title: To heat or not to heat: Challenges with clinical translation of thermosensitive liposomes.
abstract: Thermosensitive liposomes have been put forward as a strategy to improve upon the limited tumor drug availability associated with conventional non-thermosensitive liposomes. ThermoDox® is the first and only thermosensitive liposome formulation to reach clinical development. The initial Phase III clinical trial on ThermoDox® (i.e. HEAT trial) evaluating the combination of ThermoDox® and radiofrequency ablation (RFA) in comparison to RFA alone for treatment of inoperable hepatocellular carcinoma (HCC) failed to reach its primary endpoint in progression-free survival (PFS). Nevertheless, a subgroup analysis demonstrated a marked improvement in PFS and a significant improvement in overall survival (OS) for patients who underwent RFA treatment for at least 45min. Potential reasons for failure of the HEAT trial have been summarized in this review and include issues with clinical trial design, lack of supporting preclinical data, and improvements in the control arm (i.e. RFA alone). In recent years, there have been many developments and improvements in heating infrastructure, thermometry and treatment planning of hyperthermia and ablation treatments. Still, there are many barriers to the clinical implementation and accessibility of heat treatment. This review provides an in-depth analysis of the current status, as well as potential challenges faced by continued clinical translation of thermosensitive liposomes.
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, M5S 3M2, ON, Canada.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Physical Sciences, Odette Cancer Research Program, Sunnybrook Research Institute, Toronto, M4N 3M5, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, M5G 1L7, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, M5S 3G9, ON, Canada.
authors.forename: Kullervo
authors.initials: K
authors.lastname: Hynynen
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, M5S 3M2, ON, Canada; Physical Sciences, Odette Cancer Research Program, Sunnybrook Research Institute, Toronto, M4N 3M5, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, M5S 3G9, ON, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, M5S 3E5, ON, Canada. Electronic address: cj.allen@utoronto.ca.
authors.forename: Christine
authors.initials: C
authors.lastname: Allen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D017115:Catheter Ablation / Q000379:methods; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy / Q000379:methods*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000627:therapeutic use*; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods; D008081:Liposomes / Q000008:administration & dosage / Q000627:therapeutic use*; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology / Q000601:surgery / Q000628:therapy*
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D008081:Liposomes
keywords: Celsion HEAT clinical trial; Clinical translation; Hyperthermia; ThermoDox®; Thermosensitive liposomes; Triggered release