Liposome Technology for Solid Tumors: Where Does it Work?

Abstract

The expectations from preclinical data that liposomes improve the therapeutic index of anthracyclines has now been verified in clinical studies of several liposomal preparations. The liposomes that have been used have varied in size, lipid composition, stability when injected in-vivo and pharmacology. Liposomes coated with polyethylene glycol on the surface are protected from the attack of lipoproteins and opsonins, and consequently have prolonged circulation. Based on superior activity to free doxorubicin against a number of xenografts, clinical studies with Doxil were initiated. Doses between 20 and 80 mg/m2 in free-doxorubicin equivalents were explored with Doxil. The toxicity has been well characterized to consist primarily of hand-foot syndrome and other skin manifestations, which may get progressively more severe when the drug is dosed at three-week intervals. At four weeks, cumulative toxicity is exceptional. At the higher doses, stomatitis becomes increasingly more common, and some myelosuppression is observed, particularly in patients who have received much prior treatment. Activity was seen against a number of solid tumors that are classically anthracycline-sensitive (e.g., breast and ovarian cancers), and also some that are known to be refractory (e.g., renal) and others with intermediate degrees of sensitivity (e.g, head and neck cancers). Some very durable responses, and lack of radiation recall reactions, were also noteworthy features of these studies. Studies with radioactively tagged liposomes of the ‘Stealth’ variety, and of Doxil have shown half-lives of 50 to 100 hours. The kinetics of this agent fit an open, two-compartment structural model with linear distribution between the central and peripheral compartments, and a nonlinear elimination from the central compartment. The volume of distribution is equivalent to the blood volume. Factors that alter the clearance have been insufficiently studied, but the status of the reticuloendothelial system and presence of large tumors may play a role. Both DaunoXome and Doxil were approved for use against Kaposi's sarcomas at doses lower than the recommended dose for solid tumor studies. In solid tumors, reports of activity of DaunoXome against lymphoma will be covered earlier. In our studies, activity against platinum- and paclitaxel-refractory ovarian cancer has been documented. The nine of 35 objective responses (26%) were characteristically durable. We have extended these series to other patients with consistent results, and have also begun to study combinations: paclitaxel is ongoing, and cisplatin began accruing March 1997. The toxicity profile as well as activity predict some of these combinations will prove attractive against a number of solid tumors.