The 7th Joint Session between JDDW-KDDW-TDDW4(JDDW)
Thu. November 2nd   14:00 - 17:00   Room 10: Portopia Hotel Waraku
JKT4-2
 Surgical Conversion in Locally Advanced Hepatocellular Carcinoma Through Multimodal Systemic Therapy
Su Jong Yu
Department of Internal Medicine, Seoul National University College of Medicine
In recent years, advanced Hepatocellular Carcinoma (HCC) management has seen remarkable advancements. The combination of atezolizumab and bevacizumab in immunotherapy achieved a groundbreaking 12% Complete Response (CR) rate, potentially transforming the treatment landscape for previously deemed incurable HCC(1). Even in cases where programmed cell death protein-1/ programmed cell death ligand-1 antibody therapy had failed, promising outcomes were observed with lenvatinib monotherapy(2).
However, a significant challenge arises when patients achieve radiologically favorable responses through multimodal systemic therapy. The optimal course of action becomes uncertain-should they undergo aggressive interventions like surgery or transplantation, continue with maintenance therapy, or simply be closely monitored?
Research led by Mazzaferro has shed light on this complex dilemma(3). Liver transplantation emerged as a significant contributor to improved survival, with a median Overall Survival (mOS) of 14.5 months. Notably, an important distinction emerged: patients achieving a partial response after downstaging and conversion experienced a substantially prolonged mOS of 26.5 months, whereas those with CR who did not proceed to transplantation had a lower mOS of 9.9 months. This underscores that radiologically favorable responses may not consistently align with pathologically favorable responses, and some patients with radiologically favorable responses may still face disease progression, often due to refusing transplantation.
Furthermore, other studies have underscored that some patients who initially respond to treatment may eventually experience disease progression(4). This underscores the significance of considering curative options such as conversion surgery or local ablation for individuals achieving radiologically favorable responses through immunotherapy, potentially extending their survival(5).
On a different front, research has illuminated the possibility of surgical conversion in initially unresectable HCC through systemic or local therapies. Previous attempts with two-drug combinations yielded discouraging conversion rates, typically around 15-20%(6). Current studies are focused on comprehensive combination therapies that merge hepatic arterial infusion chemotherapy (HAIC)-based locoregional therapy with targeted therapy and immunotherapy(7). This innovative approach aims to bolster surgical conversion rates and achieve more favorable objective responses by harnessing synergistic effects.
While data on combination immunotherapy for downstaging and conversion to surgery remain limited and require further research, these breakthroughs herald a new era in HCC treatment. They offer fresh opportunities and improved outcomes for patients with advanced disease, holding the promise of a brighter future for individuals who were once considered untreatable.

References
1. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894-905.
2. Aoki T, Kudo M, Ueshima K, Morita M, Chishina H, Takita M, et al. Exploratory Analysis of Lenvatinib Therapy in Patients with Unresectable Hepatocellular Carcinoma Who Have Failed Prior PD-1/PD-L1 Checkpoint Blockade. Cancers (Basel). 2020;12(10).
3. Mazzaferro V, Citterio D, Bhoori S, Bongini M, Miceli R, De Carlis L, et al. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol. 2020;21(7):947-56.
4. Kudo M. A New Treatment Option for Intermediate-Stage Hepatocellular Carcinoma with High Tumor Burden: Initial Lenvatinib Therapy with Subsequent Selective TACE. Liver Cancer. 2019;8(5):299-311.
5. Kudo M, Ueshima K, Chan S, Minami T, Chishina H, Aoki T, et al. Lenvatinib as an Initial Treatment in Patients with Intermediate-Stage Hepatocellular Carcinoma Beyond Up-To-Seven Criteria and Child-Pugh A Liver Function: A Proof-Of-Concept Study. Cancers (Basel). 2019;11(8).
6. Goto Y, Hisaka T, Sakai H, Takagi K, Fukutomi S, Akagi Y, et al. Salvage Surgery for Initially Unresectable Locally Advanced Hepatocellular Carcinoma Downstaged by Hepatic Arterial Infusion Chemotherapy. Anticancer Res. 2020;40(8):4773-7.
7. Zhang T, Merle P, Wang H, Zhao H, Kudo M. Combination therapy for advanced hepatocellular carcinoma: do we see the light at the end of the tunnel? Hepatobiliary Surg Nutr. 2021;10(2):180-92.
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