Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Miscellaneous Anticancer Drugs: 

  • Mitotane

    • Mitotane (Lysodren)

    •  

      DDT (Insecticide)

     

    • Overview:

      • Mitotane (Lysodren) is structurally similar to the prominent insecticides DDT (dichlorodiphenyltrichloroethane, see above structure) and DDD (dichlorodiphenyldichloroethane).¹ 

      • Mitotane is used in treating adrenal cortex carcinoma, exhibiting somewhat selective destruction of both normal and neoplastic adrenocortical cells.

        • Accordingly, it is classified as an adrenolytic drug directly suppressing the adrenal cortex and thus changing peripheral steroid metabolism.⁹

          • Mitotane administration induces a rapid decrease in adrenocortical steroid levels and metabolites in both blood and urine.

            • This response may be used in dose calibration as well as describing the hyperadrenocorticism (Cushing's syndrome), a consequence of adrenal hyperplasia or adrenal tumor.¹

              • Cushing Syndrome¹³

                Facial appearance following inhaled fluticasone administration. In addition to a round, red face, other signs and symptoms of Cushing's syndrome (extended exposure to glucocorticoids e.g. cortisol) include weak muscles, fatty lump between shoulders, acne and others). Attribution:  Ozlem Celik, Mutlu Niyazoglu, Hikmet Soylu and Pinar Kadioglu [CC BY 2.5 (https://creativecommons.org/licenses/by/2.5)] https://commons.wikimedia.org/wiki/File:CushingsFace.jpg https://en.wikipedia.org/wiki/Cushing%27s_syndrome

    • Absorption, Distribution, Biotransformation, Excretion: 

      • Mitotane is absorbed following oral administration (about 40%).^1,12 

      • Relatively high-fat solubility accounts for extended detection of mitotane in plasma after drug discontinuation (6-9 weeks).¹

      • Most of the administered mitotane dose (60%) is excreted unchanged in feces.

        • A mitotane water-soluble metabolite has been identified in urine and accounts for about 25% of the administered dose (oral or parenteral).¹

      • The half-life for elimination ranges from 18 to 159 days (median: 53 days).⁹

      • To achieve an antitumor response, a mitotane serum concentration of  ≥ 14 µg/mL is required.⁹

    • Mechanism of Action:

      • The mechanism of mitotane adrenocortical cytoxicity  remains to be determined.¹

    • Clinical Uses:

      • Mitotane is typically administered in divided oral doses for a minimum period of about three months.¹ 

      • Therapy may be continued indefinitely provided beneficial effects are observed.

      • In the case of palliation for adrenocortical carcinoma (inoperable), symptomatic improvement occurs in about 30%-50% of patients so categorized.¹ 

      • Adrenocortical carcinoma is considered both rare and very aggressive among the endocrine neoplasms.¹⁴ 

        • These tumors are most likely to occur during the first and fourth decades. In the pediatric setting, germline mutations (TP53 mutations) are typical predisposing factor.

        • Clinical presentations due to adrenocortical carcinoma involve either signs and symptoms associated with elevated androgen production or elevated cortisol levels (e.g. Cushing's syndrome).

          • Mixed syndromes are also observed with some frequency.

        • In the older group of patients nonfunctioning tumors appear more common; however, most children (90%) exhibit functioning neoplasms.

        • Excessive production of androgens manifesting as virilization signs represent the most typical presentation in children.¹⁴

      • The primary therapeutic approach for adrenocortical carcinoma is surgery and in patients with limited, regional disease complete resection with the intent of cure may be tried in about 75% of patients.

        • However, even in patients with localized primary tumor, as many as 80% experience recurrence.

          • Recurrences may be either local, local and distant, or solely distant (50%).

        • In adult patients exhibiting advanced disease or are thought to be at substantial recurrence risk, systemic therapy with mitotane or chemotherapy is considered most appropriate.¹⁴ 

          • Because mitotane suppresses adrenal steroidal secretion, symptomatic improvement with reduced endocrine dysfunction often occurs.

          • The adrenolytic effect is associated with higher doses.

            • In advanced disease,"objective responses" occurs in about 25% of cases.

              • These responses, however, are usually temporary and may not influence survival.

        • In children mitotane administration for advanced adrenocortical carcinoma awaits more complete evaluation.¹⁴ 

          • However, in children with advanced or metastatic disease complete responses are typically rare.

            • At the higher doses over extended periods required for adrenolytic activity, mitotane administration induces problematic gastrointestinal and neurologic toxicities.

              • Especially in children these toxicities reduce adherence to treatment.

        • Chemotherapeutic drugs other than mitotane have been considered for treating adrenocortical carcinoma.¹⁴ 

          • Regimens containing cisplatin may produce responses in about 30% of patients.

            • The combination of etoposide-containing agents with mitotane has also been considered.¹⁴

    • Toxicities/Adverse Effects:

      • A number of side effects or adverse effects have been associated with mitotane administration.¹ 

        • Most patients experience anorexia and nausea.

        • Lethargy and somnolence is noted in about 34% of patients with dermatitis occurring in about 17%.

        • Due to adrenocortical damage, replacement doses of adrenocorticosteroids is likely necessary.¹

        • Other CNS effects:⁹ 

          • Depression (≤ 40%)

          • Dizziness (≤ 40%)

          • Vertigo (≤ 40%)

        • Dermatologic:⁹

          • Skin rash (15%)

        • Cardiovascular:⁹

          • Flushing

          • Orthostatic hypotension

          • Hypertension

        • Genitourinary:⁹

          • Hematuria

          • Hemorrhagic cystitis

        • Hematologic/Oncologic:⁹

          • Neutropenia

          • Prolonged bleeding time

        • Liver:⁹

          • Hepititis

          • Elevated liver enzymes

        • Neuromuscular:⁹

          • Skeletal muscle weakness

        • Ophthalmic:⁹

          • Cataract

          • Diplopia

          • Blurred vision

          • Maculopathy

          • Retinopathy⁹

      • Adrenal crisis may occur in patients experiencing severe trauma and shock, with the response to shock being impaired in patients receiving mitotane.⁹ 

        • Discontinuation of mitotane until recovery is noted and hydrocortisone administration and monitoring may be appropriate.

        • As noted above, patients receiving mitotane and therefore developing adrenal-insufficiency may require steroid replacement treatment.

          • Appropriate steroid replacement can be assessed by measuring free cortisol and corticotropin (ACTH) levels.

        • Also, as noted above, mitotane may induce vomiting; therefore, antiemetic administration may be required to mitigate nausea and vomiting.

        • In premenopausal females receiving mitotane ovarian macrocysts have been described.

          • Complications associated with cysts such as adnexal torsion and hemorrhagic cyst rupture may occur.

        • Lastly, prolonged bleeding time may occur with mitotane.

          • This complication is considered uncommon but may have to be taken into account due to elevated bleeding risk associated with surgery.⁹