Drug Allows Higher Doxorubicin Doses in Breast Ca Patients

NEW YORK--Dexrazoxane (Zine-card), which was developed in GreatBritain in the 1960s as an anticancer drug, is extremely effectivein blocking the cardiotoxic effects of doxorubicin, said JamesL. Speyer, MD, professor of clinical medicine, Department of Oncology,New York University Medical Center.

Dexrazoxane was recently approved by the FDA for use in at-riskbreast cancer patients, but may be useful for other malignancies,including several pediatric cancers, he said in a presentationat the Chemotherapy Foundation symposium.

Doxorubicin is a mainstay of chemotherapy in breast cancer, Hodgkin'slymphomas, childhood leukemias, and many solid tumors, Dr. Speyersaid. Nonetheless, its tendency to induce cardiomyopathy at higherdoses poses a major clinical problem in the management of thesemalignancies.

With higher doses and dose-intensive therapies, the problem isbecoming more common. The result is that, in an effort to avoidtoxicity, many patients do not receive optimal doses, and amongthose that do, some suffer cardiac symptoms.

Children are among those whose treatments may be modified becauseof cardiac risk. "Recent reports in children highlight theincreased sensitivity of this population as a function of dose,dose intensity, age at which treatment is received, and sex,"Dr. Speyer said.

Dexrazoxane appears to work through chelation of intracellulariron with reduction of the iron-doxorubicin complex and decreasedfree-radical production. It is not effective for preexisting cardiacconditions, but when given in conjunction with a doxorubicin-containingregimen, it appears to confer cardiac protection without interferingwith the antitumor action of doxorubicin. Its dose-limiting toxicityis myelosuppres-sion, Dr. Speyer said.

Randomized Trials

Randomized trials were conducted at NYU with 150 breast cancerpatients receiving a regimen of fluorouracil, doxorubicin, andcyclophosphamide (FAC). Seventy-six women were pretreated with1,000 mg/m² of dexrazoxane, followed by chemotherapy; thecontrol group received chemotherapy alone. Study endpoints weredevelopment of cardiotoxicity or disease progression.

The dexrazoxane group received more aggressive treatment thanthe controls, with higher cumulative doses of doxorubicin andmore treatment cycles. The response rates, time to progression,and survival were similar in both groups.

In confirmatory, double-blinded multicenter trials, 500 mg/m²of dex-razoxane was tried in patients receiving chemotherapy forbreast cancer and small-cell lung cancer. The toxicity profilesand cardioprotection were confirmed. There appeared, however,to be some interference with the antitumor efficacy of the FACregimen in one breast cancer trial.

In an amended trial of breast cancer patients, both dexrazoxaneand control groups received dexrazoxane after the sixth chemotherapycycle and after each subsequent cycle. This demonstrated thatdexrazoxane given even after the sixth cycle of treatment wassignificantly car-dioprotective without interfering with antitumoreffects.

Further trials are needed to determine the best dose and schedulefor dexrazox-ane, especially with more dose-intense doxorubicinregimens, Dr. Speyer said. Other questions to be answered by additionalclinical trials are whether the cardioprotection applies to pediatricpatients, and whether the protection without compromise of doxorubicin'scytotoxic effects is limited to breast cancer or applies to awider range of cell lines.