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Lipid Doxorubicin Is Active in Ovarian Cancer

Lipid Doxorubicin Is Active in Ovarian Cancer

PARIS--A new formulation of doxorubicin in "stealth" liposomes (Doxil) provides durable responses in refractory epithelial ovarian cancer and primary peritoneal cancer, while apparently sidestepping the cardiotoxicity that limits the continued use of free doxorubicin in responding patients, according to two phase II studies performed at the University of Southern California (USC), Los Angeles.

Doxil, administered in a dose of 50 mg/m²every 21 days for three cycles (and every 28 days thereafter or before cycle 3 if toxic effects were already apparent), produced an objective response in more than 25% of relatively heavily pretreated patients who had not responded to pacli-taxel (Taxol) and platinum, Franco M. Muggia, MD, said at the 7th International Congress on Anti-Cancer Treatment.

Roughly a third of the 35 study participants had bulky disease. "Most remarkable was the duration of response, which varied from 10-plus months time on treatment to upwards of 18 months," said Dr. Muggia, who is now at New York University's Kaplan Cancer Center. Median survival reached 13.7 months.

Despite median cumulative Doxil doses exceeding 700 mg/m², none of the patients exhibited a drop in left ventricular ejection fraction. "So clearly, cumulative cardiotoxicity has not been reached at these doses," he said.

The USC investigators have gone on to launch a second phase II study open to any epithelial ovarian cancer patient who is refractory to multiple therapies, including radiation and bone marrow transplant. Preliminary results have confirmed the activity documented in the earlier trial, Dr. Muggia said. He noted that the most durable responses tend to be seen in the least heavily pretreated patients.

The dose-limiting toxicities of Doxil are hand and foot syndrome, which is related to the frequency of dosing, and stomatitis, related to the doxorubicin dose. "The favorable toxicity profile renders it a useful drug for salvage," he said, "but I think that because there is very little hematologic toxicity, it may have promise as a first-line therapy."

Because the active drug in Doxil is packed in a tight gel in a bilipid layer with polyethylene glycol on the surface, it is able to evade the macrophages, leading to prolonged circulation in the blood. He suggested that the tumor vasculature may allow preferential localization of the circulating liposomes, with the result that more drug is driven into the tumor.

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