) during the acute phase (0–24 h) and 95.6% (174/182) during the delayed phase (24–120 h), resulting in an overall CR rate of 94.5% (172/182; Table II). Similarly, CC rates were 98.9% (180/182) during the acute phase and 92.3% (168/182) during the delayed phase, yielding an overall CC rate of 91.2% (166/182; Table II). CP rates reached 98.9% (180/182) during the acute phase but decreased to 78.0% (142/182) during the delayed phase, yielding an overall CP rate of 76.3% (139/182; Table II). Notably, identical CR and CP rates observed during the acute phase (both 98.9%) indicate that all 180 patients who achieved CR also reported no nausea (VAS 0) within the first 24 h following chemotherapy. This finding reflects the robust acute-phase efficacy of NEPA combined with dexamethasone. Nevertheless, retrospective diary collection may have contributed to the underreporting of transient mild nausea (VAS 1–3) that did not interfere with daily activities. Furthermore, the 20.9% difference between the acute- and delayed-phase CP rates suggests greater efficacy of NEPA during the first 24 h post-chemotherapy than during the subsequent delayed phases. Only 1.1% (2/182) of patients required rescue therapy with olanzapine. Regarding nausea severity assessed using the VAS, 15.4% (28/182) of patients reported mild nausea (scores 1–3) during the delayed phase, whereas 6.0% (11/182) and 2.2% (4/182) reported moderate (scores 4–6) and severe nausea (scores 7–10), respectively. Vomiting was reported by 1.1% (2/182) of patients during the acute phase and 4.4% (8/182) during the delayed phase, with the highest frequency occurring between 48 and 72 h after chemotherapy. Overall, the combination of NEPA and dexamethasone demonstrated substantial efficacy in preventing CINV among high-risk patients with CRC receiving MEC.

Table II.

Efficacy of NEPA plus dexamethasone in patients with CRC receiving MEC (n=182).

Outcome	Acute phase (0–24 h)	Delayed phase (24–120 h)	Overall phase (0–120 h)
Complete response	180 (98.9)	174 (95.6)	172 (94.5)
Complete control	180 (98.9)	168 (92.3)	166 (91.2)
Complete protection	180 (98.9)	142 (78.0)	139 (76.3)

Data are n (%). Complete response: No vomiting and no rescue use; Complete control: No significant nausea, no vomiting and no rescue use; Complete protection: No nausea, no vomiting and no rescue use. CRC, colorectal cancer; MEC, moderately emetogenic chemotherapy; NEPA, netupitant-palonosetron.

Because certain clinical guidelines classify the mFOLFOXIRI regimen as HEC, a post hoc sensitivity analysis was performed after excluding the 18 patients (9.9%) who received this regimen. Among the remaining 164 patients treated with MEC regimens, including mFOLFOX6, FOLFIRI or XELOX, the overall CR, CC and CP rates during the 0–120 h period were 93.3% (153/164), 90.2% (148/164) and 75.0% (123/164), respectively. These outcomes were highly comparable to those observed in the full cohort, where the corresponding CR, CC and CP rates were 94.5, 91.2 and 76.3%, respectively. Furthermore, subgroup analyses restricted to the MEC-only cohort revealed consistent CR rates across all prespecified high-risk factors, although the data are not presented. Collectively, these findings indicate that the inclusion of patients receiving mFOLFOXIRI did not materially affect the overall study outcomes.

To assess potential heterogeneity in treatment response, outcomes were descriptively evaluated according to prespecified high-risk factors. Table III summarizes CR rates during the overall phase (0–120 h), stratified by sex, age group, alcohol consumption status and CINV history. Across all subgroup comparison, CR rates remained consistent: 93.1% (67/72) in the female patients vs. 95.5% (105/110) in the male patients; 94.0% (47/50) in patients aged <50 years vs. 94.7% (125/132) in those aged ≥50 years; 94.7% (124/131) in patients with no alcohol consumption vs. 94.1% (48/51) in those with alcohol consumption; 92.5% (37/40) in patients with a history of CINV vs. 95.1% (135/142) in those without CINV history. Collectively, these descriptive findings suggest that NEPA combined with dexamethasone maintained consistently high efficacy across the evaluated subgroups. Nevertheless, the limited sample size in the <50-year age stratum (n=50) restricts the ability to draw definitive conclusions regarding age-related differences in treatment response.

Table III.

Subgroup analyses of CR rates during the overall phase (0–120 h) according to prespecified high-risk factors (n=182).

Subgroup	n	Overall CR (%)
Sex
Woman	72	93.1 (67/72)
Man	110	95.5 (105/110)
Age
<50 years	50	94.0 (47/50)
≥50 years	132	94.7 (125/132)
Alcohol consumption
No	131	94.7 (124/131)
Yes	51	94.1 (48/51)
Prior CINV history
Yes	40	92.5 (37/40)
No	142	95.1 (135/142)

CINV, Chemotherapy-induced nausea and vomiting; CR, complete response.

Given the limited evidence regarding prolonged prophylaxis for CINV, outcomes during the extended period from 120 to 168 h after chemotherapy were further evaluated. Among the 182 patients included in the full cohort, 120 (66.0%) had complete daily records covering the entire 7-day observation period (0–168 h). The remaining 62 patients lacked diary data for days 6–7 because of incomplete documentation associated with the retrospective study design. Comparisons of baseline characteristics, including age, sex, chemotherapy regimen and prespecified high-risk factors, revealed no significant differences between patients with and without 168 h of data; however, selection bias cannot be entirely excluded. Within the subgroup of 120 patients with complete 7-day follow-up, the overall CR, CC and CP rates during the 120–168 h remained clinically meaningful at 96.6% (116/120), 91.6% (110/120) and 84.2% (101/120), respectively (Table IV). Additional rescue antiemetic therapy was required by 1.7% (2/120) of patients during this interval. Furthermore, efficacy was maintained across successive treatment cycles. In Cycle 1, CR rates were 98.9% during the acute phase, 94.0% during the delayed phase and 92.3% during the overall phase. Across Cycles 2–4, the overall CR rate remained stable, ranging from 93.8 to 95.1%, indicating sustained antiemetic protection without evidence of tachyphylaxis.

Table IV.

Extended efficacy of NEPA plus dexamethasone in CRC patients receiving MEC (n=120).

Outcome	Patients (n, %)
Complete response	116 (96.6)
Complete control	110 (91.6)
Complete protection	101 (84.2)
Rescue medication use	2 (1.7)

Complete response: No vomiting and no rescue use; Complete control: No significant nausea, no vomiting and no rescue use; Complete protection: No nausea, no vomiting and no rescue use; CRC, colorectal cancer; MEC, moderately emetogenic chemotherapy; NEPA, netupitant-palonosetron.

Safety

NEPA in combination with dexamethasone demonstrated a favorable tolerability profile. Treatment-related adverse events (TRAEs) were reported in 46 of 182 patients (25.3%), all of which were grade 1 or 2. No grade 3 or 4 TRAEs were observed. Constipation was the most frequently reported TRAE, occurring in 20 patients (11.0%), including grade 1 events in 17 patients (9.3%) and grade 2 events in 3 patients (1.6%). Fatigue was reported in 10 patients (5.5%), including grade 1 events in 8 (4.4%) and grade 2 events in 2 (1.0%). Headache occurred in 4 patients (2.2%), with all cases classified as grade 1. Less frequent TRAEs included hiccup (3, 1.6%), dizziness (3, 1.6%), abdominal discomfort (2, 1.0%), urticaria (2, 1.0%), abdominal pain (1, 0.5%) and dyspepsia (1, 0.5%); all of these events were grade 1 in severity. Detailed safety data are provided in Table V.

Table V.

Adverse events of NEPA plus dexamethasone in CRC patients receiving MEC (n=182).

Adverse events	Any grade (n, %)	Grade 1	Grade 2	Grade 3/4
Any TRAEs	46 (25.3)	46 (25.3)	0	0
Constipation	20 (11.0)	17 (9.3)	3 (1.6)	0
Fatigue	10 (5.5)	8 (4.4)	2 (1.0)	0
Headache	4 (2.2)	4 (2.2)	0	0
Hiccup	3 (1.6)	3 (1.6)	0	0
Dizziness	3 (1.6)	3 (1.6)	0	0
Abdominal discomfort	2 (1.0)	2 (1.0)	0	0
Urticaria	2 (1.0)	2 (1.0)	0	0
Abdominal pain	1 (0.5)	1 (0.5)	0	0
Dyspepsia	1 (0.5)	1 (0.5)	0	0

TRAEs, treatment-related adverse events; CRC, colorectal cancer; MEC, moderately emetogenic chemotherapy; NEPA, netupitant-palonosetron.

Discussion

Although NEPA is widely recommended for preventing CINV in patients receiving HEC, its role in high-risk patients undergoing MEC has not been extensively investigated. Notably, the present study was descriptive and designed to evaluate the efficacy and safety of NEPA combined with dexamethasone in high-risk patients with CRC receiving MEC. Because no control group was included, the findings do not permit conclusions regarding the comparative efficacy or superiority of NEPA relative to other antiemetic regimens. High-risk factors considered in the present study included younger age, female sex, no alcohol consumption, history of motion sickness and pregnancy-related vomiting (12). Patients treated with the mFOLFOXIRI regimen received CINV prophylaxis according to MEC guidelines. Among these patients, 9.9% identified as having high-risk factors received NEPA combined with dexamethasone. The results demonstrated that this combination was highly effective and well tolerated in preventing CINV. During the overall phase (0–120 h), CR, CC and CP rates were 94.5, 91.2 and 76.3%, respectively. These outcomes underscore the substantial antiemetic efficacy of NEPA, particularly during the first 24 h after chemotherapy, and support its use in high-risk patients with CRC receiving MEC. Although these findings are consistent with the established efficacy profile of NEPA in broader MEC populations, the present study provides dedicated evidence in a previously underrepresented subgroup of high-risk patients with CRC receiving standard MEC regimens. To the best of our knowledge, the present study is the first to report extended efficacy of NEPA during the 120–168 h period in this specific population and the first to systematically evaluate its effectiveness across multiple chemotherapy cycles in patients with CRC enriched for established CINV risk factors.

Previous studies have reported variable efficacy among different antiemetic regimens in patients receiving MEC (13,14). Notably, a comparative trial demonstrated that palonosetron plus aprepitant without dexamethasone achieved superior outcomes compared with palonosetron plus dexamethasone in patients with CRC receiving MEC, with significantly higher CR rates in the overall phase (88.8 vs. 74.2%; P=0.0010) and delayed phase (90.6 vs. 75.5%; P<0.0001), whereas efficacy in the acute phase was comparable between the two regimens (93.8 vs. 93.5%; P=0.94) (15). In a previous investigation involving high-risk patients with gastrointestinal cancer receiving MEC, the addition of olanzapine to 5-HT₃ RA and dexamethasone significantly improved outcomes compared with 5-HT₃ RA combined with dexamethasone alone. The triple regimen resulted in higher CR rates during the delayed (75.0 vs. 54.7%; P=0.044) and overall phases (70.0 vs. 47.2%; P=0.028), as well as improved CC rates (62.5% vs. 39.6%; P=0.029) (16). Building on these findings, the present study evaluated the efficacy of NEPA plus dexamethasone for preventing CINV in high-risk patients with CRC receiving MEC, with olanzapine permitted as rescue medication when necessary.

The NEPA plus dexamethasone regimen demonstrates high efficacy in preventing CINV, with effective symptom control, a favorable safety profile and cost-effectiveness supporting its use as a NEPA-based strategy for CINV management. Subgroup analyses further suggest particularly strong efficacy of NEPA in patients receiving MEC (17). Several studies have evaluated the efficacy of NEPA for CINV prevention in the MEC setting. A multicenter study conducted in India reported high efficacy of NEPA combined with dexamethasone in patients receiving MEC, with CR rates of 96.9, 96.9 and 95.4%, CC rates of 81.5, 86.1 and 76.9%, and CP rates of 90.8, 95.4 and 87.7% during the acute, delayed, and overall phases, respectively (18). Another study assessing the NEPA plus dexamethasone regimen for preventing CINV in patients receiving non-anthracycline cyclophosphamide MEC regimens reported CR rates of 85.0, 91.2 and 76.1% in the acute, delayed, and overall phases, respectively, with superior efficacy compared with aprepitant-based combination regimens (19). In the present study, CR rates were 98.9, 95.6 and 94.5%, and CC rates were 98.9, 92.3 and 91.2% during the acute, delayed and overall phases, respectively. CP rates were 98.9% in the acute phase but declined to 78.0% in the delayed phase, resulting in an overall CP rate of 76.3%. Notably, a clinically significant 20.9% reduction in CP rates was observed between the acute and delayed phases, indicating a greater challenge in sustaining full symptom control during the later post-chemotherapy period. The relatively lower CP rates observed in the delayed phase may be attributed to the fact that nearly half of the enrolled patients received capecitabine-based regimens. Capecitabine requires 2 weeks of oral administration, which is associated with an inherently increased risk of nausea during treatment and contributes to the observed reduction in CP rates during the delayed phase. The study population also comprised high-risk patients who were intrinsically more susceptible to nausea. This baseline susceptibility was further exacerbated by the gradual attenuation of the anti-inflammatory effect of single-day dexamethasone during the delayed phase, together with additional contributing factors such as continuous oral capecitabine administration. Collectively, these factors explain the decline in CP rates over time. Future studies may consider incorporating low-dose dexamethasone or olanzapine on days 2–3 to improve control of delayed-phase nausea. By contrast, NEPA combined with dexamethasone demonstrated superior efficacy in the acute phase, with a CP rate of 98.9%. Across multiple cycles in patients receiving MEC, oral NEPA-based therapy demonstrated CR rates of 93.2–97.2% in the acute phase and 81.7–91.7% in the delayed phase, indicating sustained antiemetic efficacy (20). Consistent with these findings, the combination of NEPA and dexamethasone demonstrated stable efficacy in preventing CINV across multiple cycles, with overall CR rates of 92.3–95.1%. Within the meta-analysis of patients receiving MEC, 167 cases (24%) experienced prolonged delayed nausea beyond 120 h, while 42 cases (6%) experienced prolonged delayed vomiting beyond 120 h. Although less frequent than standard delayed nausea and vomiting, prolonged delayed CINV affects a clinically meaningful proportion of patients with comparable severity. Patients experiencing delayed CINV, particularly during days 4–5, may be at increased risk of prolonged delayed CINV (21). However, the long-term effectiveness of NEPA in preventing CINV remains unclear. In the present study, between 120 and 168 h after chemotherapy, the overall CR, CC and CP rates remained clinically meaningful at 96.6, 91.6 and 84.2%, respectively, indicating sustained long-term prevention of CINV with the combination of NEPA and dexamethasone in patients with CRC receiving MEC. Additionally, the identical CR and CP rates in the acute phase (both 98.9%) warrant careful interpretation. Although this finding reflects a strong antiemetic effect of NEPA within the first 24 h, such complete concordance is statistically uncommon in routine clinical settings. Several factors may contribute to this observation. First, transient mild nausea (VAS 1–3) may have been underreported due to recall bias associated with retrospective diary collection. Second, the combination of single-day high-dose dexamethasone (12 mg) and NEPA may suppress the majority of nausea in the acute phase; however, the absence of any mild nausea in 180 of 182 patients remains notable. Third, the binary classification of nausea (present/absent) based on the VAS, with ‘no nausea’ strictly defined as VAS 0, may have reduced sensitivity for detecting very mild symptoms that did not reach the threshold for patient reporting. Prospective studies using real-time electronic diaries or daily patient-reported outcome measures are required to generate more granular data to validate or refine this observation. Overall, in conjunction with existing evidence, these findings suggest that NEPA combined with dexamethasone is an effective regimen for reducing the incidence of CINV in high-risk patients with CRC receiving MEC.

The safety profile of NEPA plus dexamethasone was favorable in this high-risk CRC population. TRAEs occurred in 46 of 182 patients (25.3%), all of which were grade 1 or 2, and no grade 3 or 4 events were reported. Constipation was the most common TRAE, occurring in 11.0% of patients, including grade 1 events in 9.3% and grade 2 events in 1.6%. The observed incidence of constipation may be attributable to the known gastrointestinal effects of the regimen's individual components. Netupitant possesses mild anticholinergic properties that can slow gastrointestinal transit, whereas palonosetron, a 5-HT₃ RA, is independently associated with constipation. Consistent with these pharmacologic effects, a pharmacokinetic study conducted in healthy Chinese volunteers reported constipation incidences of 4.2% with netupitant and 7.1% with palonosetron when administered separately (22). Furthermore, oxaliplatin, which constituted the backbone of most chemotherapy regimens in the present study (90.1% of patients), has been reported to induce enteric neuropathy and colonic dysmotility through oxidative stress pathways, thereby directly contributing to constipation (23). Additional evidence supporting the favorable tolerability of NEPA has been reported in a recent study evaluating single low-dose dexamethasone (6 mg) plus NEPA for CINV prevention in mixed MEC/HEC populations. In that study, constipation occurred in 4.4% of patients receiving NEPA combined with dexamethasone (6 mg), with no grade 3 events and no treatment discontinuations (24). The higher incidence observed in the present study (11.0%) may be attributable to the predominance of oxaliplatin-based chemotherapy (90.1%), the inclusion of oral capecitabine in 48.9% of patients and the use of a higher single-day dexamethasone dose (12 mg). Continuous administration of capecitabine over 2 weeks may further exacerbate gastrointestinal adverse effects. Notably, no grade 3 or 4 constipation was observed and no patient discontinued antiemetic prophylaxis or chemotherapy because of this event. All cases of constipation were successfully managed with dietary modifications or oral laxatives, indicating that constipation associated with this regimen is predictable and clinically manageable. Beyond antiemetic prophylaxis, other supportive care strategies have been investigated to improve treatment tolerability in patients with CRC receiving oxaliplatin-based chemotherapy. A recent meta-analysis suggested that the addition of cinobufacini capsules to oxaliplatin-based regimens may enhance tumor response and reduce certain chemotherapy-related toxicities (25). However, the role of such complementary therapies in preventing CINV remains unclear and warrants further investigation.

The findings of the present study have important implications for clinical practice and future guideline development. The simplified regimen consisting of a single dose of NEPA combined with a single day of dexamethasone is consistent with current MASCC/ESMO recommendations for high-risk patients receiving MEC who require triple antiemetic therapy. In addition, this approach offers greater convenience and may enhance treatment adherence compared with conventional multi-day regimens. The consistently high efficacy observed across several high-risk subgroups suggests that this regimen may provide particular benefit for vulnerable populations that are frequently underrepresented in clinical trials. In real-world clinical settings, administration of a single oral dose of NEPA combined with a single intravenous dose of dexamethasone eliminates the need for multi-day oral medication regimens, thereby substantially reducing pill burden and minimizing the need for additional outpatient visits. These advantages are especially relevant for patients receiving chemotherapy in community-based settings, where simplified treatment schedules may improve adherence while reducing healthcare resource utilization. Consequently, these findings may contribute to future guideline revisions that explicitly include NEPA as a treatment option for high-risk patients with CRC receiving MEC. Nevertheless, prospective randomized trials are required to confirm these hypothesis-generating findings.

The present study has several limitations that warrant consideration. First, the present study was a single-arm retrospective analysis conducted without a contemporaneous control group. Consequently, no conclusions can be drawn regarding the superiority or incremental benefit of NEPA compared with standard antiemetic regimens, including 5-HT₃ RA plus dexamethasone or aprepitant-based triplet therapy. Accordingly, the findings should be interpreted as descriptive and hypothesis-generating rather than comparative. Second, the retrospective design is inherently susceptible to selection bias. In addition, the extended efficacy analysis (120–168 h) was restricted to 120 patients (66%) with complete 7-day records, potentially introducing further bias. Third, the single-center design limited the generalizability of the findings. Fourth, although sensitivity analysis indicated that the inclusion of mFOLFOXIRI (9.9%), classified as HEC by certain guidelines, did not materially influence efficacy outcomes, its inclusion constitutes a source of clinical heterogeneity. Fifth, patient-reported quality-of-life data were not collected; therefore, the effect of this regimen on patients' overall quality of life could not be evaluated. Sixth, no pharmacoeconomic assessment was conducted; consequently, the cost-effectiveness of NEPA combined with dexamethasone relative to alternative antiemetic regimens remains uncertain. Prospective randomized controlled trials incorporating appropriate comparator groups are urgently required to validate these findings.

In conclusion, this single-arm retrospective study demonstrated that the combination of NEPA and dexamethasone was associated with high response rates and favorable tolerability for preventing CINV in high-risk patients with CRC receiving MEC. Nevertheless, in the absence of a concurrent control group, these findings do not establish superiority over standard antiemetic regimens and should therefore be interpreted as preliminary. Although NEPA combined with dexamethasone may represent a potentially valuable therapeutic option in this clinical setting, its routine clinical adoption should await confirmation in prospective randomized controlled trials directly comparing it with current guideline-recommended therapies.

Funding Statement

This work was supported by Bethune Charitable Foundation, Shenzhen Science and Technology Program (grant nos. JCYJ20250604183713018, KCXFZ20200201101050887 and ZDSYS20190902092855097) and Shenzhen San-Ming Project of Medicine (grant nos. SZSM202211036 and 202411004), Shenzhen High-level Hospital Construction Fund and Peking University Shenzhen Hospital Scientific Research Fund.

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

JF, WL, BC, MC, JG, SW and GT contributed to the study's conception and design. JF conceived the study and wrote the first draft of the manuscript. WL and BC designed the experiment and revised the manuscript. MC, JG, SW and GT conducted the experiments and analyzed the data. All authors commented on previous versions of the manuscript. JF and GT confirm the authenticity of all the raw data. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

The present study was approved by the Ethics Committee of the Peking University Shenzhen Hospital [Shenzhen, China; approval no. (2024) No. (175)]. Written informed consent was obtained from all participants in accordance with the national legislation and institutional requirements.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.