Transarterial Chemoembolization in Combination with a Molecular Targeted Agent: Lessons Learned from Negative Trials (Post-TACE, BRISK-TA, SPACE, ORIENTAL, and TACE-2)

Abstract

sessment Randomized Protocol (SHARP) and Asia-Pacific studies [1,2] . In 2007, sorafenib was approved in the EU and USA, where it became a first-line agent for unresectable advanced HCC. Transarterial chemoembolization (TACE) is the first-line treatment option for intermediate-stage HCC [3][4][5][6] ; however, repeated TACE sessions tend to impair liver functional reserve. Reducing the frequency of TACE, which is generally repeated upon tumor progression, is a challenging issue in the treatment of patients with intermediate-stage HCC. To address this issue, previous trials combined molecular targeted agents with TACE; however, the safety and efficacy of this combination could not be demonstrated, and none of the combination therapies is currently recommended.In the SHARP study, subanalysis showed that the hazard ratio (HR) for overall survival (OS) in patients with HCC with no vascular invasion or extrahepatic spread, which are regarded as good indications for TACE, was 0.52 and, thus, extremely good in the sorafenib group. The median survival of these patients was extended approximately 1.5-fold [7] , suggesting that the addition of sorafenib as adjuvant therapy to TACE improves prognosis. The combination of TACE with sorafenib does not simply represent the administration of 2 types of treatment; the combination is expected to extend the period during which TACE controls tumor progression because sorafenib strongly suppresses post-TACE tumor recur- AbstractThe multikinase inhibitor sorafenib is the first oral molecular targeted agent with proven prognostic benefit in unresectable advanced hepatocellular carcinoma (HCC). However, as with other drugs, sorafenib has its limitations, and various clinical trials have been conducted to develop novel molecular targeted agents for use alone or in combination with existing locoregional therapies. Despite this, clinical trials of molecular targeted agents combined with transarterial chemoembolization (TACE) have not reported major treatment outcomes to date. In this review, we describe previous clinical trials of combination therapy with TACE and a molecular targeted agent in patients with unresectable HCC.

Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma

“…143,146 Most of the previous randomised clinical trials that tested the combination of systemic therapy and locoregional therapy for HCC, either concurrent or sequential, failed to demonstrate a survival benefit of combination therapy. [147][148][149][150][151][152][153][154][155] The post-randomisation confounding factors previously mentioned contributed greatly to the failure of these trials. About 10 to 20% of patients randomised to the locoregional therapy arm of the clinical trials could not receive the assigned treatment because of technical difficulties.…”

Role of locoregional therapies in the wake of systemic therapy

“…The median OS was 29.7 months in the sorafenib group, whereas a median was not reached in the placebo group. 33 A phase II trial from Japan, TACTICS highlights the potential impact of study design on results. A significantly improved PFS was reported in those receiving TACE + sorafenib compared to TACE alone: 25.2 vs. 13.5 months, respectively (hazard ratio [HR] 0.59; 95% CI 0.41-0.87; p = 0.006).…”

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

“…Therefore, the trials failed for different reasons [8, 10]. These reasons will not be discussed in this paper but are discussed elsewhere [16]. …”