The aim of THE STUDY to determine whether an olanzapine-based dexamethasone-sparing antiemetic regimen is non-inferior to the standard dexamethasone-containing regimen in preventing delayed-phase Chemotherapy-induced nausea and vomiting while reducing metabolic toxicity in breast cancer patients with metabolic risk factors.
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.
Administered as 40 mg orally once daily on Days 1 to 3 (1 hour before breakfast) in both arms as standard gastroprotective co-medication to prevent chemotherapy- and corticosteroid-induced gastritis and dyspepsia.
Administered as 5 mg orally once daily at bedtime, Days 1-3, for delayed-phase antiemetic prophylaxis.
Administered as 4 mg orally twice daily (total 8 mg/day), Days 1-3, for delayed-phase antiemetic prophylaxis.
Alexandria Main University Hospital
Alexandria, Alexandria Governorate, Egypt
RECRUITINGComplete response during the delayed phase chemotherapy-Induced Nausea and Vomiting (CINV)
Proportion of patients with no emetic episodes and no use of rescue antiemetic medication during the delayed phase, comparing the olanzapine-based dexamethasone-sparing regimen (Arm A) to the standard dexamethasone-containing regimen (Arm B).
Time frame: 24-120 hours after initiation of AC chemotherapy (Day 0)
Total Control during the delayed phase
Proportion of patients with no emetic episodes, no use of rescue antiemetic medication, and no nausea during the delayed phase, comparing the two treatment arms.
Time frame: 24-120 hours after initiation of AC chemotherapy (Day 0)
Change in Fasting Plasma Glucose
Mean change in fasting plasma glucose (FBG) levels from Baseline (Day 0) to Peak Toxicity (Day 4) and Recovery Phase (Day 21), comparing the olanzapine-based and dexamethasone-based arms.
Time frame: Baseline (Day 0), Day 4, and Day 21
Change in Insulin Resistance (HOMA-IR)
Mean change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), calculated from fasting glucose and insulin levels, from Baseline (Day 0) to Peak Toxicity (Day 4) and Recovery Phase (Day 21).
Time frame: Baseline (Day 0), Day 4, and Day 21
Purine Turnover / Metabolic Marker (Uric Acid) Assessment
Mean changes in serum uric acid levels from Baseline (Day 0) to Day 4 and Day 21 to monitor short-term metabolic cellular turnover and hyperuricemia risk.
Time frame: Baseline (Day 0), Day 4, and Day 21
Incidence of Hyperglycemia
Proportion of patients developing hyperglycemia (defined per protocol threshold) at any post-baseline assessment, compared between treatment arms.
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Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
90
Time frame: From Baseline (Day 0) through Recovery Phase (Day 21)
Intermediate Glycemic Control (Serum Fructosamine)
Mean change in serum fructosamine levels from Baseline (Day 0) to Recovery Phase (Day 21), reflecting glycemic control over the preceding 2-3 weeks; interpretation adjusted using Day 0 and Day 21 serum albumin/total protein.
Time frame: Baseline (Day 0) to Day 21
Change in High-Sensitivity C-Reactive Protein (hs-CRP)
Mean change in hs-CRP levels from Baseline (Day 0) to Peak Toxicity (Day 4) and Recovery Phase (Day 21), as a marker of systemic inflammation.
Time frame: Baseline (Day 0), Day 4, and Day 21
Serum Electrolyte Fluctuations (Potassium, Sodium, Magnesium)
Change in serum potassium (K+), sodium (Na+), and magnesium (Mg2+) levels from Baseline (Day 0) to Peak Toxicity (Day 4), to evaluate acute electrolyte shifts related to CINV or metabolic perturbations.
Time frame: Baseline (Day 0) to Day 4
Severity and Interference of Treatment-Related Symptoms (Modified National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events)
Patient-reported severity, frequency, and interference of treatment-related symptoms, assessed using a modified version of the National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (NCI-PRO-CTCAE). Each item is scored on a 5-point scale ranging from 0 (None/Not at all) to 4 (Very severe/Very much), where higher scores indicate worse symptom severity, frequency, or interference. Scores will be compared between arms.
Time frame: Baseline (Day 0), Peak Toxicity (Day 4), and Recovery Phase (Day 21)
Daily Nausea Severity, Drowsiness, and Sleep Disturbance (MD Anderson Symptom Inventory)
Daily patient-reported severity of nausea, drowsiness, and sleep disturbance using Part I (Core Symptom Severity items) of the MD Anderson Symptom Inventory (MDASI). Each symptom is rated on an 11-point numeric scale from 0 (symptom not present) to 10 (as severe as you can imagine), where higher scores indicate worse symptom severity. Assessments will be collected via telephone follow-up on Days 1-3 and in person at other visits.
Time frame: Day 0 as the baseline and Days 1, 2, 3, 4, and 21
Response Categorization by Emetic Episode Frequency
Patients categorized as Complete Response (0 emetic episodes), Partial Response (1-2 episodes), or No Response (more than 2 episodes) during the observation period.
Time frame: From initiation of chemotherapy through 120 hours (Day 5)
Time to Treatment Failure
Time interval from initiation of chemotherapy to the first emetic episode or first use of rescue antiemetic medication, whichever occurs first.
Time frame: From initiation of chemotherapy through 120 hours (Day 5)
Complete Control (CC)
Proportion of patients with no emesis, no rescue medication use, and only mild nausea (MDASI nausea item score ≤2 on a 0-10 scale) during the delayed phase.
Time frame: 24 to 120 hours after initiation of AC chemotherapy (Day 0)