VA Class:AN900

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Mitotane

Chemical Name:

• 1,1-Dichloro-2-( o -chlorophenyl)-2-( p -chlorophenyl)ethane

Molecular Formula:

• C₁₄H₁₀Cl₄

Mitotane, an adrenocortical cytotoxic agent, is an antineoplastic agent and selective inhibitor of adrenocortical function.

Adrenocortical Carcinoma

Mitotane is used in the palliative treatment of inoperable functional and nonfunctional adrenocortical carcinoma, and most clinicians consider mitotane the drug of choice for the treatment of inoperable adrenocortical carcinoma.101,102,103 To minimize the possibility of infarction and hemorrhage in the tumor, all possible tumor tissue should be surgically removed from large metastatic masses prior to beginning mitotane therapy.101 Mitotane produces measurable tumor regression (determined by palpation or radiographic evaluation) in about 50% of patients with inoperable adrenocortical carcinoma. In patients treated for a median duration of 2.5-4 months, the median onset of tumor regression has been 4-6 weeks after starting treatment with the drug and the median duration of regression has been 6-7 months. About 75% of patients treated with mitotane have a steroid response characterized as a greater than 30% decrease in urinary excretion of 17-OHCS and/or 17-KS from elevated pretreatment values. Almost all patients whose tumors regress with mitotane have a steroid response, but only about 40% of those who have a steroid response have tumor regression. Urinary steroid excretion usually decreases within a few days to weeks after beginning mitotane therapy. The mean duration of steroid response has been about 5 months. About 50% of patients receiving mitotane have a general response characterized as symptomatic relief (e.g., decreased pain, weakness, or anorexia), increased ambulation, and/or reduction of physical effects caused by excessive steroid production.

Although it has not been definitely established, mitotane appears to prolong the survival of those patients whose tumors regress. There have been reports of a few patients who achieved complete remissions with long-term survival (greater than 5 years); however, in one of these patients, the tumor recurred after 12 years. Therefore, there is insufficient evidence to date to document a cure as a result of mitotane therapy.

Mitotane has been used as an adjunct† following surgery in the treatment of operable adrenocortical carcinoma in a limited number of patients; although its value as an adjunct to surgery has not been adequately studied, some clinicians recommend its use because of the known malignancy and frequent recurrence of the tumor following apparent radical surgery for localized or regional disease. In a retrospective analysis of patients who underwent radical resection of adrenocortical carcinoma, longer recurrence-free survival was reported in patients receiving adjuvant mitotane following surgery than in those receiving surgery alone.104 Patients receiving higher doses of mitotane (3-5 g daily) experienced more toxicity, particularly GI and neurologic toxicity, than those receiving lower doses (1-3 g daily).104

Although mitotane has been used with other antineoplastic agents in the treatment of patients with adrenocortical carcinoma, the benefit of such combination chemotherapy has not been established. Metyrapone or aminoglutethimide has been used in some patients receiving mitotane in order to decrease the dosage of mitotane and minimize its adverse GI effects.

Cushing's Syndrome

Mitotane has been effective in the treatment of Cushing's syndrome† secondary to pituitary disorders. Ideally, treatment of the disease should be aimed at normalization of the clinical and biochemical abnormalities involved. When mitotane was used alone, clinical remissions and normalization of cortisol indexes (i.e., cortisol secretion rate, plasma cortisol concentration, urinary free cortisol excretion) occurred in about 75-80% of patients, generally within 8 months after beginning treatment. Although many of these patients relapsed within 1-2 years after discontinuance of mitotane, additional courses of therapy usually produced further responses. In adults, mitotane used in conjunction with pituitary irradiation appears to be more effective than mitotane or radiation therapy alone. Clinical remissions and normalization of cortisol indexes have generally occurred within 4-16 months after beginning this combination therapy, and many patients have remained in remission for at least 2 years following discontinuance of mitotane. The relative efficacy of mitotane compared with other agents (e.g., aminoglutethimide, trilostane) in the treatment of Cushing's syndrome secondary to pituitary disorders has not been established in controlled studies. In addition, the best therapy or combination therapy for the treatment of such Cushing's syndrome has not been established, and comparative efficacy is continually being evaluated.

Mitotane has also been effective in some patients when used alone or in conjunction with metyrapone and/or aminoglutethimide in the treatment of Cushing's syndrome† secondary to ectopic corticotropin-producing tumors, usually when surgery was not feasible.

Administration

Mitotane is administered orally.

To minimize risk of dermal exposure, impervious gloves should be worn during handling of mitotane tablets or bottles of mitotane tablets in all settings, including storerooms, pharmacies, clinical settings, and home healthcare settings.101 Use of impervious gloves is recommended at all times during handling of mitotane tablets or bottles containing mitotane tablets, including unpacking and inspection, transport within a facility, and dose preparation and administration.101

Dosage

Dosage of mitotane must be based on the clinical response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects. Since mitotane causes adrenocortical insufficiency in most patients, replacement steroid therapy is usually necessary.101 (See Cautions: Precautions and Contraindications.) In order to minimize or prevent the potential adverse effects of adrenocortical insufficiency, many clinicians recommend that replacement steroids be started (and continued) when treatment with mitotane is initiated, rather than after signs of adrenocortical insufficiency appear.

Adrenocortical Carcinoma

In the palliative treatment of inoperable adrenocortical carcinoma, the initial adult dosage of mitotane is 1-6 g daily administered in 3 or 4 divided doses. Dosage is usually increased incrementally to 9-10 g daily;101 some clinicians increase mitotane dosage by 2-4 g daily, every 3-7 days. If severe adverse effects occur, dosage should be reduced until the maximum tolerated dosage is attained.101 In patients who can tolerate higher dosage and in whom improved clinical response appears possible, dosage may be increased until intolerable adverse effects occur.101 The maximum tolerable adult dosage of mitotane may range from 2-16 g daily but is usually 9-10 g daily;101 however, dosages up to 20 g daily have been used. Some clinicians have suggested that dosages higher than 6 g daily may not be necessary since responses have occurred at lower dosages and there is little evidence to support the necessity of increasing dosage until toxicity occurs.

The pediatric dosage of mitotane has not been well characterized. In the few reports of children treated with the drug, dosages of 1-4 g daily were generally used in children approximately 2-8 years of a in one 7-year-old girl, dosages up to 5-10 g daily were administered. Mitotane therapy in children can generally be initiated at a dosage of 0.5-1 g daily and increased according to the patient's response and tolerance.

Although mitotane has been administered intermittently in some patients with adrenocortical carcinoma, many of these patients did not respond after the third or fourth course of therapy; therefore, continuous administration of mitotane appears to be the preferred method of treatment.101 Mitotane therapy should be continued as long as clinical benefits are observed.101 Clinical benefit is evidenced as decreased cortisol secretion rate, plasma cortisol concentration, and urinary free cortisol or steroid excretion; as slowed growth or regression of the tumor; as maintenance of the patient's clinical status; and/or as symptomatic relief or reduction of physical effects caused by excessive steroid production. If no clinical benefits occur within 3 months of continuous mitotane therapy at the maximum tolerable dosage, the patient may be considered unresponsive; in clinical studies, only 10% of patients who had no measurable tumor regression by 3 months of mitotane treatment at the maximum tolerable dosage had a response to continued therapy.101 If an apparent complete remission occurs, some clinicians believe that continuous maintenance therapy may be necessary since relapse has occurred in at least 1 patient after 12 years in remission. Because the tumor recurred in this patient following a reduction in maintenance dosage and was subsequently controlled by increasing the dosage, it was suggested that a minimum effective dosage may be required to maintain a remission.

Cushing's Syndrome

In the treatment of Cushing's syndrome†, mitotane dosages of 1-12 g daily have been used. In the treatment of Cushing's syndrome secondary to pituitary disorders, the usual initial adult dosage of mitotane has been 3-6 g daily administered in 3 or 4 divided doses, and maintenance dosage has ranged from 500 mg twice weekly to about 2 g daily. In some of these patients, mitotane has been administered for as long as 7 years.

GI Effects

GI disturbances are the most common adverse effects of mitotane and are dose related. GI disturbances occur in about 80% of patients and are manifested as anorexia, nausea, vomiting, or diarrhea.101

Nervous System Effects

Adverse CNS effects occur in about 40% of patients and are manifested most frequently as lethargy and somnolence (which may be initially severe) and less frequently as dizziness or vertigo.101 Mental depression, headache, irritability, confusion, tremors, weakness, or fatigue may also occur. Rarely, speech difficulty, impaired memory, ataxia, neuropathy, myelopathy, hallucinations, psychosis, and encephalopathy have been reported. Brain damage and functional impairment may result from prolonged administration of high doses of mitotane.101

Adrenal Effects

Adrenocortical insufficiency occurs in most patients receiving mitotane, and the need to administer exogenous corticosteroids should be anticipated. (See Cautions: Precautions and Contraindications.)

Dermatologic Effects

Maculopapular rash occurs in about 15% of patients receiving mitotane. The rash is generally transient and does not appear to be dose related; in some patients, the rash may disappear despite continued treatment and without dosage adjustment. Urticaria, erythema multiforme, hyperpigmentation, chloasma, perinasal scaling, facial or periorbital swelling, and alopecia have been reported rarely.

Ocular Effects

Blurring of vision, diplopia, lens opacities, and toxic retinopathy occur infrequently in patients receiving mitotane.101 Other adverse ocular effects of mitotane, including optic neuritis, and papilledema and retinal hemorrhage associated with toxic retinopathy, have been reported.

Genitourinary Effects

Adverse genitourinary effects, such as hematuria, hemorrhagic cystitis, and albuminuria, occur infrequently in patients receiving mitotane.101

Cardiovascular Effects

Hypertension, orthostatic hypotension, and flushing occur infrequently in patients receiving mitotane.101

Other Adverse Effects

Hypouricemia and elevations in serum cholesterol occur frequently in patients receiving mitotane. The decrease in serum uric acid concentration generally begins within 1 day and is maximal within 5-10 days after beginning therapy with the drug. Gynecomastia has occurred in men receiving mitotane and has been associated with increased urinary excretion of estrogens.

Other adverse effects of mitotane that occur infrequently include decreased hearing, excessive salivation, wheezing, shortness of breath, arthralgia, myalgia, and fever. Generalized aching, hyperpyrexia, and lowered protein-bound iodine have occurred in patients receiving mitotane.101 Rarely, leukopenia or thrombocytopenia has been reported. Elevations in serum β- or pre-β-lipoproteins, alkaline phosphatase, AST (SGOT), and bilirubin have also occurred.

Precautions and Contraindications

The incidence of adverse effects in patients receiving mitotane is very high. The manufacturer states that patients should be hospitalized when mitotane therapy is initiated and until a stable dosage regimen is established (usually 5-7 days); however, some clinicians state that, unless the patient is severely debilitated, hospitalization is usually not necessary during initiation of mitotane therapy when replacement steroids are administered concomitantly. Mitotane must be used only under constant supervision by physicians experienced in therapy with the drug.101

Glucocorticoid therapy is usually necessary in patients receiving mitotane. Administration of a mineralocorticoid may also be required, especially with prolonged mitotane therapy. Because mitotane alters the extra-adrenal metabolism of steroids, higher than usual replacement doses of steroids may be necessary. If mitotane is discontinued in patients receiving steroids, some clinicians recommend that steroid therapy should not be discontinued without closely observing the patient for signs of adrenocortical insufficiency since mitotane is eliminated slowly from the body. Although some clinicians believe that the adrenocortical inhibitory effects of mitotane generally subside within several weeks after discontinuance of the drug, permanent replacement corticosteroid therapy may be required rarely. Because acute adrenocortical insufficiency may be precipitated by shock, severe trauma, or infection in patients receiving mitotane, mitotane should be temporarily discontinued and corticosteroids administered immediately following the occurrence of any of these conditions.101 Because of an increased risk of acute adrenocortical insufficiency, patients should also be instructed to contact their physician immediately if injury, infection, or other illness occurs. In order to alert medical and paramedical personnel in emergency situations, it may be advisable for patients receiving mitotane to carry a notice stating that they are undergoing mitotane therapy and adrenocortical insufficiency may occur.

Since prolonged mitotane therapy may cause severe adverse neurologic effects including brain damage and functional impairment, behavioral and neurologic assessments should be performed periodically in patients receiving mitotane continuously for longer than 2 years.101

Patients should be warned that mitotane may impair their ability to perform hazardous activities requiring mental alertness or physical coordination such as operating machinery or driving a motor vehicle.101

Some clinicians recommend that hepatic function be monitored in patients receiving mitotane. The manufacturer states that mitotane should be administered with caution in patients with liver disease other than metastasis of adrenocortical carcinoma, since metabolism of mitotane may be reduced in these patients with resultant accumulation of the drug;101 however, there is no evidence to date that it is necessary to routinely reduce mitotane dosage in patients with impaired hepatic function.

If mitotane is used in patients receiving a coumarin-derivative anticoagulant (e.g., warfarin), careful monitoring is required, and dosage adjustment of the anticoagulant may be necessary.101

Mitotane is contraindicated in patients with known hypersensitivity to the drug.101

Pediatric Precautions

The manufacturer states that safety and efficacy of mitotane in children have not been established.101

Geriatric Precautions

Clinical studies of mitotane did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.101 While other clinical experience has not revealed age-related differences in response or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.101 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.101

Mutagenicity and Carcinogenicity

The mutagenic and carcinogenic potentials of mitotane are not known; however, because of its mechanism of action, the drug probably has less carcinogenic potential than most other antineoplastic agents.101

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies have not been performed with mitotane.101 It is not known whether mitotane can cause fetal harm when administered to pregnant women or can affect reproduction capacity.101 Mitotane should be used during pregnancy only when clearly needed.101 The prolonged elimination of mitotane from the body after discontinuance of the drug should be considered.

Lactation

It is not known whether mitotane is distributed into milk.101 Because of the potential for serious adverse reactions to mitotane in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.101 The prolonged elimination of mitotane from the body after discontinuance of the drug should be considered.

Hepatic Microsomal Enzyme Induction

Mitotane has been reported to increase the metabolism of coumarin through induction of hepatic microsomal enzymes.101 If mitotane is used in patients receiving a coumarin-derivative anticoagulant (e.g., warfarin), careful monitoring is required, and dosage adjustment of the anticoagulant may be necessary.101 In addition, mitotane should be administered with caution to patients receiving other drugs (e.g., barbiturates, phenytoin) influenced by hepatic enzyme induction.101

CNS Depressants

Additive CNS depression may occur when mitotane is administered concomitantly with other CNS depressants.

Other Drugs

In one patient with Cushing's syndrome secondary to adrenal hyperplasia, spironolactone reportedly blocked the action of mitotane; since a study in dogs provided supporting data for such an interaction, it has been suggested that the drugs should not be administered concomitantly.

Laboratory Test Interferences

Tests for Adrenal Steroids

Since mitotane apparently increases the extra-adrenal metabolism of cortisol to 6-β-hydroxycortisol, the proportion of cortisol excreted in urine as the tetrahydrocortisol and tetrahydrocortisone glucuronides (measurable 17-OHCS) is reduced. Thus, although measurable urinary 17-OHCS may decrease in the first several weeks of mitotane therapy, the reduction may not necessarily reflect a decrease in cortisol secretion rate or plasma cortisol concentration. Therefore, in addition to measurement of urinary 17-OHCS, most clinicians recommend that the therapeutic effects of mitotane be monitored by determinations of peak diurnal (usually morning) plasma cortisol concentration and urinary free cortisol excretion. Some clinicians also recommend that the effects of mitotane on aldosterone be monitored by determinations of serum aldosterone concentration, since it has been suggested that decreased urinary excretion of aldosterone metabolites may not necessarily reflect a decrease in serum aldosterone concentration.

Tests for Thyroid Function

Mitotane competitively binds to thyroxine-binding globulin and decreases serum protein-bound iodine; total serum thyroxine concentration may be unchanged or slightly decreased, but free thyroxine concentrations apparently remain in the normal range. Resin triiodothyronine uptake test results are apparently not affected by the drug.

Pharmacology

The exact mechanisms of action of mitotane have not been clearly established. Although mitotane is an adrenocortical cytotoxic agent, the drug can also apparently inhibit adrenocortical function without causing cellular destruction.101 Mitotane appears to selectively inhibit adrenocortical function as well as functional and nonfunctional adrenocortical neoplasms by a direct cytotoxic effect; this effect may be mediated through covalent bonding of mitotane metabolites to mitochondrial proteins. The drug causes focal degeneration in the zona fasciculata and reticularis of the adrenal cortex with resultant atrophy. The drug usually causes only minimal degeneration in the zona glomerulosa (site of aldosterone biosynthesis); however, the zona glomerulosa may be damaged with prolonged mitotane therapy. (See Cautions: Precautions and Contraindications.) Mitotane also reportedly inhibits the growth of human renal carcinoma cells, astrocytoma cells, and fibroblasts in vitro.

Mitotane inhibits production of corticosteroids and alters extra-adrenal metabolism of endogenous and exogenous steroids. Mitotane inhibits the normal 11-β-hydroxylation of 11-deoxycortisol (compound S) and 11-deoxycorticosterone (DOC) in the adrenal cortex, thus blocking conversion of compound S to cortisol (hydrocortisone) and DOC to corticosterone. The drug can also inhibit 18-hydroxylase activity in the adrenal cortex and thus decrease the production of aldosterone by blocking the conversion of corticosterone to 18-hydroxycorticosterone (the immediate precursor of aldosterone). Mitotane decreases cortisol secretion rate; plasma cortisol concentration; urinary excretion of free cortisol, 17-hydroxycorticosteroids (17-OHCS), 17-ketosteroids (17-KS), and 17-ketogenic steroids; and adrenocortical response to stimulation by corticotropin (ACTH). A feedback increase in plasma corticotropin concentration is generally observed in patients receiving mitotane; however, a lack of feedback increase or a decrease in plasma corticotropin concentration has been observed in some patients. Therefore, it has been suggested that the drug may have a partial suppressive effect on pituitary corticotropin-secreting cells. Mitotane apparently increases the extra-adrenal metabolism of cortisol to 6-β-hydroxycortisol which results in decreased urinary excretion of measurable 17-OHCS; this occurs even in the presence of unchanged cortisol secretion rate or plasma cortisol concentration. (See Laboratory Test Interferences: Tests for Adrenal Steroids.) Although urinary excretion of aldosterone metabolites may decrease, serum aldosterone concentrations may remain in the normal range. Therefore, it has been suggested that mitotane may also alter the extra-adrenal metabolism of aldosterone. Mitotane decreases the extra-adrenal conversion of androgens to androsterone and etiocholanolone; this results in decreased urinary excretion of 17-KS. The drug also inhibits the extra-adrenal conversion of 3-β-hydroxysteroids to 3-α-hydroxypregnane derivatives.

Mitotane has uricosuric activity and thus decreases serum uric acid concentrations; the exact mechanism of the increase in renal uric acid clearance has not been established.

Pharmacokinetics

Absorption

Approximately 35-40% of an oral dose of mitotane is absorbed from the GI tract. Peak plasma mitotane concentrations occur 3-5 hours after a single oral dose of the drug and distribution of the drug between plasma and tissues is complete within 12 hours. In one study in patients with adrenocortical carcinoma who were receiving an oral dosage of 5-15 g of mitotane daily, serum mitotane concentrations were 7-90 mcg/mL and serum concentrations of mitotane metabolites were 29-54 mcg/mL. Serum concentrations of mitotane and its metabolites appear to plateau after about 8 weeks of continuous mitotane therapy and generally have not appeared to correlate with therapeutic or toxic effects of the drug; however, some data suggest that tumor regression in patients with adrenocortical carcinoma is associated with serum mitotane concentrations greater than 14 mcg/mL and that adverse CNS effects are associated with serum concentrations greater than 20 mcg/mL.100 The onset of inhibition of adrenocortical function usually occurs within 2-4 weeks after beginning therapy with mitotane.

Distribution

Mitotane and its metabolites are distributed to essentially all body tissues with fat being the primary storage site; there is no selective accumulation in the adrenals. Following discontinuance of mitotane therapy, persistent plasma concentrations of mitotane and its metabolites are probably caused by their slow release from fat and other tissues. Although unchanged mitotane has not been detected in CSF, small amounts of one mitotane metabolite have been detected in CSF. It is not known if mitotane or its metabolites cross the placenta or distribute into milk.

Elimination

Mitotane reportedly has a plasma elimination half-life of 18-159 days.101 Plasma and tissue concentrations of mitotane and its metabolites decline slowly. Following discontinuance of mitotane, unchanged drug and trace amounts of metabolites have been detected in plasma for up to 8 months and 18 months, respectively.

Mitotane is metabolized in the liver and other tissues principally to o,p '-dichlorodiphenyl-ethene and -acetate derivatives; small amounts of these derivatives apparently undergo aromatic hydroxylation and glycine conjugation. Mitotane is excreted as metabolites in urine and bile. Approximately 10% of an oral dose of mitotane is excreted in urine and up to 15% is excreted in bile within 24 hours.

Chemistry and Stability

Chemistry

Mitotane is an adrenocortical cytotoxic agent which is structurally related to the insecticide chlorophenothane (DDT). The drug occurs as a white, crystalline powder with a slight aromatic odor and is practically insoluble in water and soluble in alcohol.

Stability

Commercially available mitotane tablets should be stored in tight, light-resistant containers. Mitotane tablets should be stored at 25°C, but excursions to 15-30°C are permitted.101

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs.

Only references cited for selected revisions after 1984 are available electronically.

100. van Slooten HV, Moolenaar AJ, van Seters AP et al. The treatment of adrenocortical carcinoma with o,p '-DDD: prognostic simplifications of serum level monitoring. Eur J Cancer Clin Oncol . 1984; 20:47-53. [PubMed 6537915]

101. Bristol-Myers Squibb. Lysodren^® (mitotane tablets) prescribing information. Princeton, NJ; 2006 Aug.

102. Anon. Drugs of choice for cancer. Treat Guidel Med Lett . 2003; 1:41-52.

103. Adrenocortical carcinoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 May 16.

104. Terzolo M, Angeli A, Fassnacht M et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med . 2007; 356:2372-80. [PubMed 17554118]