3.1. TACE with Radiofrequency Ablation

An RCT in patients with a solitary recurrent HCC lesion < 5 cm in diameter demonstrated that sequential therapy with TACE followed by radiofrequency ablation (RFA) significantly improved OS compared to the therapy with RFA alone. The one-, three-, and five-year survival rates were 94%, 69%, and 46% for the combination therapy, respectively, and 82%, 47%, and 36% for RFA alone (p = 0.037). In addition, sequential combination therapy resulted in significantly longer recurrence-free survival in patients with tumors larger than 3 cm in diameter. Another RCT demonstrated the superiority of the TACE-RFA combination therapy over RFA alone in patients with HCC lesions with a diameter of less than 7 cm in both OS (HR = 0.525; p = 0.002) and recurrence-free survival (HR = 0.575; p = 0.009). For small HCC lesions (2–3 cm in diameter), there was no significant difference in long-term therapeutic outcomes between TACE combined with RFA and surgical resection, which implies that the TACE/RFA combination therapy could be an alternative treatment for patients with a single small HCC lesion for whom surgical resection is unsuitable. Two meta-analyses reported that TACE combined with RFA was more effective than RFA alone, especially for intermediate- and large-sized HCC, and in younger patients with HCC.

3.2. TACE with Radiation Therapy

There has been mounting evidence regarding the efficacy of combination therapy of TACE and radiation therapy (RT) for treating patients with intermediate-stage HCC, as well as advanced-stage HCC with PVTT. According to an extensive meta-analysis involving 11 RCTs and 14 non-RCTs, treatment with TACE plus RT resulted in significantly improved response and survival rates compared to TACE alone in patients with unresectable HCC. In addition, TACE plus RT has shown a promising response rate and OS among HCC patients with macrovascular invasion in several observational studies. Based on these observational studies, a well-designed RCT was conducted, which demonstrated that first-line treatment with TACE plus RT was well tolerated and improved various treatment outcomes compared to those associated with sorafenib treatment among advanced-stage HCC patients with macrovascular invasion. This research provides a new treatment paradigm to treat patients with locally advanced HCC using a combination of TACE and RT.

2.3. TACE with Systemic Therapy

The anticancer mechanisms of TACE involve a tumor embolic effect leading to tissue necrosis, in addition to the local delivery of cytotoxic agents. TACE causes tissue hypoxia that results in the upregulation of vascular endothelial growth factor (VEGF), which may lead to tumor revascularization and local recurrence. In this regard, the combination of antiangiogenic agents with TACE was expected to inhibit the revascularizing action of upregulated VEGF induced by TACE. Accordingly, the combination of TACE with anti-angiogenic agents may delay tumor progression or recurrence, and thus improve OS.

Several attempts have been made to combine TACE with other systemic agents whose main mechanism of action is anti-angiogenesis: The SPACE and TACE 2 trials compared TACE plus sorafenib and TACE alone, while the BRISK-TA study did the same with brivanib, and the ORIENTAL study with orantinib. Despite the plausible rationale for the combination strategy, all four RCTs evaluating the combination of TACE with systemic agents failed to show any clinical benefit compared to TACE alone. Kudo et al. presented several reasons for these repeated negative trials. They suggested that the duration of the study was too short to evaluate OS as a primary endpoint. In addition, post-trial treatments after progression likely affect OS, making it difficult to evaluate treatment outcomes using OS. The definition of time to progression or PFS also needs to be more standardized, and tailored to the specifics of TACE treatment. Based on the lessons from the previous trials, Kudo et al. demonstrated positive results of the TACTICS trial, a randomized phase II trial comparing TACE plus sorafenib with TACE alone. The use of TACE plus sorafenib resulted in a major improvement in PFS: 25.2 months in the TACE plus sorafenib group versus 13.5 months in the TACE alone group (p = 0.006). The improved outcomes observed in the TACTICS trial can be explained by the differences in the study protocol compared to those of the previous trials. The most distinctive difference is that new intrahepatic lesions were not regarded as progressive disease because they do not imply treatment failure based on the natural tumor biology of HCC. Progression in this trial was defined as untreatable (unTACEable) progression; e.g., > 25% of intrahepatic tumor progression, deterioration of liver function to Child-Pugh class C after TACE, macrovascular invasion, or extrahepatic spread. Treatment was continued until unTACEable progression, TACE refractoriness, or unacceptable toxicity. Sorafenib was started two–three weeks prior to the first TACE in this trial. As a result, patients in the TACTICS trial received sorafenib treatment for a much longer period than in previous trials, with a median of 38.7 weeks and 17.0 to 21.0 weeks, respectively. This new TACE-specific endpoint and protocol should be validated in future TACE combination trials.

Another approach being investigated is the combination of immune checkpoint inhibitors with TACE. Locoregional therapies, including TACE, activate the host immune system by promoting local inflammation and triggering the release of tumor antigens. When tumor antigens are released by TACE, subsequent administration of immune checkpoint inhibitors can prevent intrahepatic micrometastases, which are typically undetectable, and are the main cause of recurrence. One prospective study demonstrated that ablative therapies, such as RFA and TACE, induced a peripheral immune response and enhanced the efficacy of tremelimumab in patients with advanced-stage HCC. The combination of TACE and tremelimumab afforded favorable outcomes, with a partial response rate of 26% and OS of 12.3 months. At present, a phase III trial of combination therapy with TACE plus durvalumab and/or bevacizumab (the EMERALD-1 trial) is ongoing (NCT03937830).