The Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement, which was established on August 31, 2019, in Sapporo, proposed a new treatment strategy for patients with intermediate stage hepatocellular carcinoma (HCC). Since intermediate stage HCC is a heterogeneous disease in terms of tumor burden and liver function, not all patients benefit from TACE. Preservation of liver function is as important as achieving a high objective response, because the treatment goal is to prolong overall survival in this stage. Therefore, the treatment option should be changed according to the patient-tumor condition. Superselective conventional TACE (cTACE) is recommended as the first choice of treatment in patients eligible for effective (curative) TACE, whereas in patients who have tumors beyond the up-to-7 criteria, TACE-resistant tumors, or modified albumin-bilirubin grade 2b liver function, systemic therapy is recommended as the first-choice treatment. However, such a TACE-unsuitable HCC is not always contraindicated for TACE monotherapy, and superselective cTACE may also be indicated for some tumors when tumors are localized in limited segments. The opportunities for systemic therapy-TACE sequential therapy may also increase during the treatment course. Therefore, TACE still plays an important role in the treatment of intermediate stage HCC, and the advancement of TACE technology contributes to prolonging the life-span of HCC patients.
Systemic therapy for hepatocellular carcinoma (HCC) has changed markedly since the introduction of the molecular targeted agent sorafenib. Despite many attempts to develop new drugs after sorafenib, many clinical trials failed. Finally, 4 drugs (lenvatinib as a first-line agent and regorafenib, cabozantinib, and ramucirumab as second-line agents) have become available for clinical use. A recent phase III trial (IMbrave150) showed that combination immunotherapy with atezolizumab plus bevacizumab improved overall survival compared with sorafenib therapy. This article reviews recent advances in systemic therapy for HCC.
Due to the development of new molecular targeted agents (MTAs) and immune checkpoint inhibitors (ICIs), the treatment strategy for intermediate stage HCC is changing. To clarify the indications for TACE, MTAs/ICIs, or combination therapy, it is necessary to show the results and limitations of TACE for intermediate stage HCC. The Asia-Pacific Primary Liver Cancer Expert Consensus Statement suggested that “beyond up-to-7 criteria” was unsuitable for TACE. However, in clinical practice, the criteria to determine the contraindications to TACE are still controversial. Our data demonstrated that tumor number ≥ 11 was the significant factor. In addition, from Asian countries, up-to-11 criteria and 7-11 criteria, which would replace the up-to-7 criteria, were reported. Achievement of complete response (CR) by TACE can prolong overall survival. Our recent analysis of TACE for beyond up-to-7 criteria cases demonstrated that 57% of patients achieved CR. The significant factor related to CR was up-to-11 criteria. TACE techniques are important to improve efficacy. The 3D-safety-margin is one of the important factors to obtain curability. Current TACE navigation using angio-CT or cone-beam CT is useful to identify the tumor feeding artery. Development of tiny microcatheters and guidewires is also important for superselective TACE. In addition, the recently developed pumping emulsification device with a microporous glass membrane could increase the antitumor effect of selective cTACE.
The tumor microenvironment is composed of multiple cells and structures, including blood vessels, fibroblasts, immune cells and the extracellular matrix. The tumor and its surrounding microenvironment are closely related and constantly interact for growth. The tumor microenvironment is characterized by abnormal tumor neovascularization, intra-tumor hypoxia, acidic environment, and increased number of tumor-associated immune cells, which play different roles in the growth and progression of cancer cells. Therefore, the tumor microenvironment is considered to be of great importance in understanding cancer biology and devising therapeutic strategies. Recently, it has been reported that local therapies such as TACE and RFA produce adverse reactions that are different from the original therapeutic effect, activating the tumor microenvironment. Based on these findings, a new strategy is needed to control the adverse reactions associated with local treatment and lead to death of the tumor. In this chapter, we describe the tumor microenvironment and the impact of TACE on hepatocellular carcinoma based on multiple in vitro and in vivo studies. We will also discuss the impact of newly approved tyrosine kinase inhibitors and immune checkpoint inhibitors on the microenvironment and their synergistic and complementary efficacy in combination with local therapies.
Primary liver cancer is the third most common cause of cancer mortality in the world. Hepatocellular carcinoma (HCC) is the dominant type of liver cancer, accounting for approximately 75% of the total. Molecular targeted agent (MTA) therapy is the guideline-recommended treatment for patients with well-preserved liver function (Child-Pugh A) and with advanced-stage (Barcelona Clinic Liver Cancer [BCLC] Stage C) HCC. There is a high level of evidence supporting transarterial chemoembolization (TACE) as the current standard of care for intermediate-stage (BCLC-B) HCC. The development of MTAs encourages us to consider a new treatment strategy for intermediate-stage HCCs. We must maximize the benefits of both treatments, TACE and MTA, for patients with intermediate and advanced HCC. Recently, some reports showed that patients with intermediate-stage HCC beyond up-to-7 criteria received initial treatment with lenvatinib (LEN) followed by TACE (LEN-TACE sequential therapy). LEN-TACE sequential therapy was shown to prolong survival compared to LEN monotherapy. We have had cases in which re-challenge TACE was effective after LEN therapy for cases refractory to initial TACE. Our re-challenge TACE cases were in the state of LEN-refractoriness/intolerance. In our clinical results, LEN with re-challenge TACE prolonged survival compared to LEN monotherapy. Re-challenge TACE showed a good overall response rate (CR+PR) at 65.2%. As adverse events of LEN, it causes tumor-related hemorrhages despite rapid suppression of tumor blood flow. In our clinical results, five of 68 consecutive cases developed tumor hemorrhages. These five cases had larger tumors than those without hemorrhages.