A 32-year-old woman undergoing chemotherapy with cisplatin for ovarian cancer develops severe nausea and vomiting on day 1 of treatment. She has no prior history of GERD or gastroparesis. The oncologist prescribes ondansetron 8 mg IV 30 minutes before chemotherapy and every 8 hours for 3 days. Despite this, she continues to experience breakthrough nausea on day 2. Which of the following agents would be the most appropriate addition to her antiemetic regimen?

## Chemotherapy-Induced Nausea and Vomiting (CINV) Management **Key Point:** Cisplatin is a highly emetogenic chemotherapy agent (Level 5 emetogenicity). Breakthrough CINV despite 5-HT₃ antagonist monotherapy requires combination antiemetic therapy. ### Pathophysiology of CINV Cisplatin triggers emesis through multiple pathways: 1. Direct chemoreceptor trigger zone stimulation (5-HT₃ release) 2. Substance P release in chemoreceptor trigger zone and GI tract (NK₁ pathway) 3. Inflammatory cytokine release (IL-1, IL-6) 4. Delayed emesis (24–120 hours) mediated primarily by substance P ### Optimal CINV Prophylaxis Strategy | Agent Class | Mechanism | Timing | Evidence | |---|---|---|---| | 5-HT₃ antagonist (ondansetron) | Blocks serotonin at CTZ | Acute (0–24 hrs) | Effective for acute phase only | | Corticosteroid (dexamethasone) | Suppresses cytokine release; NK₁ potentiation | Delayed (24–120 hrs) | Essential for delayed CINV | | NK₁ antagonist (aprepitant) | Blocks substance P | Acute + delayed | Gold standard but expensive | | Metoclopramide | D₂ antagonist | Limited role | Weak; not recommended as sole agent | **High-Yield:** For highly emetogenic chemotherapy (cisplatin, doxorubicin), the standard regimen is **5-HT₃ antagonist + corticosteroid + NK₁ antagonist** (3-drug combination). Dexamethasone is the most cost-effective addition when NK₁ antagonists are unavailable. ### Why Dexamethasone is the Answer - Addresses the **delayed emesis component** (day 2 onwards) that ondansetron alone cannot prevent - Recommended dose: 8 mg daily on days 2–4 post-chemotherapy - Synergizes with 5-HT₃ antagonists - Supported by ASCO, NCCN, and MASCC guidelines **Clinical Pearl:** Delayed CINV (>24 hours post-chemo) is mediated primarily by **substance P and NK₁ receptors**, not serotonin. This is why 5-HT₃ antagonists alone fail for delayed symptoms. ### Mnemonic for CINV Regimen **"5-HT-Dex-NK"** = 5-HT₃ antagonist + Dexamethasone + NK₁ antagonist (when available)