Proposal of Primary Endpoints for TACE Combination Trials with Systemic Therapy: Lessons Learned from 5 Negative Trials and the Positive TACTICS Trial

The multikinase inhibitor sorafenib is the first oral molecular targeted agent to improve survival in patients with unresectable advanced hepatocellular carcinoma (HCC). Various clinical trials have been conducted with the ultimate goal of extending survival not only in advanced HCC patients, but also in intermediate-stage HCC patients. The aim of these trials was to test the hypothesis that combination therapy with transcatheter arterial chemoembolization (TACE) and molecular targeted agents (1) attenuates the release of vascular endothelial growth factor and other angiogenic growth factors in response to hypoxia induced by TACE and (2) prevents a decrease in hepatic functional reserve by extending the interval between TACE sessions through suppression of residual tumor proliferation. Five trials investigating combination therapy with TACE and molecular targeted agents have ended in failure. In the wake of these failures, the recent positive TACTICS trial, which combined TACE and sorafenib and reported extension of the primary endpoint of progression-free survival, was a breakthrough. This editorial interprets the design of the TACTICS trial, provides an in-depth review of factors related to its success by comparison with previous failed trials, and discusses the lessons learned regarding the endpoints to be considered in future trials of combination therapy with TACE. Received: July 28, 2018 Accepted: July 30, 2018 Published online: August 23, 2018