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

Abstract

Purpose: 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 (d max ) of 3 to 7 cm.Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA AE LTLD. The 701 enrolled patients had to have 4 unresectable HCC lesions, at least one of which had a d max of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy.Results: The primary endpoint was not met; in intention-totreat analysis, the PFS HR of RFA þ LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P ¼ 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76-1.20; P ¼ 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; P < 0.05) in favor of combination therapy. RFA þ LTLD had reversible myelosuppression similar to free doxorubicin.Conclusions: 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 þ LTLD efficacy is improved when RFA dwell time for a solitary lesion !45 minutes. Clin Cancer Res; 24(1); 73-83.Ó2017 AACR.

Blood Interactions, Pharmacokinetics, and Depth-Dependent Ablation of Rat Mammary Tumors with Photoactivatable, Liposomal Doxorubicin

“…Alternatively, several stimulus controlled systems have been developed to address this problem, including systems that use heat, light, and pH to trigger drug release (25)(26)(27)(28)(29)(30)(31). The most advanced of which, Thermodox, a heat-triggered, liposome-encapsulated Dox, has been tested clinically for the treatment multiple forms of cancer, including liver cancer and breast cancer (32)(33)(34). The combination of light therapy and chemotherapy, chemophototherapy (CPT), is an emerging treatment paradigm for solid tumors (35).…”

Image-guided thermosensitive liposomes for focused ultrasound drug delivery: Using NIRF-labelled lipids and topotecan to visualise the effects of hyperthermia in tumours

“…Thermodox® in combination with RFA is being tested in clinical trials to treat hepatocellular carcinoma (OPTIMA study) and recurrent wall breast cancer (DIGNITY) [11,19]. Recently published result from the HEAT study indicated that RFA + thermosensitive liposomal doxorubicin efficacy is improved when RFA dwell time for a solitary lesion ≥ 45min [20].…”

Combined Treatments in Liver Ablations

“…During heating, at temperatures above 40°C, the drug is released from the liposomes at high doses and its cytotoxicity may be increased by the concomitant cell damage caused by the sublethal heating 51,52 Given these premises, a phase 3 prospective randomized study (the HEAT [adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions] trial) was performed comparing RFA combined with thermosensitive liposomal doxorubicin (LTLD) versus RFA alone in 701 patients with lesions 3 to 7 cm in size. 53 The study did not show any significant increase in OS and progression-free survival in the overall population. However, a post hoc subgroup analysis of 285 patients demonstrated improved efficacy in patients with solitary lesions who received prolonged tumor heating (> 45 minutes).…”