Doxorubicin

Doxorubicin (adriamycin, others) is available for intravenous use. The recommended dose is 50-75 mg2m2, administered as a single rapid intravenous infusion that is repeated after 21 days. A doxorubicin liposomal product (doxil) is available for treatment of AIDS-related Kaposi's sarcoma and is given intravenously in a dose of 20 mg2m2 over 30 minutes and repeated every 3 weeks. As for daunorubicin, patients should be advised that the drug may impart a red color to the urine. Doxorubicin is effective in malignant lymphomas but also is active in a number of solid tumors, particularly breast cancer. used in combination with cyclophosphamide, vinca alkaloids, and other agents, it is an important ingredient for the treatment of lymphomas. it is a valuable component of chemotherapy regimens for adjuvant and metastatic carcinoma of the breast and small cell carcinoma of the lung. The drug also is beneficial in a wide range of pediatric and adult sarcomas, including osteogenic, Ewing's, and soft tissue sarcomas.

The toxic manifestations of doxorubicin are similar to those of daunorubicin. Myelosuppres-sion is a major dose-limiting complication, with leukopenia usually reaching a nadir during the second week of therapy and recovering by the fourth week; thrombocytopenia and anemia follow a similar pattern but usually are less pronounced. Stomatitis, GI disturbances, and alopecia are common but reversible. Erythematous streaking near the site of infusion ("adriamycin flare") is a benign local allergic reaction and should not be confused with extravasation. Facial flushing, conjunctivitis, and lacrimation may occur rarely. The drug may produce severe local toxicity in irradiated tissues (e.g., the skin, heart, lung, esophagus, and GI mucosa). Such reactions may occur even when the two therapies are not administered concomitantly.

cardiomyopathy is the most important long-term toxicity. Two types of cardiomyopathies may occur:

1. An acute form is characterized by abnormal electrocardiographic changes, including ST- and T-wave alterations and arrhythmias. This is brief and rarely a serious problem. An acute reversible reduction in ejection fraction is observed in some patients in the 24 hours after a single dose, and elevation of troponin T is found in a minority of patients in the first few days following drug administration. An exaggerated manifestation of acute myocardial damage, the "pericarditis—myocarditis syndrome," may be characterized by severe disturbances in impulse conduction and frank congestive heart failure, often associated with pericardial effusion.

2. Chronic, cumulative dose-related toxicity (usually at or above total doses of 550 mg/m2) is manifested by congestive heart failure. The mortality rate in patients with congestive failure approaches 50%. Total dosage of doxorubicin as low as 250 mg/m2 can cause myocardial changes, including a decrease in the number of myocardial fibrils, mitochondrial changes, and cellular degeneration. Sequential echocardiograms have detected structural abnormalities in 25% of children who received up to 300 mg/m2 of doxorubicin, although <10% have clinical manifestations of cardiac disease in long-term follow-up. The frequency of clinically apparent cardiomyopathy is 1—10% at total doses below 450 mg/m2, increasing to >20% at total doses higher than 550 mg/m2; this total dosage therefore should be exceeded only under exceptional circumstances or with concomitant use of dexrazoxane, a cardioprotective iron-chelating agent. Cardiac irradiation, administration of high doses of cyclophosphamide or another anthracycline, or concomitant herceptin increases the risk of cardiotoxicity. Late-onset cardiac toxicity, with congestive heart failure years after treatment, may occur in both pediatric and adult populations. In children treated with anthracyclines, there is a three- to tenfold elevated risk of arrhythmias, congestive heart failure, and sudden death in adult life. A total dose limit of 300 mg/m2 is advised for pediatric cases; concomitant administration of dexrazoxane may reduce troponin T elevations that predict later cardiotoxicity.

newer analogs of doxorubicin Valrubicin (valstar) is approved for intravesical therapy of bacille Calmette-Guerin-refractory urinary bladder carcinoma in situ in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality. Epiru-bicin (4'-epidoxorubicin, ellence) is approved as a component of adjuvant therapy following resection of early lymph node-positive breast cancer. A related anthracenedione, mitoxantrone, has been approved for use in AML. Mitoxantrone has limited ability to produce quinone-type free radicals and causes less cardiac toxicity than does doxorubicin. Acute myelosuppression, cardiac toxicity, and mucositis are its major toxicities; the drug causes less nausea and vomiting and alopecia than doxorubicin. It also is used as a component of experimental high-dose chemotherapy regimens, with uncertain efficacy. Mitoxantrone (novantrone) is supplied for intravenous infusion. To induce remission in acute nonlymphocytic leukemia in adults, the drug is given in a daily dose of 12 mg/m2 for 3 days as a component of a regimen that also includes cytosine arabinoside. Mitoxantrone also is used in advanced, hormone-resistant prostate cancer in a dose of 12-14 mg/m2 every 21 days. Mitoxantrone is also approved for the treatment of late-stage, secondary progressive multiple sclerosis.

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