Furthermore, Atez/Bev treatment may be preferred in patients with WNT/β-catenin mutations and non-viral infections. Anti-VEGF therapies, including Atez/Bev and TKI regimens, improve the tumor microenvironment and produce moderate responses. By contrast, Dur/Tre may be less effective in patients with WNT/β-catenin mutations and non-viral-associated HCC. Although increasing evidence has shown that systemic therapy is effective and safe for patients with advanced-stage HCC, the specific regimens that are suitable for first-line treatment remain unknown.
4. Combination of TACE and Molecular-Targeted Drugs
Systemic therapy using a highly responsive agent such as lenvatinib (LEN) in combination with subsequent selective TACE for residual tumors enhances the curative effect of TACE, preserves liver function, suppresses hypoxia-induced cytokines, and ultimately improves the patients’ survival. Therefore, the Asian Pacific Experts on Primary Liver Cancer (APPLE)  and the Japanese Society of Hepatology (JSH)  consensus statements recommend LEN as the first-line treatment for patients with intermediate-stage HCC who are not suitable for TACE. Recently, clinical practice guidelines from the E-updated European Society for Medical Oncology recommended upfront systemic therapy for patients who are ineligible for TACE .
The combined effect of TACE and molecular-targeted drugs can be explained as follows: the molecular-targeted drug acts on residual tumors caused by TACE, exerting anti-angiogenic and anti-tumor growth effects to prevent the exacerbation of residual tumors, avoid the development of new intrahepatic lesions, and suppress vascular invasion and distant metastasis. Molecular-targeted drugs with an anti-VEGF effect act on tumor blood vessels to improve the vascular permeability; reduce the tumor interstitial pressure; improve the drug delivery; enhance the treatment efficacy ; and suppress the effect of the transient increase of VEGF immediately after the occurrence of TACE-related ischemia, which is considered as one of the causes of tumor exacerbation . Although multiple clinical trials investigating the efficacy of combination therapy with TACE and molecular-targeted drugs have been conducted, their efficacy has not been demonstrated. Under these circumstances, the TACTICS trial (TACE therapy in combination with sorafenib), which investigated the combined effect of sorafenib and lipiodol TACE, showed the potential effects of treatment with a combination of targeted drugs and TACE.
Sorafenib-TACE sequential therapy also extended the OS by 3.7 months compared with TACE alone (35.6 months vs. 31.9 months, HR: 0.924). These data indicate that sequential therapy with sorafenib and TACE was more effective than TACE alone in prolonging the PFS . Although the TACTICS treatment improved the PFS, it did not significantly extend the OS. For this reason, 76.3% of the patients who received TACE alone also received post-trial treatment, and nearly half of these patients received sorafenib. Therefore, patients generally received aggressive post-trial treatment, which can extend the post-progression survival (PPS) and weaken the benefit obtained from the original trial treatment .
5. New Treatment Strategy for Intermediate Stage HCC: TACE plus Cancer Immunotherapy, and Conversion Therapy
Currently, the development of new drugs for HCC focuses on establishing an effective cancer immunotherapy. With the advent of effective cancer immunotherapy, nivolumab monotherapy, pembrolizumab monotherapy, Atez/Bev combination therapy, and Dur/Tre combination therapy have been used as postoperative adjuvant chemotherapy for HCC, and their recurrence-suppressive effects after hepatic resection or ablation are being verified 
Atez/Bev combination therapy yielded a high response rate in patients with intermediate-stage HCC (44% ORR per RECIST v1.1) 
. Unlike targeted agents, the use of Atez/Bev combination therapy resulted in a significant tumor shrinkage, even in patients with highly malignant positron emission tomography-positive HCC 
, including those with confluent multinodular and poorly differentiated HCC. Consequently, surgical excision, ablation, or curative TACE is feasible, resulting in the achievement of pathological CR and drug-free status in 20–30% of patients 
If systemic therapy is continued, the appropriate timing and method of TACE enforcement should be determined as no clear criteria have been established related to these aspects, that is, whether TACE should be performed “before PD occurs”, “what is the best response”, whether TACE should be administered in “nodules that showed PD”, whether TACE should be used “as conventional-TACE or DEB-TACE”, etc. This is because meta-analytic assessment is hampered by the excessive heterogeneity of intermediated-stage HCC between trials 
. In addition, the progression pattern of patients treated with sorafenib influences the prognosis, and new vascular invasions or new extrahepatic lesions correlate with the worst prognosis 
. This finding indicates that the prognosis differs depending on the type of PD caused by systemic therapy 
. Therefore, the timing of TACE during continuous systemic therapy should be determined based on treatment responsiveness and type of PD assessed through radiological imaging. In intermediate-stage HCC, which has a variety of treatment patterns (whether TACE should be administered in combination with a single drug or performed three times, and whether the drugs should be changed to four or more), the appropriate treatment should be selected after considering the changes in liver function and tumor marker values. When systemic therapy is used in combination with TACE, systemic therapy with the same drug is continued, while TACE is only used for an existing tumor that shows slowed growth or for a new solitary nodule that appears as an intra-hepatic lesion even in patients with PD; when multiple tumor recurrences, distant metastasis, or vascular invasion occur, switching to new systemic therapeutic agents might be required (Figure 1
Figure 1. Proposal for the timing of additional TACE treatment for intermediate-stage HCC patients receiving systemic therapy. White tumors indicated disappeared lesions, and yellow ones showed PD lesions.
Thus, the concept of systemic therapy for intermediate-stage HCC is completely different from that of conventional sequential therapy for advanced-stage HCC. Intermediate-stage HCC is treated by switching from TACE to drug therapy or by combining TACE and drug therapy (Figure 2).
Figure 2. Treatment strategy for intermediate-stage HCC.