A randomised phase II/III trial of 3-weekly cisplatin-based sequential transarterial chemoembolisation vs embolisation alone for hepatocellular carcinoma

Abstract

Background:Transarterial chemoembolisation (TACE) has not been shown to be superior to bland embolisation (TAE) for treatment of hepatocellular carcinoma (HCC).Methods:We conducted a randomised phase II/III trial in patients with untreated HCC. Patients were randomised to TAE with polyvinyl alcohol (PVA) particles alone or sequential TACE (sTACE) in which cisplatin 50 mg was administered intrarterially 4–6 h before PVA embolisation. Treatment was repeated 3-weekly for up to three treatments. The primary endpoint was overall survival and secondary endpoints were progression-free survival, toxicity and response. Target sample sizes for phase II and III were 80 and 322.Results:The trial was terminated at phase II after 86 patients had been randomised. Patients were well matched for prognostic criteria. All three planned treatments were given to 57.1% (TAE) and 56.8% (TACE) patients. Grade 3/4 toxicity occurred in 63.5% and 83.7%, respectively (P=0.019). End-of-treatment RECIST response (CR+PR) was 13.2 and 32.6% (P=0.04) (mRECIST 47.3% and 67.4) and median overall survival and progression-free survival was 17.3 vs 16.3 (P=0.74) months and 7.2 vs 7.5 (P=0.59), respectively.Conclusion:Transarterial chemoembolisation according this novel schedule is feasible and associated with a higher response rate than TAE alone. The survival benefit of TACE over TAE remains unproven.

The Overall Survival of Patients with Hepatocellular Carcinoma Correlates with the Newly Defined Time to Progression after Transarterial Chemoembolization

“…Although many clinical trials of TACE alone or targeted agents in combination with TACE use OS as a primary endpoint, it takes a long time before its effects are proved [11][12][13] . Furthermore, the OS benefit is diluted by prolonged post-progression survival [14] , because post-trial treatments such as intra-arterial infusion chemotherapy, sorafenib, or other trial agents (including regorafenib, lenvatinib, or immunotherapy) can have a chance of marked antitumor effect, resulting in longer post-progression survival irrespective both in the testing and control arms.…”

Locoregional Therapy for Hepatocellular Carcinoma with and without Extrahepatic Spread

“…Furthermore, in a meta-analysis of seven randomized clinical trials of patients with unresectable HCC by Llovet et al [10] embolization was shown to provide a significant survival benefit when compared to observation alone. Although TACE is regarded by some as the superior method of embolization, recently published randomized clinical trial data have demonstrated no significant survival difference between TACE, DEB TACE and bland HAE [11–13]. Consequently, the most recently published National Comprehensive Cancer Network consensus guidelines for the treatment of HCC suggest embolization, either bland HAE or TACE, as the standard of care for patients with intermediate/advanced HCC without extra hepatic spread or main portal vein involvement [14]…”

Ischemia Induces Quiescence and Autophagy Dependence in Hepatocellular Carcinoma

“…Optimal therapy is limited by a paucity of proven adjuvant therapies to potentiate embolotherapy-induced ischemia. Prospective randomized trials have demonstrated TACE and TAE to be equally effective with respect to survival, and none of the currently used chemotherapeutic agents has demonstrated superiority to others (7–13). …”