Image-guided radiofrequency (RF) tumor ablation is being used to treat focal liver, renal, and other tumors. Yet, complete ablation is often difficult to achieve, particularly at tumor margins, presenting substantial barriers toward clinical efficacy. Our preliminary studies take advantage of complementary interactions between RF ablation and liposomal doxorubicin, and demonstrate that this combination may markedly increases tumor destruction in animals and patients, and animal survival compared to RF alone or RF combined with free doxorubicin. RF ablation also increased intratumoral liposomal doxorubicin 7 fold compared to controls, particularly in a peripheral region immediately adjacent to the zone of RF induced coagulation. Thus, this combined treatment paradigm has the unique potential both to potentiate preferential delivery of cytotoxic agents in liposomal vehicles, and to maximize the completeness of ablation of a treated tumor, in humans. Our immediate goals are to address several key issues that require further knowledge prior to initiation of Phase II or larger multicenter clinical trials. 1) Our data indicate that gains in both drug uptake and tumor destruction can be further increased through the systematic optimization of the relevant treatment parameters. 2) The mechanisms driving this interaction particularly the hyperthermic dosimetry of increased tissue destruction and the causes for increased tumor destruction seen when empty liposomes are given without doxorubicin need to be better understood, as this could lead to developing clinical strategies having even greater efficacy. 3) Local and systemic toxicities need to be better defined. This will be accomplished over 3 aims. 1) We will improve tumor destruction of combined therapy using simplex optimization in canine venereal sarcoma. The relationship between intratumoral thermal dosimetry to increased doxorubicin uptake and increased tumor destruction will be characterized to elucidate the role of hyperthermia, threshold thermal dosage, and the conditions under which combined therapy is most effective. 2) We will test specific hypotheses about the possible role of the liposome carrier components. RF and empty liposomes will be studied to define the relative contributions of the lipids and of the doxorubicin to the mechanisms of cell killing. We will further determine whether increased tumor destruction can be ascribed to enhanced oxidative stress and lipid peroxidation and whether manipulation of the substrate upon which lipid peroxidation occurs can further potentiate the antitumor effect of thermal ablation. 3) We will characterize potential local and systemic treatment toxicity including determining the thermal dosimetry at which tissue effects are seen in normal canine liver and kidney and in a one-month survival study in renal tumors.
