Adjuvant Liposomal Doxorubicin Markedly Affects Radiofrequency Ablation–induced Effects on Periablational Microvasculature

Abstract

PurposeTo evaluate the effects of radiofrequency (RF) ablation without and with adjuvant intravenous (IV) liposomal doxorubicin (Doxil) on microvessel morphology and patency and intratumoral drug delivery and retention. Materials and MethodsThere were 133 tumors/animals used in this experiment. First, single subcutaneous tumors (R3230 in Fischer rats and 786-0 in nude mice) were randomly assigned to receive RF ablation alone or no treatment and sacrificed 0–72hours after treatment. Next, combined RF ablation and liposomal doxorubicin (1mg given 15min after RF ablation) was studied in R3230 tumors at 0–72hours after treatment. Histopathologic assessment, including immunohistochemical staining for cleaved caspase-3, heat-shock protein 70, and CD34, was performed to assess morphologic vessel appearance, vessel diameter, and microvascular density. Subsequently, tumors were randomly assigned to receive RF ablation alone, RF ablation and liposomal doxorubicin, or no treatment (control tumors), followed by IV fluorescent-labeled liposomes (a surrogate marker) given 0–24hours after RF ablation to permit qualitative assessment. ResultsRF ablation alone resulted in enlarged and dysmorphic vessels from 0–4hours, peaking at 12–24hours after RF ablation, occurring preferentially closer to the electrode. The addition of doxorubicin resulted in earlier vessel contraction (mean vessel area, 47,539μm2±9,544 vs 1,854μm2±458 for RF ablation alone at 15min; P<.05). Combined RF ablation and liposomal doxorubicin produced similar fluorescence 1hour after treatment (40.88AU/μm2±33.53 vs 22.1AU/μm2±13.19; P = .14) but significantly less fluorescence at 4 hours (24.3AU/μm2±3.65 vs 2.8AU/μm2±3.14; P<.002) compared with RF ablation alone denoting earlier reduction in microvascular patency. ConclusionsRF ablation induces morphologic changes to vessels within the ablation zone lasting 12–24hours after treatment. The addition of liposomal doxorubicin causes early vessel contraction and a reduction in periablational microvascular patency. Such changes would likely need to be considered when determining optimal drug administration and imaging paradigms.