A 28-year-old man with Li-Fraumeni syndrome (TP53 mutation) presents with a newly diagnosed adrenocortical carcinoma. Which agent is the preferred first-line systemic therapy for advanced adrenocortical carcinoma in this patient?

Explanation

## First-Line Therapy for Adrenocortical Carcinoma **Key Point:** Mitotane is the only adrenolytic agent with proven efficacy in adrenocortical carcinoma (ACC) and is the standard of care for both adjuvant and palliative treatment. ### Mechanism of Action Mitotane causes selective necrosis of the adrenocortical tissue through: - Inhibition of multiple cytochrome P450 enzymes (11β-hydroxylase, 17α-hydroxylase, C17,20-lyase) - Direct cytotoxic effects on adrenocortical cells - Induction of apoptosis in ACC cells ### Clinical Evidence **High-Yield:** The FIRM-ACT trial demonstrated that mitotane combined with etoposide, doxorubicin, and cisplatin (EDP) improves recurrence-free survival in ACC compared to EDP alone. ### Treatment Algorithm ```mermaid flowchart TD A[Adrenocortical Carcinoma] --> B{Resectable?} B -->|Yes| C[Surgery] C --> D{High risk/<br/>Advanced?} D -->|Yes| E[Adjuvant Mitotane] D -->|No| F[Observation] B -->|No| G[Palliative Mitotane] G --> H{Response?} H -->|Poor| I[Add EDP Chemotherapy] H -->|Good| J[Continue Mitotane] ``` ### Dosing and Monitoring - **Target plasma level:** 14–20 mg/L (therapeutic window) - **Monitoring:** Serum levels, liver function, lipid profile, neurological symptoms - **Side effects:** GI disturbance, ataxia, hyperlipidemia, hepatotoxicity **Clinical Pearl:** Mitotane has a long half-life (18–159 days) requiring weeks to reach steady state; therapeutic drug monitoring is essential. **Warning:** Chemotherapy agents (doxorubicin, cisplatin, etoposide) are used as adjuncts in combination regimens (EDP) for advanced disease, not as monotherapy first-line.