Combination treatment including targeted therapy for advanced hepatocellular carcinoma

Abstract

Management of advanced hepatocellular carcinoma (HCC), one of the most lethal cancers worldwide, has presented a therapeutic challenge over past decades. Most patients with advanced HCC and a low possibility of surgical resection have limited treatment options and no alternative but to accept local or palliative treatment. In the new era of cancer therapy, increasing numbers of molecular targeted agents (MTAs) have been applied in the treatment of advanced HCC. However, mono-targeted therapy has shown disappointing outcomes in disease control, primarily because of tumor heterogeneity and complex cell signal transduction. Because incapacitation of a single target is insufficient for cancer suppression, combination treatment for targeted therapy has been proposed and experimentally tested in several clinical trials. In this article, we review research studies aimed to enhance the efficacy of targeted therapy for HCC through combination strategies. Combination treatments involving targeted therapy for advanced HCC are compared and discussed.

Keywords: combination treatment; hepatocellular carcinoma; molecular targeted agents; targeted therapy.

Figure 1. Major pathways of multiple target co-inhibition in advanced hepatocellular carcinoma

Mutations in the RAS/RAF/MEK/ERK and PI3K/Akt/mTOR pathways enhance angiogenesis, drug resistance, cell proliferation, and apoptosis to facilitate the growth of cancer. These two pathways are the major targets of strategies involving co-inhibition of dual or multiple targets in the treatment of advanced HCC. The patterns of combined inhibition include dual targets at the level of growth factors and at the level of their downstream pathways. Molecular targeted agents involved in multiple target co-inhibition therapy are listed in this figure.

Figure 2. Schematic of combination treatment based on targeted therapy in advanced hepatocellular carcinoma

In patients with advanced HCC, combination treatment based on targeted therapy involves molecular targeted agents combined with other modalities such as surgery, TACE, immunotherapy, chemotherapy, or radiotherapy. The lack of precise target population selection may be the primary reason for limited cancer control using these strategies. Treatment will become more precise and effective through effective screening of patients with potential benefits. This may be achieved by genome sequencing to identify therapeutic targets or by more reliable molecular classification of the tumor.