Adrenocortical carcinoma (ACC) – an exceedingly rare endocrine malignancy with an incidence of only 0.5 per million – now has a globally approved orphan drug and a standardized therapeutic drug monitoring (TDM) protocol. Mitotane (Lysodren®) ensures that ACC is no longer a disease without effective medical treatment.

The adrenal glands, small organs located atop the kidneys, are responsible for secreting critical hormones that regulate blood pressure and fluidelectrolyte balance. When malignancy develops, the consequences go far beyond simple endocrine disturbance: ACC proliferates rapidly, metastasizes distantly, and oversecretes hormones, leading to refractory hypertension, central obesity, persistent fatigue, and other severe complications.

For a long time, clinical management of this rare tumor faced significant gaps. Surgery remains the firstchoice for earlystage disease, but postoperative recurrence rates in highrisk patients exceed 50%. For patients who are inoperable, have metastatic disease, or are at high risk of recurrence after surgery, there has been a longstanding lack of effective drugs. The introduction of mitotane now breaks this therapeutic deadlock.

The Only Globally Approved Orphan Drug for ACC – A New Dawn for Rare Disease Treatment

Adrenocortical carcinoma is highly aggressive with a poor prognosis, and treatment options are extremely limited.

Mitotane (brand name: Lysodren®) is the only drug approved by the FDA, EMA, and NMPA for the treatment of ACC, and it is classified as an orphan drug. It exerts its therapeutic effects through a dual mechanism: directly killing adrenocortical tumor cells and inducing apoptosis, while also suppressing the secretion of harmful hormones such as cortisol and aldosterone, thereby alleviating the endocrine symptoms caused by the tumor.

As of January 2025, mitotane is officially available for sale in the domestic Chinese market. The drug has been introduced at Guangzhou Royal Lee Cancer Hospital, where the Department of Pharmacy can routinely issue inhospital prescriptions for mitotane. Our hospital is one of the earliest medical institutions in Guangdong Province with the capability to provide standardized dosing and comprehensive TDM services, bringing internationally aligned treatment options to ACC patients in South China.

Indications

Patients with locally advanced ACC that cannot be completely resected surgically;

Patients at high risk of recurrence after radical tumor resection, requiring adjuvant consolidation therapy;

Patients with advanced ACC who have developed distant metastases.

Established Clinical Efficacy: Maximizing Benefit through Standardized Therapy
Numerous clinical cohorts and metaanalyses have confirmed the survival benefits of mitotane. All these benefits, however, are predicated on achieving target therapeutic drug concentrations and adhering to a standardized, fullcourse regimen:

Reduction in postoperative recurrence risk: In patients at high risk of recurrence after surgery, those receiving mitotane per protocol achieved a median recurrencefree survival of 42 months, compared with only 10 months in untreated highrisk patients – corresponding to a 58% reduction in recurrence risk.

Significant improvement in longterm survival: Patients who maintained stable plasma concentrations within the target range of 14–20 mg/L had a 5year overall survival rate of 47%, versus 28% in those with subtherapeutic levels; efficacy declines markedly when concentrations are insufficient.

Control of advanced disease: Mitotane combined with EDP chemotherapy is the only internationally approved firstline standard regimen for metastatic ACC, effectively reducing tumor size and prolonging disease stabilization.

Critical point: Blood drug concentration directly determines therapeutic efficacy. Therapeutic drug monitoring (TDM) is the core of the entire treatment course, and regular blood sampling is essential.

Patient Education and Medication Guide

01 Potential side effects during longterm mitotane use

Gastrointestinal reactions: Nausea, vomiting, diarrhea (very common; may be alleviated by taking with food), anorexia, abdominal pain.

Neurological reactions: Somnolence, fatigue, dizziness (very common, may affect driving and operating machinery), headache, confusion, slurred speech.

Skin reactions: Rash (incidence 5%25%).

Adrenal cortical suppression: Manifesting as adrenal insufficiencylike symptoms – persistent fatigue, weakness, hypotension, nausea, appetite loss, dizziness (especially upon standing), electrolyte disturbances (e.g., hyponatremia, hyperkalemia).

02 Precautions when taking mitotane

Take strictly as prescribed; do not adjust the dose on your own. Dose adjustments must be made by the physician based on laboratory parameters and blood drug concentrations; do not increase, decrease, or stop the medication without medical advice.

It is recommended to take with meals; taking with food can help reduce nausea and gastric discomfort.

If a dose is missed, do not double the next dose. Simply resume with the next scheduled dose. Never take a double dose, as this may increase hepatic and systemic burden.

Swallow tablets whole; do not crush or chew, to ensure stable drug absorption.

03 Dietary considerations
Mitotane is lipophilic and has significant side effects; special attention to diet is required:

Take with meals and include moderate fat. Always take with food, particularly with an appropriate amount of fat (e.g., whole milk, eggs, avocado, nuts).

Examples of highfat meals: one egg, a glass of whole milk, or a small handful of nuts when taking the medication.

Do not arbitrarily change dietary habits. Maintain a regular eating pattern, avoid spicy, irritating, or raw/cold foods, and also avoid overeating.

04 How often should blood drug concentrations be monitored after starting mitotane?

At initiation/dose titration: Every 2–4 weeks until concentrations stabilise within the target range (generally 14–20 mg/L).

After dose stabilisation, target levels achieved, and clinical stability: Every 1–3 months; for most patients, once every 1–2 months is sufficient.

Contact your physician and follow their advice if you experience: marked anorexia, headache, somnolence, worsening fatigue, muscle weakness, epigastric discomfort, etc.; if you have selfadjusted the dose or missed multiple doses; or if you start any new concomitant medication.

Royal Lee’s Standardized FullCycle Medication Management
Although ACC is a ultrarare tumor (with an incidence of 1 per million), the survival needs of every patient deserve attention. Guangzhou Royal Lee Cancer Hospital, operating under international JCIstandard pharmaceutical management systems, has established a comprehensive closedloop treatment pathway for mitotane: multidisciplinary risk assessment → individualized dosing regimen → periodic TDM → dynamic intervention for adverse reactions. Our oncologists work together with dedicated clinical pharmacists throughout the process to ensure medication safety and therapeutic success. If you or your family members have inquiries regarding novel antitumor drug access, please contact our Department of Pharmacy for further consultation.

References
[1] Peking Union Medical College Hospital Rare Disease Multidisciplinary Collaboration Group. Expert Consensus on Mitotane for Adrenocortical Carcinoma (2021). Medical Journal of Peking Union Medical College Hospital, 2021, 12(5): 674-683. (in Chinese)
[2] Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med, 2012, 366(23): 2189-2197.
[3] Chinese Society of Endocrinology. Clinical Guideline for Mitotane Therapeutic Drug Monitoring. Chinese Journal of Rare Diseases, 2025. (in Chinese)
[4] National Medical Products Administration. Drug Registration Approval Certificate for Mitotane Tablets (Lysodren®), 2023.

Important Disclaimer: This article is intended for academic reference by healthcare professionals only and does not constitute diagnostic, treatment, or medication advice for any disease. Whether this drug is appropriate for any individual patient must be determined by a physician after comprehensive evaluation. All efficacy and safety data should be based on the drug label approved by the National Medical Products Administration.