A study on the efficacy and safety of aprepitant injection in preventing and treating nausea and vomiting induced by platinum‐based chemotherapy in lung cancer

This study aimed to assess the clinical efficacy and safety of aprepitant injection in preventing and treating nausea and vomiting induced by platinum‐based chemotherapy in lung cancer patients. Forty‐eight patients with advanced first‐line lung cancer undergoing cisplatin‐ or carboplatin‐based chemotherapy were randomly assigned to either the experimental group or the control group, with 24 patients in each group. The control group received dexamethasone and palonosetron for vomiting prevention, whereas the experimental group received dexamethasone, palonosetron, and aprepitant injection. The study compared the incidence of acute and delayed vomiting, functional life index (FLIE) scores for nausea and vomiting at 24 and 120 h postchemotherapy and the occurrence of adverse drug reactions between the two groups. The effective control rate of acute‐phase vomiting in the treatment group was 83.33%, significantly higher than 45.83% in the control group, with a statistically significant difference (p < .05). The treatment group also demonstrated a higher effective control rate of delayed vomiting, with 75% compared with 41.67% in the control group, which was statistically significant (p < .05). Furthermore, FLIE scores in the treatment group at 24 and 120 h after chemotherapy were higher compared with the control group, with a statistically significant difference (p < .05). The incidence of complications such as fatigue, headache, dyspepsia, anorexia, hiccup, and constipation showed no significant difference between the two groups (p > .05). Aprepitant injection effectively prevents platinum‐based chemotherapy‐induced nausea and vomiting, enhances patients' quality of life, and demonstrates good safety, justifying its clinical adoption.

treatment can lead to nausea and vomiting symptoms in over 90% of patients who use cisplatin and area under curve (AUC) ≥4 carboplatin 3 and may even cause patients to interrupt treatment or delay the treatment process.Therefore, preventing and treating CINV is crucial for lung cancer patients.At present, multiple international and domestic guidelines have recommended various plans and drugs for the prevention and treatment of CINV, including 5-hydroxytryptamine-3 receptor antagonist (5-HT3 RA), neurokinin-1 receptor antagonist (NK-1 RA), glucocorticoids, and benzodiazepines. 4,5Although these drugs have achieved certain results, a common pathway that induces vomiting response has not been found, so there is no drug that can completely block different types of nausea and vomiting.Clinically, combination therapy is often used, and clinical needs have not been met. 6Therefore, further research and development of new drugs are of great significance for improving the treatment efficacy and quality of life of lung cancer patients.
Aprepitant is a selective and high-affinity NK-1 RA that exerts its action by blocking the binding of substance P to the NK-1 receptor, effectively preventing acute-phase (0-24 h) and delayed-phase (25-120 h) chemotherapy-induced nausea and vomiting. 7The oral capsule formulation of aprepitant has been extensively studied and applied.However, for patients unable to tolerate oral administration, the impracticality of oral formulations is a crucial issue.In certain scenarios, such as instances of vomiting or pain, patients may struggle to retain the medication within their system, leading to the complete expulsion of the drug and consequently affecting absorption.
Fosaprepitant injection, a precursor to aprepitant, demonstrates equivalent bioequivalence to aprepitant within the human body.
Nevertheless, a distinguishing factor lies in the inclusion of polysorbate 80 in fosaprepitant-a synthetic nonionic surfactant commonly employed in food, cosmetics, and pharmaceutical formulations as a solubilizer, stabilizer, or emulsifier.Polysorbate 80 is not an inert compound and is implicated in numerous systemic and infusion-site adverse events.The current intravenous administration of fosaprepitant is associated with an increased risk of allergic systemic reactions. 8To address these issues, aprepitant injection, as an innovative submicron emulsion formulation, 9 was approved for marketing in October 2022.Aprepitant injection can be administered intravenously, offering advantages like rapid onset, good tolerability, and ease of dose control. 10Consequently, it holds promise for the management of emesis in malignancy.Nevertheless, the efficacy and safety data of aprepitant injection in the context of antiemetic therapy for lung cancer remain unclear.Therefore, this study aims to investigate the efficacy and safety of aprepitant injection in preventing and treating chemotherapy-induced nausea and vomiting in lung cancer patients receiving cisplatin chemotherapy, with the goal of providing patients with more effective and safer antiemetic treatment strategies.

| Study design
The innovation of aprepitant injection lies in its unique formulation.In contrast to other injectable NK-1 RAs, such as fosaprepitant, aprepitant injection is formulated without polysorbate 80 and synthetic surfactants.This distinctive composition minimizes the risk of adverse reactions associated with these components.As an NK-1 RAinjectable emulsion, aprepitant offers improved tolerability, presenting a valuable augmentation to current antiemetic strategies.Aprepitant injection has recently received approval for use in the Chinese region.
However, there is a lack of studies on the efficacy and safety of aprepitant injection in the Chinese population.This recent approval provides a unique opportunity to explore its effectiveness and safety in this specific demographic.
This study was designed as a prospective, single-center, randomized, single-blind, positive-drug controlled trial.

| Baseline information
A total of 48 advanced first-line lung cancer patients receiving platinum-based chemotherapy regimens, admitted to our hospital from December 2022 to February 2023, were randomly divided into two groups, the treatment group and the control group, with 24 patients in each group.This study has obtained approval from the Medical Ethics Committee of Nanjing Medical University, and informed consent was obtained from the patients and their families.

| Study methods
Both groups of patients received chemotherapy based on cisplatin (75 mg/m 2 , on the first day) or carboplatin (AUC = 5, on the first day).
Chemotherapy included paclitaxel liposome + cisplatin/carboplatin, albumin-bound paclitaxel + cisplatin/carboplatin, gemcitabine + cisplatin/ carboplatin, and pemetrexed + cisplatin/carboplatin.The Functional Living Index-Emesis (FLIE) assessed the impact of nausea and vomiting on the patients' quality of life. 11The scale included two subscales for nausea and vomiting.Each subscale comprised nine items, evaluating the severity of symptoms and their interference with daily life, including eating, drinking, recreational activities, housework, daily social interactions, and self-concern.Each item was scored using the Likert 0-7 scoring method, with higher scores indicating less impact on daily life.

| Observation indicators and efficacy evaluation
Adverse reactions: The study recorded the occurrence of fatigue, headache, dyspepsia, reduced appetite, hiccup, constipation, and other adverse reactions in both groups during the treatment.

| Statistical analysis
Assuming a control group complete response (CR) rate of 45% and an aprepitant group CR rate of 85%, with statistical power set at 80% and a two-sided significance level (α) for type I error of 5%, the estimated sample size is 42 participants (21 per group).To enhance the study's robustness, the sample size was expanded to 48 participants (24 per group).Data were processed using SPSS 26.0 statistical software.Continuous data were presented as x ± s, and t-tests were performed.Categorical data were presented as proportions (percentages), and chi-square tests were performed.A difference was considered statistically significant if p < .05.

| Baseline characteristics
In the treatment group, there were 14 males and 10 females, with ages ranging from 32 to 77 years (mean age 54.58 ± 12.69 years).ECOG performance scores were as follows: 21 patients scored 0-1, and 3 patients scored 2. There were six patients with a history of alcohol consumption, nine patients with a history of hyperemesis gravidarum, and five patients with a history of motion sickness.
In the control group, there were 15 males and 9 females, with ages ranging from 48 to 71 years (mean age 59.12 ± 8.16 years).ECOG performance scores were as follows: 20 patients scored 0-1, and 4 patients scored 2. There were 4 patients with a history of alcohol consumption, 7 patients with a history of hyperemesis gravidarum, and 6 patients with a history of motion sickness (Table 1).

| Comparison of acute phase vomiting control rate between the two groups
The treatment group exhibited a significantly higher effective control rate of acute-phase vomiting than the control group, and the difference between the two groups was statistically significant (p < .05)，asshown in Table 2.

| Comparison of delayed phase vomiting control rate between the two groups
The treatment group exhibited a significantly higher effective control rate of delayed phase vomiting than the control group, and the difference between the two groups was statistically significant ( p < .05),as shown in Table 3.

| Comparison of FLIE scores at 24 and 120 h after chemotherapy between the two groups
The treatment group had significantly higher FLIE scores at 24 and 120 h after chemotherapy compared with the control group, and the difference between the two groups was statistically significant ( p < .05),as shown in Table 4.

| Safety
The incidence rates of adverse reactions, including fatigue, headache, indigestion, reduced appetite, hiccups, and constipation were compared between the two groups.There were no statistically significant differences in these adverse reactions (p > .05),as shown in Table 5.

| DISCUSSION
CINV is one of the most common gastrointestinal toxic side effects during chemotherapy.Severe CINV can lead to dehydration, electrolyte imbalances, malnutrition, and further complications such as gastrointestinal bleeding and infections, which can be life-threatening.
The current standard antiemetic drugs are not very effective and significantly impact the patient's chemotherapy process and quality of Comparison of effective control rates of acute vomiting between the two groups.life.Currently, CINV is primarily prevented using a combination of 5-HT3 RA and dexamethasone, but they do not completely prevent CINV. 12Therefore, finding more effective methods for preventing and treating CINV is crucial.
CINV is caused by multiple factors and mechanisms, with the NK-1 receptor playing a critical role in the regulation of nausea and vomiting.The NK-1 receptor is a neuropeptide receptor widely distributed in various tissues and organs in the body, including the digestive system, central nervous system, and peripheral nervous system. 13In the medullary vomiting center, the NK-1 receptor has the highest concentration and a strong binding capacity with substance P, which can induce adverse reactions, such as nausea, vomiting, and migraines.In addition, the NK-1 receptor plays an important role in chemotherapy-induced chemical irritation and inflammatory responses. 14Therefore, regulating and controlling the NK-1 receptor is one of the important strategies for preventing and treating CINV.CINV induced by chemotherapy can be classified into acute and delayed phases.The acute phase usually occurs within the first 24 h after chemotherapy and is mainly related to the activation of 5-HT3 receptors in the peripheral and central nervous systems.The delayed phase usually occurs within 24 h to several days after chemotherapy and involves the participation of multiple neurotransmitters and receptors, with the NK1 receptor playing a particularly important role. 15Therefore, NK1 RA have a significant advantage in preventing delayed-phase vomiting. 16Consequently, international and national guidelines recommend the combined use of three or four drugs, including NK-1 RA, 5-HT3 RA, and dexamethasone, to control the occurrence of nausea and vomiting in highly emetogenic chemotherapy regimens. 17,18Currently, aprepitant is the only NK-1 RA approved for preventing moderate to high emetogenic chemotherapy regimens. 19However, the poor water solubility, first-pass metabolism, and low intestinal mucosal permeability of aprepitant capsules may reduce its bioavailability and limit its application.
In this study, 48 patients with advanced first-line lung cancer who received platinum-based chemotherapy were included.Twenty-four patients received a dual preventive antiemetic regimen with palonosetron injection and dexamethasone, whereas the other 24 patients received a triple preventive antiemetic regimen that included aprepitant injection in addition to the dual regimen.Nausea and vomiting were observed and assessed in patients within 24 h after chemotherapy and between 25 and 120 h after chemotherapy.The results showed that in the treatment group, 58.33% of patients did not experience vomiting during the acute phase, 25% had mild vomiting, 12.5% had moderate vomiting, and 4.17% had severe vomiting, resulting in an effective control rate of acute-phase vomiting of 83.33%.
This was significantly higher than in the control group ( p < .05).In the treatment group, 45.83% of patients did not experience vomiting during the delayed phase, 29.17% had mild vomiting, 16.67% had moderate vomiting, and 8.33% had severe vomiting, resulting in an effective control rate of delayed-phase vomiting of 75%, which was also significantly higher than in the control group ( p < .05).The FLIE scores at 24 and 120 h after chemotherapy were higher in the treatment group than in the control group, with statistically significant differences (p < .05).Additionally, the occurrence rates of complications such as fatigue, headache, indigestion, reduced appetite, hiccups, and constipation showed no statistically significant differences between the two groups ( p > .05).This study further confirms the efficacy and safety of aprepitant injection in lung cancer patients and provides important clinical references for the development of personalized strategies for preventing CINV.
However, this study has some limitations: the relatively small sample size may be influenced by subjective factors of the researchers and the characteristics of the patients, which may introduce some bias.This study only assessed the efficacy and safety of aprepitant injection in preventing CINV, and further research is needed on the long-term use and dose effects of this drug.
In summary, aprepitant injection demonstrates a significant preventive effect against platinum-based chemotherapy-induced nausea and vomiting.It improves patients' quality of life and exhibits good safety.Therefore, it is worthy of clinical application and further promotion.

( 1 )
Cytological or histological diagnosis of primary lung malignancy.(2) Blood routine, cardiac function, liver and kidney function, and coagulation function are all within the normal range.(3) The Eastern Cooperative Oncology Group (ECOG) score is 0-2 points.(4) The expected survival period is ≥3 months.(5) Has not received chemotherapy in the past.(6) Apply chemotherapy regimens based on cisplatin or carboplatin (AUC = 5).

( 1 )
Abnormal blood routine, cardiac function, liver or kidney function, or coagulation function.(2) Occurrence of vomiting, dry retching, or nausea within 24 h before randomization.(3) Allergy to the study drugs.(4) Primary or metastatic malignancies of the central nervous system.(5) Severe uncontrolled infections, hepatic, renal, or cardiovascular system diseases.
Vomiting reactions during chemotherapy were categorized into five levels according to the Common Terminology Criteria for Adverse Events (CTCAE 4.0) established by the National Cancer Institute.Level 0 indicated no vomiting, Level I indicated one to two episodes of mild vomiting within 24 h, Level II indicated three to five episodes of moderate vomiting within 24 h, Level III indicated six or more episodes of vomiting within 24 h, requiring nasal feeding, total parenteral nutrition support, or hospitalization.Level IV indicated life-threatening vomiting requiring immediate emergency treatment.The effective control rate of vomiting was calculated as the proportion of patients at Levels 0 and I.
Comparison of effective control rates of delayed vomiting between the two groups.Comparison of FLIE scores between the two groups at 24 and 120 h after chemotherapy.Comparison of adverse reactions between the two groups.
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