What is the recommended chemotherapy regimen for a patient with adrenocortical carcinoma?

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Last updated: January 11, 2026 • View editorial policy

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Chemotherapy Regimen for Adrenocortical Carcinoma

The recommended first-line chemotherapy regimen for adrenocortical carcinoma requiring cytotoxic therapy is EDP-M: etoposide, doxorubicin, cisplatin, plus mitotane. 1

First-Line Treatment Selection

EDP-M Regimen (Standard of Care)

EDP-M is the superior first-line regimen based on the landmark FIRM-ACT trial, which demonstrated significantly better progression-free survival (5.0 months vs 2.1 months) and response rates (23.2% vs 9.2%) compared to streptozocin plus mitotane. 1, 2

Specific dosing schedule: 1, 3

  • Etoposide: 100 mg/m² on days 2-4 (or days 5-7 in alternative schedule)
  • Doxorubicin: 40 mg/m² on day 1 (or 20 mg/m² on days 1 and 8)
  • Cisplatin: 40 mg/m² on days 3 and 4 (or days 1 and 9)
  • Mitotane: Continuous oral dosing up to 4 g/day or maximum tolerated dose, targeting therapeutic levels of 14-20 mcg/mL
  • Cycle frequency: Every 4 weeks 1

When to Use EDP-M vs Mitotane Monotherapy

Mitotane monotherapy is indicated for: 1

  • Low tumor burden disease
  • More indolent/slowly progressive disease
  • Patients with favorable prognostic parameters

EDP-M combination is indicated for: 1

  • Rapidly progressing disease
  • Life-threatening extensive metastatic disease
  • Radiological progression under mitotane monotherapy
  • High tumor burden

Critical caveat: Mitotane takes months to reach therapeutic levels, making monotherapy inappropriate for aggressive disease. 1

Alternative First-Line Options for Unfit Patients

For patients unsuitable for full EDP-M: 1

  • Mitotane plus etoposide and cisplatin (without doxorubicin)
  • Mitotane plus cisplatin alone
  • These represent reasonable alternatives when the full EDP-M regimen cannot be tolerated 1

Second-Line Treatment

After EDP-M failure, treatment options are extremely limited. 1

Recommended approach: 1

  • First priority: Enroll in clinical trials
  • If trials unavailable: Gemcitabine plus capecitabine OR streptozocin
  • Expected outcomes: Median PFS only 2-4 months with second-line options 1

Mitotane continuation in second-line: This decision must be individualized based on drug tolerance and effect on hormonal secretion; consider discontinuing if progressive disease occurs despite therapeutic drug levels. 1

Critical Management Considerations

Mitotane Monitoring and Toxicity

Mandatory monitoring includes: 1

  • Plasma mitotane levels every 3-4 months
  • Target therapeutic range: 14-20 mcg/mL 1
  • Blood counts every 3-4 months
  • Lipid panels (mitotane raises cholesterol and triglycerides) 3

Dose adjustments required for: 1

  • CNS/GI side effects (grade 2 or higher)
  • Subtherapeutic or supratherapeutic drug levels

Adrenal Insufficiency Risk

Adrenal insufficiency is a significant concern, occurring in 17% of patients in real-world practice (higher than the 3.4% reported in FIRM-ACT). 4

Mandatory corticosteroid replacement: 1, 5

  • Hydrocortisone or prednisone must be prescribed due to adrenolytic effects of mitotane
  • Failure to provide adequate replacement can lead to life-threatening adrenal crisis 5

Drug Interactions

Important warning: Mitotane induces CYP3A4, which can lead to subtherapeutic levels of oral targeted agents, potentially explaining failures of newer therapies in this disease. 1

Role of Surgery and Local Therapies

Surgery or local therapies should be considered in addition to systemic therapy for: 1

  • Oligometastatic disease with feasible complete resection
  • Patients achieving objective response or long-term stable disease on systemic therapy
  • Severe symptomatic hormone excess after medical management attempts

Expected Outcomes

Realistic expectations with EDP-M: 1, 2

  • Median overall survival: 14.8 months
  • Median progression-free survival: 5.0 months
  • Response rate: 23.2%
  • Complete hormonal response in functioning tumors: achievable in subset of patients 3

These modest outcomes clearly indicate that new systemic therapy options are urgently needed. 1

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Research

Combination chemotherapy in advanced adrenocortical carcinoma.

The New England journal of medicine, 2012

5
Guideline

Treatment of Functioning Adrenaloma

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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