Current Perspectives on Perioperative Combination Therapy for Hepatocellular Carcinoma

Abstract

Background: Multidisciplinary treatment of hepatocellular carcinoma (HCC) has made notable advancements with the emergence of novel agents for systemic therapies, including receptor tyrosine kinase inhibitors (TKIs) and cancer immuno-oncology (IO) therapy utilizing immune checkpoint inhibitors. Although each of these regimens is effective as monotherapy for advanced HCCs, combining them with locoregional therapy (LRT), such as transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), and radiotherapy (RT), provides an additional antitumor effect. The emergence of novel systemic therapies has given rise to anticipation for the development of multidisciplinary treatments with a combination of systemic therapy and LRT, which aim to achieve curative-intent resection and improve long-term prognosis after resection.

Summary: Perioperative combination therapy, a combination of multiple treatment modalities including systemic therapy (TKI and/or IO) and LRT (TACE, HAIC, or RT), is attracting attention as a potentially useful approach for multidisciplinary curative-intent surgical resection or ablation. Currently, there is no evidence-based guidance regarding selection criteria and optimal regimens for perioperative combination therapy. The definition of oncological resectability for HCC is being pursued to establish the indication and protocol for perioperative combination therapy, which broadly encompasses conversion as well as neoadjuvant and adjuvant therapy for intermediate-to-advanced HCC.

Key messages: Perioperative combination therapy, which positions curative-intent surgical resection or ablation within the combination of multiple modalities including systemic therapy and LRT, provides perspectives for improving the long-term prognosis of patients with initially unresectable HCC and borderline resectable HCC with a high risk of recurrence.

Keywords: Adjuvant; Borderline resectable lesions; Conversion; Neoadjuvant therapy; Resectability.

Fig. 1.

Oncological subclassification comprises resectability criteria (Expert Consensus 2023) and an overview of recommended treatments for patients with HCC according to practical guidelines. Therapeutic modalities for HCC patients with preserved liver function (Child-Pugh A/B) and good performance status (ECOG-PS 0–1) are summarized. *Resectability criteria refer to the subclassification of BR lesions, as defined by the Japan Liver Cancer Association and the Japanese Society of Hepato-Biliary-Pancreatic Surgery Expert Consensus Statement 2023 [18]. HCC, hepatocellular carcinoma; ECOG-PS, Eastern Cooperative Oncology Group-performance status; MVI, macrovascular invasion; EHS, extrahepatic spread; BR, borderline resectable; BCLC, Barcelona Clinic Liver Cancer; TACE, transcatheter arterial chemoembolization; APASL, Asian Pacific Association for the Study of the Liver; RT, radiotherapy; HAIC, hepatic arterial infusion chemotherapy.

Fig. 2.

Perioperative combination therapy according to HCC resectability criteria. The multimodal sequential therapeutic strategy aimed at improving the prognosis after curative resection, including conversion surgery and neoadjuvant and adjuvant therapies. *BR1 and BR2 refer to the subclassification of BR lesions, as defined by the Japan Liver Cancer Association and the Japanese Society of Hepato-Biliary-Pancreatic Surgery Expert Consensus Statement 2023 [18]. R, resectable; BR, borderline resectable; MVI, macrovascular invasion; UR, unsuitable for resection; TKI, tyrosine kinase inhibitor; IO, immune oncology; LRT, locoregional therapy; TACE, transarterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy.