Mitotane Therapy (MTT)
Mitotane Therapy (MTT)
Mitotane therapy (MTT) is a specialized treatment primarily used for adrenocortical carcinoma (ACC), a rare cancer of the adrenal cortex. Mitotane, also known by the brand name Lysodren, is an oral adrenolytic agent with unique properties and a challenging side effect profile.
Indications
- Primary use: Treatment of inoperable, relapsed, or metastatic adrenocortical carcinoma (ACC)127.
- Adjuvant therapy: Used after surgical removal of ACC to reduce recurrence risk, especially in patients with high-risk features47.
- Other uses: Occasionally used off-label for Cushing’s syndrome when other treatments are unsuitable24.
Mechanism of Action
- Adrenolytic effect: Mitotane selectively destroys cells of the adrenal cortex, reducing both cancerous and normal adrenal tissue function125.
- Steroidogenesis inhibition: It inhibits key enzymes involved in steroid hormone synthesis, notably by blocking intramitochondrial pregnenolone and cortisol synthesis47.
- CYP3A4 induction: Mitotane strongly induces the liver enzyme CYP3A4, leading to rapid inactivation of cortisol and other steroids, which can complicate hormone replacement therapy7.
- Result: Decreases production and increases breakdown of adrenal hormones, helping control symptoms of hormone excess (e.g., Cushingoid features)127.
Administration
- Form: Oral tablets, taken with fatty food to enhance absorption1.
- Dosing: Carefully titrated based on blood levels and patient tolerance. Dose adjustments are often needed due to side effects and drug interactions16.
- Monitoring: Close monitoring for therapeutic levels and side effects is essential, as mitotane has a narrow therapeutic window and long half-life6.
Efficacy
- Improved outcomes: Early initiation after surgery appears more effective than delayed therapy for ACC4.
- Survival benefit: Some studies suggest improved survival in high-risk ACC patients receiving adjuvant mitotane, though its efficacy remains debated47.
Side Effects and Risks
- Common side effects: Gastrointestinal symptoms (nausea, vomiting, diarrhea), drowsiness, dizziness, skin rash, loss of appetite, darkening of the skin, mental depression, and fatigue136.
- Serious risks:
- Adrenal insufficiency: Mitotane can cause profound adrenal suppression, requiring lifelong glucocorticoid (and sometimes mineralocorticoid) replacement136.
- Adrenal crisis: Especially during stress or illness, patients are at risk for life-threatening adrenal crisis and require prompt steroid supplementation3.
- Hepatotoxicity and cytopenias: Increased liver enzymes and reduced blood cell counts may occur4.
- Drug interactions: Potent induction of CYP3A4 can reduce the effectiveness of many medications, including steroid replacements7.
- Monitoring: Regular blood tests for drug levels, liver function, and hormone status are required67.
Summary Table
| Aspect | Details |
|---|---|
| Main Indication | Adrenocortical carcinoma (inoperable, metastatic, adjuvant post-surgery) |
| Mechanism | Adrenolytic, inhibits steroidogenesis, induces CYP3A4 |
| Administration | Oral tablets with fatty food, titrated dosing, long-term monitoring |
| Key Side Effects | GI upset, drowsiness, adrenal insufficiency, skin changes, depression, hepatotoxicity |
| Major Risks | Adrenal crisis, drug interactions, cytopenias |
| Monitoring | Drug levels, hormone status, liver and blood counts |
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References
- Cancer Research UK. Mitotane (Lysodren) | Cancer information.
https://www.cancerresearchuk.org/about-cancer/treatment/drugs/mitotane-lysodren - DrugBank. Mitotane: Uses, Interactions, Mechanism of Action.
https://go.drugbank.com/drugs/DB00648 - Drugs.com. Mitotane Side Effects: Common, Severe, Long Term.
https://www.drugs.com/sfx/mitotane-side-effects.html - PubMed. Clinical results of the use of mitotane for adrenocortical carcinoma.
https://pubmed.ncbi.nlm.nih.gov/11004719/ - PubMed. A review of mitotane in the management of adrenocortical cancer.
https://pubmed.ncbi.nlm.nih.gov/39037424/ - The Journal of Clinical Endocrinology & Metabolism. Mitotane Therapy in Adrenocortical Cancer Induces CYP3A4 and …
https://academic.oup.com/jcem/article/98/1/161/2823144
Summary:
Mitotane therapy is a cornerstone in the management of advanced or high-risk adrenocortical carcinoma, with a unique mechanism targeting adrenal steroid production and significant potential for toxicity. Successful therapy requires careful dosing, monitoring, and management of side effects, especially adrenal insufficiency and drug interactions.
