Time to say goodbye: from Barcelona to Milan and the modern management of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and one of the most common causes of cancer-related death with the projection to increase during the next few decades (1). During the last 3 decades, several staging systems have been introduced for the stratification of the prognosis and management of HCC of all stages. There is no consensus regarding the universal implementation of one staging system since all the proposed classifications have limitations (2). The Barcelona Clinic Liver Cancer (BCLC) Staging System remains the most widely classification system used for HCC management guidelines that incorporates tumor size, presence of metastatic disease, portal hypertension, Child-Turcotte-Pugh score, total bilirubin and performance status. However, it does not account for tumoral behavior, and it is very “conservative” (restrictive) regarding resectability, especially for BCLC-B patients who might benefit from surgical management (3,4). Recent advances in systemic and locoregional therapies have led to changes in many guidelines regarding systemic therapy, as well as the possibility for downstaging patients to undergo surgery or transplant with curative intent.

In a recent issue of HBSN, Cheung et al. present the updated the Hong Kong consensus statements on unresectable HCC (5). The expert panel has formulated 60 consensus statements to guide the staging and treatment of HCC mainly focusing on the considerable additions that have been made to the recommendations on unresectable disease and the use of targeted therapies and immunotherapies. It is obvious that the updated Hong Kong Liver Cancer (HKLC) staging system uses more ‘granular’ data regarding tumor size, nodules and vascular invasion and identifies patients with intermediate or advanced HCC who may benefit from locoregional therapies including surgery. For example, HKLC supports resection in locally advanced HCC, if it is anatomically, technically and functionally feasible, including cases with intrahepatic portal vein or hepatic vein branch invasion, bilobar disease or even in cases with isolated extrahepatic oligometastatic in selected patients (5).

These recommendations are aligned to emerging data supporting resection of HCC beyond the conventional BCLC criteria since HCC is a very heterogenous disease, and the size or the number of nodules cannot be reliable surrogates of disease biology. For example, tumor burden score (TBS) has been recently shown to be an independent prognostic factor of outcomes in patients with HCC undergoing resection. More specifically, postresection overall survival was worse incrementally with higher TBS, whereas no differences in survival were noted among patients with similar TBS, irrespective of BCLC stage (61.6% vs. 58.9% for BCLC-A/medium TBS vs. BCLC-B/medium TBS, P=0.930). Also, patients with BCLC-B HCC and lower TBS had better survival than those with BCLC-A disease and a higher TBS (58.9% vs. 45%; P=0.005) (6). Of interest, TBS can also discriminate and predict worse survival of patients undergoing resection of multinodular HCC beyond the Milan criteria (MC) (low TBS 73.7% vs. high TBS 13.1% 5-year overall survival, P<0.001) (7).

Another area where HKLC are considered as more “liberal” in terms of resectability of conventionally perceived “unresectable disease”, is the recommendation for portal vein embolization (PVE) or associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as well as liver transplantation (LT). PVE and ALPPS are available options to induce hypertrophy of the liver and thus could increase future liver remnant (FLR) and improve the eligibility for surgery, since there are strong data supporting their role if facilitating complete tumor resection among patients with initially unresectable primary liver tumors (8). LT is the ultimate treatment modality in selected patients with liver confined HCC since it combines oncological radicality with cure of the background liver disease. MC have been the Holy Grail of most of the transplant practice worldwide since their introduction in 1994 (9). However, there is increasing body of literature raising concerns about their restrictive nature since there are patients beyond MC who benefit from LT, thus there is an ongoing effort to transition away from purely morphometric transplant selection criteria and incorporate other dynamic surrogates of underlying tumor biology to better risk stratify patients undergoing LT for HCC. The HKLC has adopted the University of California San Francisco (UCSF) criteria which consider as transplantable patients with HCC with larger or more tumors than MC (10). Again here, TBS can be reliably used to identify patients undergoing LT within [hazard ratio (HR) =1.20; 95% confidence interval (CI): 1.04–1.37; P=0.011] and beyond MC (HR =1.53; 95% CI: 1.16–2.01; P=0.002) who had higher risk of recurrence (11). Also, the combination of clinicoradiologic and pathologic data can facilitate identification of patients within or beyond MC (with or without downstaging) who can benefit from LT due to lower risk of disease recurrence (12).

Historically, around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC. The combination of atezolizumab and bevacizumab has been shown to improve overall survival relative to sorafenib. More recently, durvalumab plus tremelimumab yielded superior overall survival vs. sorafenib and atezolizumab plus cabozantinib yielded superior progression-free survival. In addition, pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab have been approved as second-line. The advent of more effective systemic and locoregional therapies has facilitated prolonged survival among patients with advanced disease, as well as allowed patients to undergo surgical intervention who would otherwise have disease considered unresectable (13).

It is well-supported in the literature that patients with HCC who undergo successful conversion therapy followed by curative-intent surgery may achieve a significant survival benefit compared to those who receive chemotherapy alone or those who are successfully downstaged with conversion therapy but not treated with surgery. As the authors highlighted, even if the success rate of conversion varies greatly, ranging from 0.8% to 60% and depending on the therapeutic protocols, combined locoregional plus systemic conversion therapy has demonstrated significant clinical advantages, with a conversion rate of up to 60%, an objective remission rate of 96% for patients, and a disease control rate of up to 100% (14). The authors omitted to discuss the potential role of hepatic artery infusion chemotherapy (HAIC) as a downstaging modality in patients with advanced HCC. Recent data showed that triple therapy, including HAIC combined with angiogenesis inhibitors and programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) blockers (AIPB) were able to prolong the survival time of patients with unresectable HCC more than AIPB regimens (15).

All in all, patients with HCC should be treated in a multidisciplinary setting focused on collaboration among surgeons, medical oncologists, radiation oncologists, as well as interventional radiologists, to provide optimal care. Treatment paradigms must consider both tumor and patient-related factors such as extent of liver disease and liver function, respectively, both of which are primary drivers of morbidity and mortality. In the context of the rapidly evolving surgical and systemic therapeutic landscape and guidelines, an emphasis on a personalized and multidisciplinary approach for patients with HCC should be considered.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Hepatobiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-53/coif). The authors have no conflicts of interest to declare.

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References

1. Beal EW, Tumin D, Kabir A, et al. Trends in the Mortality of Hepatocellular Carcinoma in the United States. J Gastrointest Surg 2017;21:2033-8. [Crossref] [PubMed]
2. Moris D, Felekouras E. Ignore reality but not the consequences of its ignorance: Broaden guidelines in surgery of hepatocellular carcinoma. Hepatology 2017;65:1772-3. [Crossref] [PubMed]
3. Tsilimigras DI, Bagante F, Sahara K, et al. Prognosis After Resection of Barcelona Clinic Liver Cancer (BCLC) Stage 0, A, and B Hepatocellular Carcinoma: A Comprehensive Assessment of the Current BCLC Classification. Ann Surg Oncol 2019;26:3693-700. [Crossref] [PubMed]
4. Moris D. A farewell to Barcelona Clinic Liver Cancer (BCLC) classification for hepatocellular carcinoma. J BUON 2021;26:298-302. [PubMed]
5. Cheung TT, Yu SC, Chan SL, et al. The Hong Kong consensus statements on unresectable hepatocellular carcinoma: narrative review and update for 2021. Hepatobiliary Surg Nutr 2023;12:366-85. [Crossref] [PubMed]
6. Tsilimigras DI, Moris D, Hyer JM, et al. Hepatocellular carcinoma tumour burden score to stratify prognosis after resection. Br J Surg 2020;107:854-64. [Crossref] [PubMed]
7. Tsilimigras DI, Mehta R, Paredes AZ, et al. Overall Tumor Burden Dictates Outcomes for Patients Undergoing Resection of Multinodular Hepatocellular Carcinoma Beyond the Milan Criteria. Ann Surg 2020;272:574-81. [Crossref] [PubMed]
8. Baili E, Tsilimigras DI, Moris D, et al. Technical modifications and outcomes after Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) for primary liver malignancies: A systematic review. Surg Oncol 2020;33:70-80. [Crossref] [PubMed]
9. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-9. [Crossref] [PubMed]
10. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394-403. [Crossref] [PubMed]
11. Moris D, Shaw BI, McElroy L, et al. Using Hepatocellular Carcinoma Tumor Burden Score to Stratify Prognosis after Liver Transplantation. Cancers (Basel) 2020;12:3372. [Crossref] [PubMed]
12. Tran BV, Moris D, Markovic D, et al. Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: Analysis of the US Multicenter HCC Transplant Consortium. Liver Transpl 2023;29:683-97. [Crossref] [PubMed]
13. Xie DY, Zhu K, Ren ZG, et al. A review of 2022 Chinese clinical guidelines on the management of hepatocellular carcinoma: updates and insights. Hepatobiliary Surg Nutr 2023;12:216-28. [Crossref] [PubMed]
14. Liang C, He Z, Tao Q, et al. From Conversion to Resection for Unresectable Hepatocellular Carcinoma: A Review of the Latest Strategies. J Clin Med 2023;12:7665. [Crossref] [PubMed]
15. Zhang W, Zhang K, Liu C, et al. Hepatic arterial infusion chemotherapy combined with anti-PD-1/PD-L1 immunotherapy and molecularly targeted agents for advanced hepatocellular carcinoma: a real world study. Front Immunol 2023;14:1127349. [Crossref] [PubMed]