Description

Chemotherapy-induced nausea and vomiting remains one of the most distressing and feared adverse effects of anticancer therapy, particularly among patients receiving highly emetogenic chemotherapy regimens such as anthracycline-cyclophosphamide (AC). Despite substantial advances in antiemetic prophylaxis, delayed-phase nausea and vomiting continue to affect a significant proportion of patients, leading to impaired quality of life, poor nutritional intake, treatment non-adherence, and increased healthcare utilization. Chemotherapy-induced nausea and vomiting is typically categorized into acute (within 24 hours), delayed (24-120 hours), anticipatory, breakthrough, and refractory phases. Among these, delayed chemotherapy-induced nausea and vomiting is more difficult to control and often persist despite adherence to guideline-recommended antiemetic regimens. The pathophysiology of delayed chemotherapy-induced nausea and vomiting involves complex interactions between central neurotransmitter pathways, including substance P acting on neurokinin-1 (NK-1) receptors, dopamine, serotonin, and histamine signaling pathways. Consequently, optimal prevention strategies require multi-receptor targeting.

Standard antiemetic regimens for highly emetogenic chemotherapy include a combination of a serotonin (5-HT3) receptor antagonist, an NK-1 receptor antagonist, and dexamethasone. Corticosteroids play a critical synergistic role in enhancing antiemetic efficacy through poorly understood mechanisms that may involve prostaglandin inhibition, blood-brain barrier modulation, and reduced inflammation. However, prolonged corticosteroid use is associated with a wide spectrum of adverse metabolic and systemic effects.

Dexamethasone-induced metabolic toxicity includes hyperglycemia, insulin resistance, fluid retention, hypertension, muscle catabolism, immune suppression, and neuropsychiatric disturbances such as insomnia and mood alterations. These adverse effects are particularly concerning in patients with pre-existing metabolic vulnerabilities, including diabetes mellitus, obesity, metabolic syndrome, and impaired glucose tolerance. Even short-term corticosteroid exposure may precipitate significant glycemic excursions in high-risk populations.

Breast cancer patients frequently present with metabolic risk factors, including obesity, insulin resistance, and dyslipidemia, which may be exacerbated by cancer therapy and supportive medications.

Recent research has focused on corticosteroid-sparing strategies that maintain antiemetic efficacy while minimizing metabolic complications. Olanzapine, an atypical antipsychotic with potent antagonistic effects at dopamine (D2), serotonin (5-HT2 and 5-HT3), histamine (H1), and muscarinic receptors, has emerged as an effective agent in the prevention of both acute and delayed CINV. Its broad receptor activity allows it to target multiple emetogenic pathways simultaneously.

Olanzapine is a multi-acting receptor-targeted medication that blocks a broad central pathway by binding to histamine H1, dopamine D2, and serotonin 5-HT2 and 5-HT3 receptors antagonistically. According to direct phase III comparative evidence, olanzapine-based triplets offer antiemetic protection and nausea management similar to NK-1 antagonist-based triplets, indicating NK-1 de-escalation in favor of an olanzapine-centred backbone.

While using a combination of multi-antiemetic medications is standard in highly emetogenic settings, substituting an olanzapine-based regimen for neurokinin-1 (NK-1) receptor antagonists is a clinically reasonable and effective strategy in resource-constrained environments where routine access to NK-1 antagonists is limited due to their high procurement cost. Furthermore, health economic analyses show that replacing highly costly NK-1 receptor antagonists (like aprepitant) with olanzapine results in significant cost savings and preserves or enhances health-related quality of life and complete response rates in patients undergoing highly emetogenic chemotherapy.

Randomized clinical trials have demonstrated that olanzapine significantly improves control of nausea and vomiting when added to standard antiemetic therapy, with particular effectiveness in controlling nausea-a symptom often inadequately managed by conventional regimens. Low-dose olanzapine (5 mg) has been shown to provide antiemetic efficacy with reduced sedation compared to higher doses. Additionally, low-dose olanzapine (5 mg) offers a 97% reduction in treatment-related antiemetic drug costs while achieving antiemetic efficacy and total protection rates comparable to a prepitant across acute and delayed Chemotherapy-induced nausea and vomiting phases, according to prospective randomized comparison data. In addition, new phase III trial findings verify that olanzapine-containing regimens allow multi-day dexamethasone to be safely stopped without compromising chemotherapy-induced nausea and vomiting management.

Emerging evidence suggests that olanzapine-containing regimens may allow reduction or elimination of multi-day dexamethasone without compromising antiemetic protection. Several trials evaluating dexamethasone-sparing approaches have demonstrated comparable complete response rates with improved tolerability profiles. Reducing steroid exposure may decrease hyperglycemia risk, improve sleep quality, and enhance overall patient comfort.

Metabolic safety is increasingly recognized as an important endpoint in supportive oncology care. Corticosteroid exposure can induce acute insulin resistance by promoting hepatic gluconeogenesis and reducing peripheral glucose uptake. This effect may lead to transient or sustained hyperglycemia, particularly in individuals with underlying metabolic dysfunction. Acute hyperglycemia during chemotherapy has been associated with increased infection risk, delayed recovery, and poorer clinical outcomes.

In addition to metabolic toxicity, corticosteroids may contribute to systemic inflammation and immunomodulation. Monitoring inflammatory biomarkers such as high-sensitivity C-reactive protein (hs-CRP) may provide insight into inflammatory responses during chemotherapy and recovery phases. Furthermore, evaluating insulin resistance using indices such as HOMA-IR allows quantification of metabolic perturbations induced by treatment.

Patient-reported outcomes are critical for assessing treatment tolerability and overall well-being. Validated tools such as the Functional Living Index-Emesis (FLIE) evaluate the impact of nausea and vomiting on daily functioning, while symptom burden can be measured using the MD Anderson Symptom Inventory (MDASI), which assesses fatigue, sleep disturbance, nausea severity, and functional interference.

Incorporating patient-reported measures ensures a comprehensive evaluation of treatment effects beyond physiological endpoints.

Despite promising evidence supporting steroid-sparing strategies, robust data focusing specifically on metabolically vulnerable breast cancer patients remain limited. Most previous trials have evaluated antiemetic efficacy as the primary endpoint without detailed assessment of metabolic outcomes. Given the increasing prevalence of metabolic syndrome and diabetes among cancer patients, individualized supportive care strategies are urgently needed.

This study seeks to address this gap by evaluating the efficacy and metabolic safety of an olanzapine-based dexamethasone-sparing regimen in breast cancer patients with metabolic risk factors receiving AC chemotherapy. By integrating metabolic biomarkers, inflammatory markers, and patient-reported outcomes, the study aims to provide a comprehensive assessment of both efficacy and safety and determine whether an olanzapine-based dexamethasone-sparing antiemetic regimen is non-inferior to the standard dexamethasone-containing regimen in preventing delayed-phase CINV while reducing metabolic toxicity in breast cancer patients with metabolic risk factors.

This study seeks to address this gap by evaluating whether an olanzapine-based dexamethasone-sparing antiemetic regimen is non-inferior to the standard dexamethasone-containing regimen in preventing delayed-phase CINV while reducing metabolic toxicity in breast cancer patients with metabolic risk factors receiving AC chemotherapy. By integrating metabolic biomarkers, inflammatory markers, and patient-reported outcomes, the trial provides a comprehensive assessment of both antiemetic efficacy and metabolic safety.