The safety and efficacy of NEPA in preventing postoperative nausea and vomiting after general anesthesia during gastrointestinal cancer surgery: a single-center retrospective study

Introduction

The digestive system is susceptible to a variety of malignancies, including gastric, liver, pancreatic, and colorectal cancers. These cancers are globally prevalent and have a significant impact on public health. According to the latest Global Cancer Statistics, gastrointestinal (GI) tumors rank among the highest in terms of incidence and mortality across all cancer types (1). In China, 2024 cancer statistics estimate that approximately 4.82 million new cancer cases and 2.57 million cancer deaths occurred in 2022 alone. Colorectal, gastric, and liver cancers are among the top five cancers in terms of both incidence and mortality and pose severe threats to public health (2). Despite continuous advancements in cancer treatment, including targeted therapies and immunotherapies, surgery remains the primary and most effective treatment for GI malignancies (3).

As anesthesia technology and safety have advanced, interest in the management of complications that may arise after surgery with anesthesia has increased (4). Postoperative nausea and vomiting (PONV) is a frequently encountered complication that often manifests following surgical procedures. It is regarded as a substantial undesirable response that presents difficulties for health care providers and individuals throughout the period surrounding the surgery. In addition, it has a noteworthy influence on how satisfied patients are with their medical treatment (5). Despite the implementation of different categories of novel antiemetics within the past quarter-century, the issue of PONV continues to be a notable concern throughout the perioperative period (6). Earlier investigations have demonstrated that the occurrence of PONV varies from 30% to 80% and is influenced by multiple variables, including patient-related factors, surgical procedures, and the administration of anesthesia (7). Patients who undergo surgery for GI cancer treatment and patients who are at high risk have relatively high incidence rates.

Study has shown that specific patient populations, such as females, younger patients, and those with a history of motion sickness or PONV, are particularly susceptible to developing PONV (8). Recent research has also revealed the influence of different anesthetic techniques and agents on PONV occurrence. Compared with inhalational anesthesia, total intravenous anesthesia (TIVA) has been found to significantly reduce PONV rates, thus providing an alternative strategy for high-risk patients (9). Moreover, multimodal PONV prophylaxis, which combines antiemetics of different classes, has gained traction as the most effective approach for managing this condition (10). Although PONV is self-limiting, it represents one of the most prevalent complications that can occur subsequent to general anesthesia (11). Accordingly, it can give rise to a sequence of undesirable consequences. In addition to diminishing patient satisfaction, it can induce complications pertaining to acid‒base balance, electrolytes, and hydration. Aspiration, dehiscence of an incision, hemorrhage, incisional hernia formation, imbalance, and aspiration pneumonia, among other complications, result in extended hospital stays and increased health care costs (12). The “Guidelines for the Management of PONV (4th Edition)” published in August 2020 underscore the importance of effective PONV management strategies (13). In the context of enhanced recovery after surgery (ERAS) protocols, effective PONV management is particularly crucial to expedite patient recovery and reduce hospital length of stay (14). ERAS protocols integrate a combination of preoperative, intraoperative, and postoperative measures to optimize patient outcomes, and PONV prevention is a key element of this comprehensive approach (15). While various antiemetic agents have been introduced over the last few decades, achieving consistent and reliable control of PONV remains elusive. Recent studies have explored new antiemetic therapies to address the challenges associated with PONV (16).

This research aimed to provide a clinical reference for reducing the incidence of PONV and enhancing postoperative recovery in digestive tract tumor patients under general anesthesia, and evaluate the safety and efficacy of preoperative oral netupitant and palonosetron (NEPA) for preventing and treating PONV. By integrating the latest antiemetic agents and multimodal approaches within ERAS protocols, this study seeks to improve PONV management and patient outcomes in GI cancer surgery. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2193/rc).

Methods

Study design and population

The individuals included in this retrospective study, which was conducted from May to September 2023 at Tianjin Cancer Hospital Airport Hospital, were aged 18 years or older with pathologically confirmed GI malignancies slated for elective surgical interventions under the administration of general anesthesia. Individuals with a physical status of 1–2, as defined by the American Society of Anesthesiologists, met the eligibility criteria for inclusion. Patients who satisfied any of the following criteria were excluded: (I) local anesthesia; (II) pregnancy or lactation; (III) American Society of Anesthesiologists (ASA) grades III–IV; (IV) severe diseases of the heart, liver, and kidneys; (V) inability to consume oral medications or conditions that substantially impede their absorption, including chronic diarrhea and intestinal obstruction; (VI) factors that can induce regurgitation, including hypocalcemia; (VII) any known or prospective use of antiemetic medications within 24 hours prior to the operation or encountered symptoms of vomiting, retching, or mild nausea; (VIII) administered CYP3A4 substrates or formidable to moderate CYP3A4 inhibitors within the seven days leading up to the scheduled surgical intervention and CYP3A4 inducers no earlier than 4 weeks prior to surgery; (IX) anaphylactic reactions to capsules containing NEPA or any excipients derived from it; and (X) opioid analgesic intake within twenty-four hours prior to surgery. Furthermore, an extensive training program was devised by the project leader to guarantee the comprehension and familiarity of all participants with the clinical protocol prior to the commencement of the clinical study. A total of 45 patients consented to participate in this investigation (Figure 1). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Research Ethics Board of Tianjin Cancer Hospital Airport Hospital (No. LWK-2024-0002), in compliance with relevant Chinese regulations governing clinical research.

Figure 1 Flow chart of study design and population. ASA, American Society of Anesthesiologists; NEPA, netupitant and palonosetron; PONV, postoperative nausea and vomiting.

Assessments and safety evaluations

For three consecutive days following the surgical procedure, patients were instructed to assess the severity of postoperative symptoms via a visual analog scale (VAS), ranging from 0 to 10, with 10 representing the most intense symptoms. This assessment encompassed various parameters, including the degree of nausea and vomiting, feelings of satiety, epigastric discomfort, gastric heaviness, regurgitation, and difficulties in consuming liquids and solids. Patient safety was meticulously monitored throughout the trial, with any adverse events or serious complications reported and documented. Safety evaluations included regular monitoring of vital signs, physical examinations, and laboratory tests. To ensure accurate tracking of medication use, patients were provided with a diary to record all medications taken during the trial period, facilitating thorough documentation of treatment adherence and overall medication intake.

Statistical analysis

Nonnormally distributed continuous variables are presented as medians with interquartile ranges, whereas normally distributed continuous variables are presented as the means with standard deviations (SDs). Categorical variables are reported as counts with percentages. The independent samples t-test was employed for comparing normally distributed continuous variables, and the Mann-Whitney U test was used for nonnormally distributed variables. Multivariate regression analyses were conducted to evaluate the factors influencing PONV occurrence, with the aim of identifying the independent effect of each variable. All the statistical analyses were carried out via R software (version 4.4.1), with a significance threshold set at P<0.05.

Safety

Throughout the treatment period, no significant adverse events were observed. A few patients experienced mild symptoms of constipation and abdominal distension, both of which were promptly managed and resolved without complications.

Results

The study initially enrolled 50 participants, but 5 were excluded due to prior use of local anesthesia or the presence of vomiting symptoms to ensure an accurate assessment of the antiemetic efficacy of the drugs being studied (four of these patients underwent local anesthesia, while one patient experienced vomiting 24 hours prior to surgery). The remaining 45 patients underwent GI tumor surgeries [laparotomy and radiofrequency ablation (RFA)] under general anesthesia (Table S1), comprising 13 women (29%) and 32 men (71%) (Table 1). The mean weight was 66.3±13.2 kg, and the average BMI was 23.1±4.2 kg/m² (Table S2). As part of the preoperative regimen, each patient received a single dose of 300 mg netupitant combined with 0.5 mg palonosetron hydrochloride at 8:00 PM the evening before surgery. Notably, all patients demonstrated excellent adherence to the prescribed nutritional guidelines throughout the study period. All patients successfully completed the study. For three consecutive days following the surgical procedure, we analyzed the correlations between patients’ basic clinical data [e.g., sex, age, body mass index (BMI)] and the number of postoperative vomiting episodes, as well as nausea scores, at different time intervals. In addition, regression models were constructed to identify and validate the factors influencing these clinical symptoms (Figures S1-S4). The results revealed that nonsmoking patients experienced significantly more vomiting episodes than smoking patients, and female patients had higher vomiting frequencies than male patients (Figure 2). Regarding nausea scores, nonsmoking patients were more likely to have elevated postoperative nausea scores, and this difference persisted over time. Most female patients consistently presented higher nausea scores than male patients at all time points (24, 48, and 72 hours postoperatively) (Figure 3). These findings align with the previously identified risk factors in the guidelines, further confirming the scientific validity and reliability of the guidelines. Within the 72-hour postoperative period, only 7 patients (15.5%) experienced vomiting. We assessed the efficacy of NEPA by examining the relationships between risk factors and the probability of postoperative PONV occurrence, as outlined in the guidelines. Our findings showed that the incidence of postoperative vomiting in patients treated with NEPA was significantly lower than the rates suggested by the guidelines. Specifically, the incidence was 0% with one risk factor, 13.33% with two risk factors, and 9.09% with three risk factors (Figure 4). Additionally, we evaluated VAS scores at different postoperative intervals: 62% of patients had a VAS score of 0–1 at 0–24 hours, whereas this score increased to 82% at 48–72 hours. In contrast, 20% of patients had a score of ≥4 at 0–24 hours, but this percentage decreased to only 4% at 48–72 hours (Figure 5). Symptom severity was evaluated with the VAS, and the results are expressed as the mean ± SD. On the day of surgery, the mean nausea score was 3.3±1.3, and by the third postoperative day, it had further decreased to 2.4±1.1, demonstrating a continued decline in nausea severity and effective symptom management (Table S3). Overall, after the preoperative administration of NEPA, the number of vomiting episodes and nausea scores were greater at 24 hours postoperatively, but both symptoms subsided significantly by 72 hours (Figure 6).

Figure 2 Relationship between smoking, sex, and postoperative vomiting episodes. (A,B) The effect of smoking or not smoking on the number of vomits at 24 and 48 hours postoperatively. (C,D) The effect of gender on the number of vomits at 24 and 48 hours postoperatively.

Figure 3 Relationship between smoking, sex, and postoperative nausea scores. (A-C) The effect of smoking or not smoking on nausea scores at 24, 48, and 72 hours postoperatively. (D-F) The effect of gender on nausea scores at 24, 48, and 72 hours postoperatively.

Figure 4 Vomiting situation within 24 hours after surgery in the guidelines group and NEPA intervention group according to different risk factors. The blue dashed line represents the incidence of vomiting according to guideline recommendations (guidelines). The orange dashed line represents the incidence of vomiting after NEPA treatment. Data for the control group are derived from the fourth consensus guidelines for the management of postoperative nausea and vomiting (13). NEPA, netupitant and palonosetron.

Figure 5 Temporal evolution of VAS scores during the initial 3 postoperative days. The Y-axis represents the percentage of patients classified into different VAS score ranges (0–1, 2–3, ≥4). VAS, visual analog scale.

Figure 6 Number of vomiting episodes and nausea scores over time in the postoperative period with NEPA treatment. (A) The change in the number of vomits over time (days 1, 2, and 3). (B) The change in the nausea score over time (days 1, 2, and 3). The red squares represent the average nausea score at each time point and the dotted lines connect the time points to show the trend of nausea score over time. Solid pink lines mean trend line, the trend in the mean change of all individuals at different time points (days 1, 2, and 3). NEPA, netupitant and palonosetron.

Discussion

Globally, GI cancers account for approximately one quarter of all cancer cases and over one third of cancer-related deaths (17). Surgical resection remains the primary curative treatment for many GI malignancies, improving patient prognosis and relieving symptoms (3). However, PONV, occurring within 24 hours after surgery, remains a common complication, with incidence rates ranging from 30% to 80%, depending on patient risk factors and surgical procedures (18). PONV delays recovery, extends hospital stays, increases health care costs, and can lead to severe complications such as aspiration pneumonia, electrolyte imbalances, and incision dehiscence (19). With the increase in ambulatory surgeries, addressing PONV has become increasingly critical.

The pathophysiology of PONV is complex and involves neurotransmitters such as 5-HT3, dopamine (D2), and NK1 receptors, which are key targets for antiemetics (20). While drugs such as 5-HT3 antagonists (e.g., ondansetron) and NK1 antagonists (e.g., aprepitant) are available, many patients still experience PONV. Ondansetron is effective for acute nausea but not for delayed symptoms, and aprepitant use is limited by dosing complexity. For example, Alam et al. reported that ondansetron reduced nausea within the first 2 hours after surgery, but its effectiveness decreased after 12 hours, with 27.5% of patients still experiencing nausea (21). Staubitz and Alfonso reported that aprepitant outperformed ondansetron in reducing vomiting episodes up to 48 hours post-surgery, although its use is limited by the complexity of oral dosing in fast-paced settings (22). Further studies have sought to explore the combination of these antiemetics to maximize their efficacy. Padilla and Habib reported that combining aprepitant with ondansetron significantly reduced vomiting rates to 9.3% compared with 29.7% with ondansetron alone (20). These findings suggest that a multimodal antiemetic approach could be more effective in high-risk PONV patients. However, it should be noted that such combinations may increase the complexity of clinical protocols, thus requiring further studies to assess the cost-effectiveness and practical implications of using these regimens.

NEPA is a combination of netupitant (NK1 antagonist) and palonosetron (second-generation 5-HT3 antagonist), and its success in preventing chemotherapy-induced nausea and vomiting (CINV) also suggests its prolonged efficacy in preventing PONV (23). A post hoc analysis by Zelek et al. reported that NEPA provided significant protection against CINV up to 144 hours after chemotherapy administration, particularly in high-risk patients such as females and those receiving carboplatin (24). This extended protection through both the acute and delayed phases is crucial for patient comfort during the perioperative period, highlighting the potential efficacy of NEPA beyond the traditional 120-hour window (25). Thus, NEPA has emerged as a promising treatment for PONV. With longer half-lives, NEPA offers extended protection, outperforming traditional antiemetics such as ondansetron. Our study has shown that NEPA significantly reduces PONV, with only 15.5% of patients experiencing vomiting within 72 hours post-surgery. Recent studies have shown that the fixed-dose combination of NEPA simplifies administration, improving patient compliance and reducing missed doses, which is an issue with complex regimens such as aprepitant (26).

According to the fourth edition of the consensus guidelines for the management of PONV, the Apfel risk score provides a simplified yet reliable method for assessing PONV risk in adults. This scoring system assigns one point for each of the following factors: female sex, nonsmoking status, history of PONV or motion sickness, and use of postoperative opioids (13). Based on these risk factors, patients are stratified into groups with a PONV risk ranging from 10% to 80%, depending on their score. In our cohort of 45 patients, the majority presented Apfel scores between 1 and 3, with corresponding risks of PONV ranging from 20% to 60%. Our study revealed that the number of vomiting episodes (Figure 2) and nausea scores (Figure 3) were significantly greater in nonsmokers and female patients than in smokers and male patients. Notably, female patients experienced more severe symptoms at 24 and 48 hours postoperatively, which aligns with the literature indicating that females are at greater risk for PONV. Similarly, nonsmokers presented more symptoms across all postoperative time periods, suggesting that smoking may have a protective effect against PONV. In addition to the influence of known risk factors, we further analyzed the incidence of PONV in patients who underwent RFA under general anesthesia. Among the 45 patients, 12 (8 males, 4 females) underwent RFA, and only one female patient (25%) experienced vomiting within 24 hours post-procedure (Table S4). This incidence is notably lower than the expected PONV rates based on Apfel risk stratification, where all female patients had an Apfel score of 3, indicating a moderate-to-high risk. Given that general anesthesia is a well-documented risk factor for PONV, the observed lower-than-expected incidence suggests that NEPA may have contributed to effective PONV prevention in this subgroup (Figure S5). Also, the absence of severe postoperative pain may have played a role in minimizing PONV occurrence, as higher pain levels are known to exacerbate nausea and vomiting through increased sympathetic activation and opioid use (27). In this study, all 12 patients exhibited a reduction in their VAS scores to <4 within 24 hours postoperatively. These findings underscore the need for further prospective studies to evaluate the independent efficacy of NEPA across different surgical procedures and PONV risk categories. A more comprehensive understanding of antiemetic prophylaxis in diverse patient populations and procedural settings will be crucial for optimizing PONV prevention strategies in clinical practice. Specifically, we explored the significant role of NEPA in alleviating clinical symptoms. Temporal changes in the VAS score revealed a progressive decrease in the extent of nausea and vomiting over time (Figure 5). The percentage of patients with VAS scores between 0–1 increased from 62% at 0–24 hours to 82% at 48–72 hours, whereas the percentage of patients with VAS scores of 4 and above decreased from 20% to just 4% by the 48–72-hour time point. These findings indicate that NEPA is highly effective in managing PONV, with notable relief at 72 hours post-surgery. Side effects, such as constipation, bloating, and headache, were mild and consistent with other studies, supporting the safety profile of NEPA (28). A pooled analysis of phase II/III trials by Aapro et al. confirmed the favorable safety profile of NEPA, with mild TEAEs such as headaches and constipation in 2% of cases and rare serious cardiac events, even in patients with cardiac risk factors (29).

NEPA has been shown to significantly improve postoperative quality of life by reducing PONV, leading to faster recovery and fewer disruptions to daily activities than traditional antiemetics. This highlights its broader benefits beyond symptom control, enhancing overall patient satisfaction. For example, Zhang et al. conducted a retrospective case-control study evaluating NEPA in patients undergoing video-assisted thoracoscopic surgery (VATS) for lung cancer. Compared with ondansetron, NEPA significantly reduced both the incidence and severity of PONV, with a PONV incidence of 21% in the NEPA group compared with 29% in the control group (30). Similarly, in high-risk bariatric surgery, where PONV rates can reach 80%, NEPA has proven more effective than traditional antiemetic protocols. Schumann et al. reported that NEPA reduced the need for rescue antiemetics and shortened post-anesthesia care unit (PACU) discharge times in bariatric surgery patients, confirming its superior efficacy in this high-risk population (31). In our study, the comparison of risk factors and postoperative vomiting rates highlighted the effectiveness of NEPA. Regardless of risk factors, patients treated with NEPA had lower vomiting rates than those in the guideline group (Figure 4). For patients with one risk factor, the NEPA group had a 0% vomiting rate, whereas the vomiting rate was 20% in the guideline group. Even for those with two or three risk factors, NEPA reduced vomiting rates to 13.33% and 9.09%, respectively. Paired dot plots (Figure 6) revealed that vomiting and nausea peaked within 24 hours postop but declined over 48 to 72 hours. By 72 hours, most patients experienced significant symptom relief, with nausea scores decreasing from 4 to 2. This highlights the efficacy of NEPA in managing both acute and delayed PONV, which is crucial for facilitating patient comfort and early discharge.

Although promising, more clinical data on the use of NEPA for PONV are needed, especially in larger studies and specific subpopulations. Our findings suggest that NEPA is a convenient and effective alternative to traditional regimens because its dual-action mechanism and single-dose administration provide lasting protection. Future research should expand on these results and explore their long-term impact on quality of life. NEPA’s integration into multimodal PONV strategies, including ERAS protocols and corticosteroids, enhances its effectiveness and supports a more holistic approach to PONV management (32).

Mechanistic action of netupitant (300 mg)/palonosetron hydrochloride (0.5 mg)

The fixed-dose combination drug netupitant/palonosetron hydrochloride (NEPA) integrates two key active ingredients, offering dual mechanisms that target the primary pathways involved in nausea and vomiting (Figure 7). Netupitant is a selective antagonist of NK1 receptors, which are primarily activated by the neuropeptide substance P, a significant player in triggering emesis. Blocking NK1 receptors in both the brainstem and the GI tract significantly mitigates vomiting, especially in the delayed phase. Palonosetron, a second-generation 5-HT3 receptor antagonist, exhibits potent action against serotonin, the main neurotransmitter responsible for the initiation of nausea and vomiting in the acute phase (33). Recent studies highlight the synergistic effects of these two mechanisms, where the combination of NK1 receptor antagonism and 5-HT3 receptor blockade provides superior efficacy in preventing nausea and vomiting across both the acute and delayed phases (34-36). Compared with earlier 5-HT3 antagonists, such as ondansetron, palonosetron is unique because of its higher binding affinity and extended half-life (approximately 48 hours), as well as its prolonged receptor inhibition through allosteric interactions, enabling sustained efficacy, particularly for delayed nausea (37). In addition to prolonged receptor inhibition, palonosetron has been shown to trigger receptor internalization, which prevents receptor reactivation, further enhancing its antiemetic efficacy (38). Netupitant, however, has an even longer half-life, approximately 90 hours, and demonstrates robust NK1 receptor occupancy (approximately 92.5% within 6 hours and 76% after 96 hours), which ensures sustained protection against delayed vomiting (39). Research has demonstrated that netupitant not only effectively blocks NK1 receptors but also results in high receptor occupancy in multiple brain regions, including the striatum and occipital cortex, which are essential for mitigating the neural signaling pathways associated with delayed emesis (38). This combination is particularly beneficial for preventing both acute and delayed nausea and vomiting associated with highly and moderately emetogenic chemotherapy, and its effectiveness in PONV management is being increasingly recognized.

Figure 7 Mechanism of postoperative PONV and the action of NEPA therapy [created in BioRender. (2025) https://BioRender.com/pz3qlo9]. 5-HT3, 5-hydroxytryptamine type 3; NEPA, netupitant and palonosetron; NK1, neurokinin 1; PONV, postoperative nausea and vomiting.

Conclusions

The present study demonstrated a lower incidence of postoperative symptoms than the other studies, demonstrating its safety and efficacy. Our findings suggest that the single-pill formulation of NEPA is both patient friendly and easy to administer. These findings can provide valuable insights for clinicians in selecting appropriate antiemetic therapies. Future studies with larger samples will further confirm the efficacy and safety of NEPA in managing PONV in patients undergoing general anesthesia for GI cancer surgery.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2193/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2193/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2193/prf

Funding: This research received financial support from the Scientific Research Plan Project initiated by the Tianjin Municipal Education Commission (No. 2022ZD066).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2193/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Research Ethics Board of Tianjin Cancer Hospital Airport Hospital (No. LWK-2024-0002), in compliance with relevant Chinese regulations governing clinical research. Informed consent was taken from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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