Mitotane: from core drug in the treatment of adrenocortical cancer to future innovation direction

Mitotane (Mitotane) is an anti-tumor drug with a long history and is still the cornerstone of adrenocortical cancer (Adrenocortical Carcinoma, ACC; adrenal cancer) treatment. Although its clinical use has been in use for decades, the role of mitotane is constantly being re-examined in recent years with the emergence of more molecularly targeted therapies and immunotherapies. This article will comprehensively explain the latest value of this classic drug from the perspectives of mechanism, clinical application, latest research progress, global market dynamics and future trends.

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1. Global epidemiology and clinical challenges of adrenocortical cancer

Adrenocortical cancer is an extremely rare but highly aggressive malignant tumor. The global annual incidence rate is only about one to two millionths. The incidence rate is similar in men and women. The clinical manifestations are complex, including endocrine disorders caused by excessive cortisol. Surgical resection is the first choice for early treatment, but many patients require systemic drug treatment because they are inoperable when discovered or have a high risk of postoperative recurrence.

Due tothe complexity and high mortality of ACC, mitotane has long been the only ACC-specific drug approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and has been one of the indispensable treatment options.

2. Mitotane’s unique pharmacological mechanism: positioned in adrenal cytotoxicity and steroid intervention

Mitotane is not a typical traditional chemotherapy drug. Its mechanism has dual properties:

1. Selective accumulation and cytotoxicity in adrenal cells: Studies have shown that mitotane can selectively accumulate in adrenocortical cells, interact with mitochondrial membrane components, trigger mitochondrial dysfunction and cell death, thereby inhibiting the proliferation of adrenocortical cancer cells. At the same time, mitotane may also promote the apoptosis of cancer cells by inducing endoplasmic reticulum stress.

2. Intervention in steroidogenesis and endocrine balance:Mitotane can affect the expression and activity of a variety of steroidogenesis-related enzymes, thereby reducing the synthesis of adrenocortical hormones, which is particularly important for patients with functional ACC or patients with excessive hormone secretion.

This unique mechanism of action makes mitotane of great value in controlling the progression of ACC and alleviating clinical symptoms caused by hormones, especially when combined with other treatment strategies.

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3. Dose adjustment and precise monitoring strategies in clinical practice

The clinical use of mitotane is not one-size-fits-all, but emphasizes individualized adjustment:

Plasma concentrations should be monitored during treatment to ensure that the therapeutic range is achieved while avoiding excessive toxicity.

Clinical consensus states that maintenance of specific plasma levels is critical for long-term efficacy.

In addition, because the drug has significant interactions with multiple metabolic enzymes in the body (such asCYP3A4), patients usually need to adjust the dosage of other concomitant drugs while taking mitotane to avoid affecting liver metabolism and hormone balance.

4. Management of high risks and adverse reactions in mitotane treatment

The toxicity and adverse reactions of mitotane cannot be ignored, including but not limited to digestive system disorders, neurological manifestations, hormone-related changes, etc. Therefore, a comprehensive clinical management strategy needs to be developed. In recent years, clinical practice has emphasized:

Regularly monitor liver function, hematological indicators and hormone levels;

Improve tolerance by optimizing medication timing and meal coordination;

Refined dose adjustment reduces long-term toxicity.

Especially in elderly patients and even patients with comorbidities, side effect management is a key part of improving quality of life and treatment experience, not just simple dose calculation.

5.Adrenal cancer treatment trends in 2025 and the future positioning of mitotane

Although mitotane still occupies a core position inACC treatment, the global cancer treatment landscape is changing, especially in the following directions:

1. Progress in precision targeted therapy: Through in-depth research on genomics and molecular pathology,key driver genes (such as TP53, CTNNB1, etc.) in ACC cells have been identified, providing a basis for the development of drugs that target and inhibit these molecular pathways. Compared with traditional non-selective toxic drugs, targeted drugs are expected to improve efficacy and reduce systemic side effects.

2. Exploration of immunotherapy in the treatment of ACC: Immune checkpoint inhibitors (such asPD-1/PD-L1 antibodies) have shown efficacy in a variety of solid tumors, and there are currently studies evaluating their application in ACC patients. Although the effectiveness still needs to be verified by more clinical data, this strategy is expected to provide a new treatment path for patients with drug resistance or relapse.

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3. New drug combinations and adjuvant treatment strategies: In clinical studies, combination therapy of mitotane with other chemotherapy drugs or targeted drugs is being evaluated, with the aim of improving tumor control rates through multi-mechanism synergy. Relevant research is progressing and more effective treatment options are expected to be developed in the future.

6. The realistic impact of the global drug market and medical insurance coverage status

In January 2025, the original drug Mitotane was officially launched in mainland China. This milestone marks the first time that Chinese patients with adrenocortical cancer (ACC) have received an internationally recognized "life-saving drug." According to the National Medical Products Administration, the drug was approved for the treatment of advanced, unresectable or metastatic ACC, becoming the first targeted drug for this indication in China. However, it has not yet been included in medical insurance, which results in a heavy medication burden for patients.

At the same time, there are different versions of mitotane (such as the European version and the Turkish version) and generic drugs on the overseas market. Specifications of the original version500mg*100 tablets may be sold for more than 9,000 yuan per box, while the price of the generic version may be more than 1,000 yuan (the price may fluctuate due to exchange rates).The price difference is large. This reality also reflects global challenges in drug access and health economics. In addition, changes in medical insurance policies and reforms in drug pricing strategies continue to affect the treatment choices and experience of ACC patients.

7. Real experience and treatment journey from the patient’s perspective

Outside of the clinic, the actual experiences of patients and families facing rare cancers are also very important. Patients' shared experiences show that problems such as fatigue and fluctuations in quality of life during mitotane use are still part of long-term management, and that family and psychological support play an important role in treatment compliance.

This reminds us that in addition to medical treatment, we also need to pay attention to the patient's overall health and his support system, which is alsoa manifestation of the "patient-centered" modern medical concept.

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8. Conclusion: Re-understand the value of mitotane in the era of change

As a classic drug that still has clinical value today, mitotane is not only an important part ofACC treatment, but also a witness to the intersection of history and future in the field of cancer treatment. With the vigorous development of precision medicine, immunotherapy and molecular targeted drugs, the role of mitotane will continue to be redefined and it will play a more comprehensive value in the new clinical and scientific research environment.

For clinicians, patients, and health policymakers, understanding the full impact of mitotane, including not only efficacy and side effects, but also drug accessibility, personalized treatment strategies, and new scientific directions, has profound implications for improving outcomes for patients with rare cancers.

References:

European Society of Endocrinology – Adrenocortical Carcinoma Clinical Practice Guidelines https://www.ese-hormones.org

NIH – Adrenocortical Carcinoma Overview https://www.cancer.gov/types/adrenocortical

PMC – Mitotane in Adrenocortical Carcinoma: Mechanisms and Clinical Use https://pmc.ncbi.nlm.nih.gov/articles/PMC7441215/

Orphanet – Adrenocortical Carcinoma and Treatment Landscape https://www.orpha.net