Aprepitant for CINV Prevention in Pleural Mesothelioma with Cisplatin/Pemetrexed/Bevacizumab
Aprepitant should be administered as part of a triple-therapy antiemetic regimen (aprepitant + 5-HT3 antagonist + dexamethasone) for patients receiving cisplatin-based chemotherapy for pleural mesothelioma, as cisplatin is classified as highly emetogenic chemotherapy requiring the most aggressive antiemetic prophylaxis.
Rationale for Aprepitant Use
The cisplatin/pemetrexed/bevacizumab regimen is the standard first-line treatment for pleural mesothelioma, with cisplatin being the key driver of emetogenic risk 1. Cisplatin is classified as highly emetogenic chemotherapy (HEC), and aprepitant has FDA approval specifically for preventing acute and delayed nausea and vomiting associated with HEC including high-dose cisplatin 2.
Evidence Supporting Aprepitant in Cisplatin-Based Regimens
Aprepitant combined with ondansetron and dexamethasone significantly improved complete response rates (no emesis, no rescue therapy) compared to standard therapy alone in cisplatin-treated patients: 63-73% versus 43-52% (p < 0.001) 1, 3.
The benefit was particularly pronounced for delayed emesis (24-120 hours post-chemotherapy), with complete response rates of 68-75% versus 47-56% in control groups (p < 0.001) 1.
A pooled analysis of 1,043 patients receiving cisplatin demonstrated a 20% absolute improvement in overall complete response with aprepitant-containing regimens, representing a number needed to treat of 5 1.
Recommended Dosing Regimen
For highly emetogenic chemotherapy with cisplatin, the standard aprepitant regimen is:
Day 1 (chemotherapy day): Aprepitant 125 mg orally 1 hour before chemotherapy + ondansetron (8 mg IV or per institutional protocol) + dexamethasone 12 mg orally 30 minutes before chemotherapy 1, 2.
Days 2-3: Aprepitant 80 mg orally once daily in the morning + dexamethasone 8 mg orally once daily 1, 2.
Day 4: Dexamethasone 8 mg orally once daily (no aprepitant) 1, 2.
Critical Dexamethasone Dose Adjustment
The dexamethasone dose must be reduced by 50% when co-administered with aprepitant due to CYP3A4 inhibition by aprepitant, which increases dexamethasone plasma concentrations 1, 2. The recommended dexamethasone dose is 12 mg on Day 1 (instead of 20 mg) and 8 mg on Days 2-4 (instead of higher doses) 1, 2.
Special Considerations for This Regimen
Bevacizumab Does Not Alter Antiemetic Strategy
The addition of bevacizumab to cisplatin/pemetrexed does not change the emetogenic classification or antiemetic requirements 1. The MAPS trial, which established bevacizumab's role in mesothelioma, used standard cisplatin-based antiemetic prophylaxis 1.
Pemetrexed Emetogenic Risk
Pemetrexed alone is classified as moderately emetogenic, but when combined with cisplatin, the regimen is treated as highly emetogenic based on the cisplatin component 1.
Drug Interaction Considerations
Aprepitant is a moderate CYP3A4 inhibitor and inducer, requiring careful attention to potential drug interactions 1:
Contraindicated combinations: Pimozide, terfenadine, astemizole, cisapride 1.
Chemotherapy agents metabolized by CYP3A4 (docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, vincristine) may have altered plasma concentrations 1.
Neither pemetrexed nor bevacizumab are significantly metabolized by CYP3A4, so no dose adjustments are required for these agents 1.
Efficacy Across Multiple Cycles
The antiemetic efficacy of aprepitant plus standard therapy is maintained for up to six cycles of chemotherapy, making it appropriate for the multiple cycles typically administered in mesothelioma treatment 3.
Alternative 5-HT3 Antagonist Option
While ondansetron is most commonly studied, palonosetron may be considered as the 5-HT3 antagonist component, as it has demonstrated superior efficacy for both acute and delayed emesis compared to other 5-HT3 antagonists 1. However, the specific combination of palonosetron with aprepitant in cisplatin-based regimens has less extensive validation than ondansetron-based combinations 1.
Common Pitfalls to Avoid
Do not use aprepitant as monotherapy or without a 5-HT3 antagonist and dexamethasone – the triple-therapy approach is essential for optimal CINV control 1.
Do not forget to reduce dexamethasone doses by 50% when using aprepitant to avoid excessive corticosteroid exposure 1, 2.
Do not use aprepitant for chronic continuous dosing beyond the 3-day regimen, as safety and drug interaction profiles may change with prolonged use 1, 2.
Do not assume aprepitant will completely prevent nausea – while highly effective for vomiting prevention, approximately 40% of patients may still experience significant nausea despite optimal antiemetic therapy 1.
Tolerability Profile
Aprepitant is generally well tolerated, with the most common adverse events being asthenia/fatigue, anorexia, constipation, diarrhea, and hiccups 3. There were no significant differences in treatment-related adverse effects between aprepitant-treated patients and controls in phase III trials 1.