Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients with Unresectable Hepatocellular Carcinoma Lesions

<b>Purpose:</b> Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (<i>d</i>_max) of 3 to 7 cm.<b>Experimental Design:</b> The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a <i>d</i>_max of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). <i>Post hoc</i> subset analyses investigated whether RFA duration was associated with efficacy.<b>Results:</b> The primary endpoint was not met; in intention-to-treat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; <i>P</i> = 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76-1.20; <i>P</i> = 0.67). Among 285 patients with a solitary HCC lesion who received ≥45 minutes RFA dwell time, the OS HR was 0.63 (95% CI, 0.41-0.96; <i>P</i> < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin.<b>Conclusions:</b> Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes. <i>Clin Cancer Res; 24(1); 73-83. ©2017 AACR</i>.