Exploring the role of liver resection as a first-line treatment option for multinodular BCLC-A hepatocellular carcinoma

Joo Hyun Oh; Dong Hyun Sinn

doi:10.17998/jlc.2024.08.08

The ultimate goals of hepatocellular carcinoma (HCC) treatment are to increase the overall survival time and improve the quality of life [1]. The likelihood of achieving these treatment goals is increased when the most appropriate treatment modality is selected for each individual patient. Currently, multiple potentially efficacious treatment options exist for HCC, making the selection of the optimal treatment a challenging task. For multinodular Barcelona Clinic Liver Cancer (BCLC) stage A HCC patients within the Milan criteria (two or three tumors each measuring 3 cm or less, without macrovascular invasion or extrahepatic metastasis), various treatment modalities are available. These include liver transplantation, radiofrequency ablation (RFA), transarterial chemoembolization (TACE), and liver resection (LR). The 2022 Korean Liver Cancer Association-National Cancer Center practice guidelines for the management of HCC recommend liver transplantation, conventional TACE, and RFA as preferred treatment options for these patients (best options), while LR is considered an alternative option, rather than a preferred option, due to high recurrence risks and the potential for decreased liver function [1]. Similarly, guidelines from the BCLC and the American Association for the Study of Liver Diseases do not recommend LR as a first-line treatment option [2,3]. These guidelines all suggest to consider LR in highly selected situations (Table 1). However, in real-life clinical practice, LR is frequently utilized as a first-line treatment for patients with multinodular BCLC stage A within the Milan criteria. Previous research on the efficacy of LR for multinodular BCLC stage A HCC has shown mixed results, with some studies indicating superior outcomes of LR compared to RFA or TACE [4-6], while others have shown similar results for these treatment options [7,8].

In this issue of the Journal of Liver Cancer, Yang et al. [9] reports the efficacy of LR compared to TACE as a first-line treatment for patients with multinodular BCLC stage A HCC within the Milan criteria. Their study involved 483 patients from 2013 to 2022, and they assessed outcomes in terms of overall survival (OS), recurrence-free survival (RFS), and postoperative adverse outcomes for patients who underwent LR. The study design was a retrospective cohort study, and it included subgroup and propensity score matching analysis. The median size of the largest tumor was 2.0 cm and 72.3% of the patients had two tumors. LR showed better OS and RFS compared to TACE. TACE was an independent factor for poorer OS and RFS. In the propensity-score-matched cohort analysis, the TACE group consistently showed poorer OS and RFS. Subgroup analyses also showed poorer OS and RFS in the TACE group for patients with two tumors. For patients with three tumors, OS did not significantly differ between the groups (P=0.11), although RFS was poorer in the TACE group. The postoperative morbidity rate was 13.9%, without any Clavien-Dindo grade 4 complications. The authors concluded that LR could be an effective treatment option for patients with multinodular BCLC stage A HCC.

While this study suggests LR as a viable first-line treatment option for patients with multinodular BCLC stage A HCC, several considerations are necessary. Among the LR group, 72.0% underwent minor resections, predominantly right anterior sectionectomy. The study lacked detailed information about the tumor location, but it is presumed that most patients who received LR had tumors favorably located for minor liver resection. It is important to note that patients treated with TACE might not have been eligible for LR or would have required major resections. In addition, RFA, another preferred option for patients with multinodular BCLC stage A within the Milan criteria, was not assessed in this study. The high recurrence rate (71.0%) in patients who underwent LR emphasizes the importance of considering the high risk of tumor recurrence.

Several studies have proposed methods to select optimal candidates for LR. For instance, Barros et al. [10] demonstrated that patients with a single negative prognostic factor (such as portal hypertension, portal vein invasion, or multiple nodules) experienced sufficient OS to justify LR, while the presence of two such factors suggests that resection should only be pursued under particularly favorable conditions, and the presence of all three typically contraindicates surgical intervention. Martin et al. [11] suggested that a tumor burden score that includes both tumor number and size could be useful in candidate selection for LR. However, there are no universally accepted criteria or algorithms for selecting optimal candidates for LR for patients with multinodular BCLC stage A. Several studies [4-6], including a study by Yang et al. [9], have shown better survival with LR than with other treatments. This indicates that there may be a subgroup of patients who could benefit from receiving LR as a firstline treatment. However, further studies are needed to determine the optimal criteria for selecting candidates for LR. In this context, the best approach for selecting LR as a first-line treatment for multinodular BCLC stage A HCC might be a multidisciplinary approach [12]. Such a multidisciplinary approach should include comprehensive evaluation and planning by a team of specialists involved in HCC care, including hepatologists, surgeons, interventional radiologists, oncologists, radiation oncologists, and other medical practitioners [12].

It is also important to remember that LR may offer several benefits over other treatments for multinodular BCLC stage A HCC, potentially justifying its use as a first-line option. Adjuvant atezolizumab plus bevacizumab in high-risk patients undergoing LR or ablation demonstrated significant improvements in RFS, with several other ongoing adjuvant or neoadjuvant trials [13]. Additionally, LR allows for the evaluation of histopathological and molecular features [14], which may guide personalized management plans. Advances in minimally invasive hepatic resection techniques have resulted in reduced perioperative bleeding, postoperative pain, and complications and shorter hospital stays [1]. These advancements suggest that the potential indications for LR as a first-line option for patients with multinodular BCLC stage A HCC may be extended in the near future. Further research and attention are needed to explore the role of LR as a first-line treatment option for multinodular BCLC stage A HCC.

Notes

Conflict of Interest

Dong Hyun Sinn is an editorial board member of Journal of Liver Cancer and was not involved in the review process of this article. Otherwise, the authors have no conflicts of interest to disclose.

Ethics Statement

This editorial is fully based on the articles which were already published and did not involve additional patient participants. Therefore, IRB approval was not necessary.

Funding Statement

Not applicable.

Data Availability

Not applicable.

Author Contribution

Writing - original draft: JHO

Writing - review & editing: DHS

References

1. Korean Liver Cancer Association (KLCA), National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. J Liver Cancer. 2023; 23:1–120.

2. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022; 76:681–693.

3. Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023; 78:1922–1965.

4. Oh JH, Sinn DH, Choi GS, Kim JM, Joh JW, Kang TW, et al. Comparison of outcome between liver resection, radiofrequency ablation, and transarterial therapy for multiple small hepatocellular carcinoma within the Milan criteria. Ann Surg Treat Res. 2020; 99:238–246.

5. Yi HM, Zhang W, Ai X, Li KY, Deng YB. Radiofrequency ablation versus surgical resection for the treatment of hepatocellular carcinoma conforming to the Milan criteria: systemic review and meta-analysis. Int J Clin Exp Med. 2014; 7:3150–3163.

6. Romano P, Busti M, Billato I, D’Amico F, Marchegiani G, Pelizzaro F, et al. Liver resection versus radiofrequency ablation or trans-arterial chemoembolization for early-stage (BCLC A) oligo-nodular hepatocellular carcinoma: meta-analysis. BJS Open. 2024; 8:zrad158.

7. Hidaka M, Hara T, Soyama A, Adachi T, Matsushima H, Tanaka T, et al. Long-term outcomes of living-donor liver transplantation, hepatic resection, and local therapy for hepatocellular carcinoma with three <3- cm nodules in a single institute. JGH Open. 2022; 6:539–546.

8. Hsu KF, Chu CH, Chan DC, Yu JC, Shih ML, Hsieh HF, et al. Superselective transarterial chemoembolization vs hepatic resection for resectable early-stage hepatocellular carcinoma in patients with Child-Pugh class a liver function. Eur J Radiol. 2012; 81:466–471.

9. Yang J, Choi WM, Lee D, Shim JH, Kim KM, Lim YS, et al. Outcomes of liver resection and transarterial chemoembolization in patients with multinodular BCLC-A hepatocellular carcinoma. J Liver Cancer. 2024; Apr. 3. doi: 10.17998/jlc.2024.03.25 [Epub ahead of print].

10. Barros AZA, Fonseca GM, Kruger JAP, Coelho FF, Herman P. Liver resection for hepatocellular carcinoma beyond the BCLC: are multinodular disease, portal hypertension, and portal system invasion real contraindications? J Gastrointest Oncol. 2022; 13:3123–3134.

11. Martin D, Smet H, Da Silva Costa AC, Halkic N, Uldry E, Tabrizian P, et al. Tumor burden in patients with early and intermediate-stage hepatocellular carcinoma undergoing liver resection: a retrospective multicenter study on clinical and oncological outcomes. HPB (Oxford). 2023; 25:836–844.

12. Oh JH, Sinn DH. Multidisciplinary approach for hepatocellular carcinoma patients: current evidence and future perspectives. J Liver Cancer. 2024; 24:47–56.

13. Singal AG, Yarchoan M, Yopp A, Sapisochin G, Pinato DJ, Pillai A. Neoadjuvant and adjuvant systemic therapy in HCC: current status and the future. Hepatol Commun. 2024; 8:e0430.

14. Kim H, Jang M, Park YN. Histopathological variants of hepatocellular carcinomas: an update according to the 5th edition of the WHO classification of digestive system tumors. J Liver Cancer. 2020; 20:17–24.

Table 1.

Comments on the role of liver resection for patients with multinodular BCLC state A HCC

Guideline	Consideration for resection
KLCA-NCC Korea, 2022 [1]	Hepatic resection may be considered for three or less multiple HCCs in patients with well-preserved liver function
BCLC, 2022 [2]	Liver resection may be considered if LT is not feasible
BCLC, 2022 [2]	Decisions to prioritize surgical resection or ablation over TACE should be based on clinical judgment and the specific characteristics of the patient’s disease.
AASLD, 2023 [3]	Liver resection is considered based on a multidimensional assessment of tumor characteristics and non-tumor factors, such as liver dysfunction
AASLD, 2023 [3]	It is especially recommended for localized HCC in the absence of underlying cirrhosis, or for limited tumor burden in wellcompensated cirrhosis without clinically significant portal hypertension

BCLC, Barcelona Clinic Liver Cancer; HCC, Hepatocellular Carcinoma; KLCA-NCC, Korean Liver Cancer Association-National Cancer Center; LT, liver transplantation; TACE, transarterial chemoembolization; AASLD, American Association for the Study of Liver Diseases.