Description: Estramustine is an oral, nitrogen mustard antineoplastic agent that is used to treat prostate cancer. Estramustine is a combination of an estradiol molecule linked to nornitrogen mustard. The oral compound contains a phosphate group that facilitates higher water solubility and oral absorption. In patients with hormone-refractory prostate cancer, estramustine has produced responses in 30�60% of patients as measured by reductions in tumor size, pain, and prostate specific antigen levels. Combination therapy of estramustine with paclitaxel, etoposide, or vinorelbine for the treatment of prostate or breast cancers is being investigated. Estramustine has also been studied in vitro and in vivo for the treatment of malignant glioma. The oral form of estramustine phosphate is the disodium salt of the compound. Estramustine was approved by the FDA in December 21, 1981. An intravenous formulation of estramustine is under investigation. Mechanism of Action: Estramustine is classified as an alkylating agent, but its mechanism of action is probably due to antimicrotubule activity. Estramustine possesses several unique pharmacologic actions. The estradiol portion of estramustine was originally designed to facilitate uptake by steroid receptors in malignant cells, to be followed by a release of the nitrogen mustard alkylating moiety. Prolonged treatment with estramustine produces elevated levels of estradiol similar to levels seen with conventional estrogen therapy for prostate cancer. Estrogenic effects as demonstrated by changes in circulating levels of steroids and pituitary hormones, are similar in patients treated with either estramustine or conventional estradiol therapy. The selective uptake and incorporation of estramustine in tumor tissues is probably due to the presence of estramustine-binding protein (EMBP), which is found in prostatate carcinoma, glioma, melanoma, and breast carcinoma. Estramustine binds to high molecular weight microtubule associated proteins and/or tubulin which results in the microtubule disassembly and arrest of cell division in the G2/M phase of the cell cycle.[2880] In addition to antimicrotubule activity, estramustine causes rapid and dose-related DNA strand breaks, and may inhibit DNA synthesis.[2879] Estramustine resistant cells exhibit no cross-resistance to other antimicrotubule agents and natural products, in which resistance is conferred by the (multidrug resistance) MDR phenotype. The phosphate moiety of orally administered estramustine may bind calcium, especially in patients with metabolic bone diseases that are associated with hypercalcemia, or in patients with renal insufficiency. Estramustine may also have cytotoxic effects through the production of apoptosis, or programmed cell death, which has been demonstrated in glioma cells in a rat model in vitro, and in vivo.[2880] Estramustine may not be totally active through hormonal mechanisms, since it is active in cell lines that lack estrogen receptors. The combination of estramustine and other microtubule agents, such as vinblastine and paclitaxel, may produce synergistic cytotoxicity in vitro. Pharmacokinetics: Estramustine is administered orally. Approximately 44�75% of orally administered estramustine phosphate is absorbed from the gastrointestinal tract. Estramustine phosphate is readily dephosphorylated during absorption, and peak plasma concentrations are achieved in 2�3 hours. The metabolites in plasma are estramustine, estromustine, estradiol and estrone. Estromustine (17-keto analog) is the major metabolite. Estramustine is excreted as metabolites of both the alkylating and estrogenic moieties in the bile, urine and feces. Nonrenal excretion is considered the main route of elimination. Elimination half-life is 20�24 hours. [ Revised Indications...Dosage For the palliative treatment of metastatic and/or progressive prostate cancer: Oral dosage: Adults: 14 mg/kg/day or 600 mg/m2/day PO administered in three or four divided doses. Therapy should be continued for as long as a favorable response lasts. Patients should be treated for 30�90 days before response is evaluated and determination of benefit is made. Some patients have been maintained on therapy for more than 3 years at a dose up to 16 mg/kg/day. Maximum Dosage Limits The suggested maximum tolerated dose (MTD) for estramustine is dependent on the disease state, performance status, and other chemotherapy agents or radiation therapy given in combination, and is as follows: �Adults: 20�25 mg/kg/day PO has been suggested. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Patients with hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Estramustine may be poorly metabolized in patients with hepatic disease, so it should be administered with caution in such patients. Oral Administration �Estramustine should be swallowed with water on an empty stomach (i.e., at least one hour prior to or two hours after a meal). Do not administer with milk, milk products, or calcium-containing foods or drugs. �Store under refrigeration 36�46 degrees F (2�8 degrees C). The capsules may be stored outside of the refrigerator at normal room temperature, out of direct sunlight, for no more than 2 days without affecting the strength of the medicine. Contraindications Estramustine should not be used in patients with active thromboembolic disease, stroke or thrombophlebitis, except in rare cases where the actual tumor mass is the cause of the thromboembolic disease and the benefits of therapy outweigh the risks. In patients with a history of thromboembolic disease or disorder, estramustine should be given with extreme caution, especially if these disorders were associated with estrogen therapy. There is an increased risk of thrombosis, including fatal myocardial infarction, in men who take estrogen and estrogen-like compounds such as estramustine for prostate cancer. Estramustine should be administered with caution to men with a history of cerebrovascular disease, or cardiac disease, including coronary artery disease or hypertension. Blood pressure should be monitored periodically in patients receiving estramustine. Patients with congestive heart failure or preexisting peripheral edema may experience exacerbations of these conditions during treatment with estramustine. Other conditions that may be affected by estramustine-induced fluid retention include seizure disorders, migraine, or renal failure. In addition, estramustine may influence the metabolism of calcium and phosphorus. Therefore, estramustine should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia, or in patients with known renal impairment. Estramustine should not be given to a woman who is breast-feeding her infant due to potential toxicities to the infant. It is not known if estramustine is excreted in breast milk. However, a metabolite of estramustine (i.e., estradiol) has been reported to interfere with milk production and duration of lactation in some women. Less than 10% of an estradiol dose passes into breast milk. Patients with a history of varicella, other herpes infection (e.g., herpes zoster), or other viral infections are at risk for reactivation of prior infections when treated with estramustine or other chemotherapy. Estramustine may decrease glucose tolerance, so patients with diabetes mellitus should be carefully observed. Estramustine may be poorly metabolized in patients with hepatic disease, so it should be administered with caution in such patients or in patients with jaundice. Although testing has failed to demonstrate mutagenicity for estramustine phosphate, it is known that both estradiol and nitrogen mustard are mutagenic (FDA pregnancy risk category D). In addition, some patients who had been impotent while on estrogen therapy have regained potency while taking estramustine; therefore, both males and females should use effective contraception while receiving estramustine therapy. The safety and efficacy of estramustine in children have not been established. Vaccination during estramustine, other chemotherapy, or radiation therapy should be avoided because the antibody response is suboptimal. Live virus vaccines are contraindicated during therapy with antineoplastic agents due to the potentiation of virus replication, adverse reactions to the virus, and the immunocompromised status of the patient. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition, to vaccination. Interactions Administration of estramustine with calcium carbonate and other calcium salts, may impair estramustine absorption significantly, due to formation of calcium-phosphate complex. It is recommended that estramustine be taken 1 hour before or 2 hours after meals as food containing calcium salts may also interfere with oral absorption of estramustine. Concurrent use of estramustine with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects. The immune response of the immunocompromised patient to vaccines is decreased and higher doses or more frequent boosters may be required. Despite these dose increases, the immune response may still be suboptimal. Live virus vaccines are contraindicated during therapy with antineoplastic agents due to the potentiation of virus replication, adverse reactions to the virus, and the immunocompromised status of the patient. Those undergoing antineoplastic therapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Estimates for postponing vaccination vary from 3 months to 1 year following discontinuation of treatment depending of the type of antineoplastic agent used and the disease state of the patient. Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; no significant change was seen with digoxin capsules, and the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. Digoxin capsules (Lanoxicaps�) may be utilized to avoid this interaction in patients receiving antineoplastic agents and digoxin tablets. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy. Adverse Reactions Nausea/vomiting are common and are considered the dose-limiting toxicities of estramustine therapy. Nausea/vomiting are usually transient and responsive to conventional antiemetics; however, intractable vomiting is occasionally noted after 6 to 8 weeks of treatment and may require the termination of therapy. Diarrhea may occur in as many as 15�30% of patients. Other gastrointestinal effects that may occur include anorexia, flatulence, and xerosis. Estramustine and estrogen-like compounds can cause sodium and fluid retention, resulting in peripheral edema, dyspnea, mild weight gain or symptoms of congestive heart failure, especially in patients with depressed cardiac function. In addition, estrogens can slightly increase blood pressure, occasionally causing hypertension. Estramustine is metabolized in the liver, and therapy may result in elevated hepatic enzymes (LDH, SGOT) or hyperbilirubinemia. Myelosupression during estramustine therapy is uncommon, but leukopenia and thrombocytopenia are occasional adverse events. Changes in mental status have been reported in patients receiving estramustine. The most commonly reported effects are emotional lability, depression and lethargy. These effects are probably due to the estrogen component of the compound. Thromboembolism, thrombophlebitis and thrombus formation are occasional, serious adverse reactions to estramustine therapy, and may include myocardial infarction, deep venous thrombosis, pulmonary embolism, or stroke. Estramustine may decrease glucose tolerance leading to hyperglycemia, so patients with diabetes mellitus should be carefully observed. Gynecomastia, mastalgia, and nipple tenderness occurs in most patients receiving estramustine therapy, but these effects can be prevented by prophylactic breast irradiation. Libido decrease can also be a troublesome adverse effect associated with the estrogenic activity of the compound. Pruritus and rash (unspecified) are occasional but troublesome adverse effects that can occur during estramustine therapy.
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Estramustine Emcyt� 2880. Bergenheim AT, Henriksson R. Pharmacokinetics and pharmacodynamics of estramustine phosphate. Clin Pharmacokinet 1998;34:163�72. 2879. Bergenheim AT, Henriksson R, Piepmeier JM et al. Estramustine in malignant glioma. J Neurooncol 1996;30:81�9. |