The development of Mitotane in adrenocortical cancer and Cushing's syndrome and a Chinese perspective (2025 edition)

Drug options are extremely limited in the treatment of rare but highly aggressive tumorsAdrenocortical carcinoma (ACC) and related endocrine abnormalities such as Cushing’s syndrome. The original drug Mitotane (Mitotane; Trade name Lysodren) is one of the few oral cytotoxic drugs currently approved for the treatment of ACC. Its usage status, indications, mechanisms, safety, monitoring and future development in the global and Chinese markets have attracted much attention.

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1. Background review:The treatment landscape of ACC and Mitotane

1. Biological background and clinical significance

Adrenocortical carcinoma is a malignant tumor originating from the adrenal cortex. Although extremely rare, it is highly aggressive and has a poor prognosis. Studies indicate that its five-year survival rate is less than35%.

Cushing's syndrome is caused by long-term abnormal elevation of cortisol in the body and may be accompanied byACC or benign adrenocortical adenoma. Management of this disease is equally complex.

2. Mitotane’s positioning in treatment

Mitotane is one of the few drugs currently used for ACC treatment. Its positioning is mainly in the following two aspects:

For patients with ACC who are inoperable or at high risk of postoperative recurrenceas an adjuvant (or delayed) treatment option after surgery.

In some cases of Cushing's syndrome, it is used as one of the drugs to control cortisol secretion (although it is not first-line and must be used with caution).

3. Chinese market and drug price reality

In China, although the original drug of mitotane is on the market, it has not yet been included in the medical insurance; in the case of 500 mg × 100 tablets, the price may be more than 9,000 yuan per box. The price in overseas markets (such as the European version and the Turkish version) is about 9,000 yuan; while the price of overseas generic drugs (such as those produced in Laos) may be much lower than this. Such a current situation of drug prices has special practical significance in terms of cost-bearing for the treatment of rare tumors in China.

2. A new perspective on the pharmacological mechanism of Mitotane

1. Review of classic mechanisms

Traditionally, mitotane is believed to inhibit adrenocortical cancer or high cortisol states by interfering with steroid anabolism of adrenocortical cells and having a cytotoxic effect on adrenocortical cells. The instructions state"It can alter the peripheral metabolism of steroids and directly inhibit the adrenal cortex."

2. New mechanisms revealed by recent research

The latest research (such as Journal of Clinical Endocrinology & Metabolism) shows:

In adrenal cancer cell lines, mitotane induces endoplasmic reticulum (ER) stress, and its key target is the enzyme sterol O-acyltransferase 1 (SOAT1).

There was a significant correlation between blood concentration monitoring and efficacy: patients who achieved blood concentrations >14 mg/L had significantly better overall survival (OS).

Although the classic mechanism focuses on the steroid metabolism pathway, the above studies suggest that its tumor suppressive mechanism may rely more on lipid metabolism and cellular metabolic stress response.

3. Extension of clinical significance in China

For Chinese ACC patients, understanding the new mechanism of mitotane will help:

Identification of potential biomarkers (such asSOAT1 expression, blood drug concentration monitoring) to predict efficacy.

Explore the possibility of combination with targeted therapy/immunotherapy—especially in the context of current limited treatment options for ACC.

Strengthening patient education and medication monitoring"Meeting blood drug concentration standards" will help improve efficacy and avoid ineffective medication.

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3. Dose Optimization and Blood Drug Monitoring Strategy

1. Key points in dose adjustment

According to the literature and guidelines, the starting dose of mitotane is usually between 2g and 6g/day orally divided into 3-4 times, and the target dose is 9-10g/day, with the purpose of maintaining the blood concentration in the range of 14-20mg/L. It is known that dose adjustments need to be based on tolerability, blood levels, and toxic effects.

The information mentioned in the instructions is less popular in the Chinese market, so it is particularly important to strengthen dose management.

2. The importance of blood drug concentration monitoring

Many studies have emphasized that blood concentration≥14mg/L is associated with better efficacy.

Monitoring is not only used for efficacy, but also for safety assessment, because mitotane has the characteristics of accumulation and long half-life (according to data, its elimination half-life can reach 18-159 days).

In clinical practice in China, a blood drug testing process has been established with the hospital where the patient is located, and a “standard → maintenance” mechanism has been established.

3. Challenges and suggestions in clinical application in China

For Chinese patients, "dose tolerance/blood drug levels/toxic reactions" should be simultaneously included in the management process to avoid blindly increasing the dose leading to serious adverse reactions.

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IV. Safety and toxicity management: looking at China’s practice from overseas data

1. Review of common adverse reactions:Data indicate that the use of mitotane may be associated with the following adverse reactions:

Digestive system: anorexia, nausea, vomiting, diarrhea (the incidence of diarrhea may be as high as80%)

Neuropsychiatric system: dizziness, depression, cognitive impairment

Blood/endocrine system: neutropenia, hypothyroidism, decreased testosterone or androgens

Special circumstances: Central nervous system toxicity (such as disturbance of consciousness), adrenal crisis (in trauma/shock state)

These toxicity characteristics require strict clinical monitoring.

2. Chinese Clinical Perspective: Monitoring and Management Suggestions

For patients with frequent diarrhea symptoms, symptomatic treatment (e.g., antidiarrhoeal drugs) should be used early and dose adjustment should be considered.

For neuropsychiatric symptoms, timely cooperation with the psychiatry or neurology department should be carried out, and mitotane treatment should be suspended if necessary.

Special reminder: In the event of shock, severe trauma or adrenal crisis, the use of mitotane should be suspended and medical first aid should be given. There are hints in the instructions, but some domestic patients and doctors may not know enough about this.

In female patients, attention should be paid to decreased androgen levels and menstrual abnormalities; in male patients, free testosterone levels and changes in sexual function need to be monitored.

Be careful when using medication during pregnancy and lactation: there are a few cases of premature birth or miscarriage reported, and Mitotane can pass into breast milk, potentially causing harm to the baby.

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V. Discussion on price, access and China’s medical insurance perspective

1. The reality of price and market access

As mentioned before, although mitotane is already on the market in China, it is not covered by medical insurance. 500 mg × 100 tablets may be sold for more than 9,000 yuan per box. The overseas market price is also about 9,000 RMB/box (affected by exchange rate fluctuations) or lower ( Laos generic drugs are about more than 1,000 RMB/box).

This price reality places a huge burden on patients, especially in the treatment of rare cancers.

2. China’s medical insurance, rare disease policies and future trends

In recent years, China has made progress in access to "rare disease drugs" and medical insurance support. In the future, if mitotane can be included, it will greatly reduce the burden on patients.

References:

ASCO 2025 Annual Meeting Abstracts: Global Cancer Drug Shortage Report

European Society for Endocrinology (ESE): Mitotane Pregnancy Guidelines

Journal of Clinical Oncology (JCO): Neurotoxicity Management Study

HRA Pharma Official Website: LYSODREN® Product Information

EudraVigilance Database: Mitotane Safety Alerts

Nature Medicine 2025: Mitochonrial UPR Mechanism