Lipid Doxorubicin Is Active in Ovarian Cancer

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

Doxil, administered in a dose of 50 mg/m²every 21 days for threecycles (and every 28 days thereafter or before cycle 3 if toxic effectswere 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 InternationalCongress on Anti-Cancer Treatment.

Roughly a third of the 35 study participants had bulky disease. "Mostremarkable was the duration of response, which varied from 10-plus monthstime on treatment to upwards of 18 months," said Dr. Muggia, who isnow at New York University's Kaplan Cancer Center. Median survival reached13.7 months.

Despite median cumulative Doxil doses exceeding 700 mg/m², noneof the patients exhibited a drop in left ventricular ejection fraction."So clearly, cumulative cardiotoxicity has not been reached at thesedoses," he said.

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

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

Because the active drug in Doxil is packed in a tight gel in a bilipidlayer with polyethylene glycol on the surface, it is able to evade themacrophages, leading to prolonged circulation in the blood. He suggestedthat the tumor vasculature may allow preferential localization of the circulatingliposomes, with the result that more drug is driven into the tumor.