Chemotherapy-induced nausea and vomiting (CINV) represents one of the most distressing and debilitating side effects experienced by cancer patients undergoing treatment, significantly impacting quality of life, treatment adherence, and overall therapeutic outcomes. Neurokinin-1 receptor antagonists (NK1RAs) have emerged as cornerstone agents in the modern management of CINV, particularly for delayed-phase symptoms that occur 24-120 hours after chemotherapy administration. These agents target substance P binding to NK-1 receptors in both central and peripheral nervous system pathways, addressing the complex neurotransmitter mechanisms underlying CINV pathophysiology.
Substance P, a neuropeptide belonging to the tachykinin family, plays a pivotal role in mediating delayed CINV through its interaction with NK-1 receptors located in the area postrema, nucleus tractus solitarius, and visceral afferent pathways. Chemotherapy agents trigger substance P release, which subsequently activates NK-1 receptors and initiates the emetic cascade. This mechanism is particularly relevant for delayed CINV, where serotonin (5-HT3) receptor-mediated pathways become less prominent. Understanding these distinct pathophysiological mechanisms has enabled the development of targeted therapeutic strategies that address both acute and delayed phases of CINV through complementary receptor antagonism.
Currently, three NK1RAs are approved for clinical use in China: aprepitant (the first-in-class oral agent), fosaprepitant (an intravenous prodrug of aprepitant), and netupitant (available as a fixed-dose combination with palonosetron). Aprepitant, approved in 2003, revolutionized CINV prevention by demonstrating superior efficacy over traditional 5-HT3 receptor antagonist and corticosteroid combinations. The standard aprepitant regimen involves 125mg administered orally on day 1, followed by 80mg on days 2-3, providing sustained NK-1 receptor blockade throughout the high-risk period for delayed CINV.
Fosaprepitant offers an intravenous alternative, particularly valuable for patients unable to tolerate oral medications or those receiving same-day chemotherapy protocols. Administered as a single 150mg intravenous dose on day 1, fosaprepitant provides equivalent efficacy to the 3-day oral aprepitant regimen while simplifying administration and potentially improving patient compliance. The conversion to active aprepitant occurs rapidly following intravenous administration, ensuring prompt therapeutic effect.
Netupitant, formulated as a fixed combination with palonosetron (NEPA), represents an innovative approach to CINV prevention by simultaneously targeting both NK-1 and 5-HT3 receptor pathways. This dual-mechanism formulation provides several advantages including single-dose administration, enhanced convenience, and potentially improved efficacy through synergistic receptor antagonism. Netupitant's long half-life of approximately 96 hours ensures sustained therapeutic concentrations throughout the critical delayed CINV period, while palonosetron's distinct pharmacological profile offers prolonged 5-HT3 receptor antagonism compared to first-generation agents.
Clinical evidence supporting NK1RA efficacy has been extensively documented through numerous randomized controlled trials and real-world studies. Landmark studies demonstrated that adding aprepitant to standard antiemetic regimens significantly improved complete response rates in patients receiving highly emetogenic chemotherapy (HEC), with particular benefit observed in the delayed phase. Subsequent studies with newer agents have consistently shown non-inferiority or superiority compared to aprepitant-based regimens, while offering advantages in terms of dosing convenience and administration simplicity.
International and Chinese antiemetic guidelines universally recommend incorporating NK1RAs into prophylactic regimens for patients receiving HEC or anthracycline-cyclophosphamide combinations. The standard triple therapy consisting of an NK1RA, 5-HT3 receptor antagonist, and dexamethasone represents the foundation of modern CINV prevention. For patients at highest risk or those experiencing breakthrough symptoms despite standard prophylaxis, quadruple therapy adding olanzapine has shown enhanced efficacy, particularly for nausea control.
Real-world evidence from Chinese clinical practice has demonstrated the practical benefits of NK1RA incorporation into routine care. Studies conducted in Chinese cancer centers have shown significant improvements in CINV control following NK1RA introduction, with particularly notable benefits in delayed-phase prevention. However, challenges remain including suboptimal adherence to guideline recommendations, particularly in community oncology settings, and underutilization of NK1RAs in certain patient populations despite established efficacy.
The clinical utility of different NK1RAs varies based on patient characteristics, treatment setting, and practical considerations. Aprepitant's extensive clinical experience and established safety profile make it a preferred choice for many practitioners, while fosaprepitant's intravenous formulation addresses specific clinical scenarios requiring parenteral administration. NEPA's fixed combination formulation offers simplified dosing and potentially enhanced compliance, particularly beneficial for outpatient chemotherapy settings where medication adherence can be challenging.
Safety profiles of NK1RAs are generally favorable, with adverse events typically mild to moderate in severity and rarely leading to treatment discontinuation. Common adverse effects include headache, constipation, and fatigue, while more serious but rare events such as hypersensitivity reactions or drug interactions require careful monitoring. The interaction profile of aprepitant with cytochrome P450 3A4 substrates necessitates dose adjustments for certain concomitant medications, particularly dexamethasone and some chemotherapy agents.
Emerging research continues to refine optimal NK1RA utilization strategies. Studies investigating biomarker-guided approaches to identify patients most likely to benefit from NK1RA therapy show promise for personalized CINV prevention. Additionally, investigations into novel combination regimens, alternative dosing schedules, and extended-duration prophylaxis for multi-day chemotherapy protocols represent active areas of clinical research.
The economic impact of NK1RA utilization warrants consideration in healthcare resource allocation decisions. While these agents represent additional treatment costs, their implementation has been associated with reduced healthcare utilization, decreased chemotherapy delays or dose reductions, and improved patient quality of life. Cost-effectiveness analyses have generally supported NK1RA use in appropriate patient populations, particularly when considering the broader healthcare system implications of inadequate CINV control.
Future directions in NK1RA development include investigation of novel formulations with enhanced pharmacokinetic profiles, development of predictive biomarkers for treatment response, and exploration of combination strategies with emerging antiemetic agents targeting novel neurotransmitter pathways. Additionally, efforts to improve guideline adherence and optimize implementation strategies in diverse clinical settings remain priorities for maximizing the clinical benefit of these important therapeutic agents.
Continued evolution of CINV management strategies incorporating NK1RAs represents a paradigm shift toward evidence-based, mechanism-targeted supportive care that has fundamentally improved the cancer treatment experience for countless patients worldwide. Ongoing research and clinical implementation efforts promise further refinements in CINV prevention and control, ultimately contributing to enhanced treatment tolerability and improved patient outcomes in oncology practice.
DOI：10.1007/s11684-025-1140-8