Evolving concepts in the management of hepatocellular carcinoma: from ‘stage hierarchy’ to the ‘multiparametric therapeutic hierarchy’ approach

We read with great interest the recently published study of Vitale et al. (1) aiming to compare the survival outcomes of liver resection (LR), percutaneous radiofrequency (RF) ablation and transarterial chemoembolization (CEL) in patients with early-stage multinodular hepatocellular carcinoma (HCC) (i.e., defined as 2 to 3 nodules each measuring ≤3 cm on compensated cirrhosis) not eligible for liver transplantation.

This Italian multicenter retrospective cohort study used data from two national registries between January 2008 and December 2020: Hepatocarcinoma Recurrence on the Liver Study (HERCOLES) group for patients who underwent LR and Italian Liver Cancer (ITALICA) group for patients who underwent RF or CEL. A total of 720 patients were included based on specific exclusion criteria: Barcelona Clinic Liver Cancer (BCLC) stage other than A, absence of cirrhosis, single nodule, previous treatment for HCC and combined therapy. Further exclusions included patients who had received a hierarchically superior treatment during follow-up, i.e., for the LR group, patients who had received a liver transplant; for the RF group, patients who had received LR for recurrence; for the CEL group, patients who had received LR or RF during follow-up.

Overall survival was calculated from the date of the intervention to the date of the patient’s death or the end of follow-up. To avoid indication or other confounding biases usually associated with observational studies, a method of matching-adjusted indirect comparison (MAIC) was applied to balance data between the 3 groups. In addition, subgroup sensitivity analyses were performed (patients who had a complete response from the first treatment, patients with Child-Pugh class B cirrhosis) as well as a competitive survival risk analysis, given that the prognosis of patients with HCC is not only influenced by cancer-related mortality but also by liver failure and other causes of extra-hepatic death. Compared with RF and CEL, the authors demonstrated that median survival at 1, 3, and 5 years was significantly higher for the LR group before and after population balancing, while taking into account competitive risks, as well as in all subgroups in stratified analysis.

The authors are to be congratulated on this work, which is of high methodological quality and addresses a highly topical issue. This comparative study based on 2 Italian registries remains one of the largest Western matched cohorts of patients with level A multinodular HCC according to BCLC. Contrary to the recommendations of the recently revised BCLC algorithm, the authors argue that LR should probably be part of the first-line therapeutic armamentarium followed by RF and CEL if surgery is not possible. The reported results are consistent with the findings of other Asian studies as well as with current recommendations in Asia-Pacific region, which suggest that all patients with HCC and compensated cirrhosis without extrahepatic metastases should be evaluated for LR before any other treatment (2-5). Other similar comparative studies in the past showed comparable results, but their robustness was often limited by small sample sizes (6-8). A meta-analysis published in 2024 also demonstrated the superiority of LR versus RF and CEL in this same context (9).

Advances in surgery and systemic therapies for HCC have considerably increased the complexity of patient management nowadays. Dynamic adaptation of treatment algorithms based on disease stage [i.e., the BCLC 2022 classification recently approved by the American Association for the Study of Liver Diseases 2023 guidelines (10)] now seems necessary to allow flexible therapeutic allocation. The management of HCC, in particular, is increasingly based on factors that are independent of traditional oncology classification, such as patient fragility, co-morbidities, tumor location, multiple liver function parameters, as well as specific technical contraindications that have an impact on the administration of treatments and the availability of resources. As a result, the allocation of treatments, historically based on the stage of the disease before treatment, is evolving towards a more personalized approach. The concept of a therapeutic hierarchy, in which the different therapeutic options are ordered according to their survival benefit (for example, from surgery to systemic therapy), as well as the concept of an inverse therapeutic hierarchy, in which therapies are classified according to their conversion or adjuvant capacity (for example, from systemic therapy to surgery), is recent (11,12). The authors’ aim was to validate this concept of a “treatment hierarchy” as opposed to the “stage hierarchy” proposed by the BCLC classification, one potentially exposing patient to an increased risk of morbidity and mortality and the other to under-treatment, respectively.

The great value of this study lies in its methodological strengths, even if a few comments need to be raised. Indeed, despite the use of MAIC, this approach depends on the choice of matching variables. The allocation of weights for matching may not eliminate all potential confounding factors, especially in this particular setting where the study is based on two different Italian registries between which there may be differences in data collection and recording standards. Secondly, among of the variables used for MAIC in this study [i.e., age, sex, Charlson comorbidity index, Child-Pugh class, model for end-stage liver disease (MELD) score, clinically relevant portal hypertension, cause of cirrhosis, number and diameter of nodules and serum α-fetoprotein level], neglecting tumor location could lead to significant bias. Indeed, tumor location, access and future liver remnant volume if LR is proposed are essential information for treatment decision-making. Indeed, for superficial HCC confined to a specific liver lobe, surgery could be considered, whereas for small deep HCC requiring extensive resection in the context of cirrhosis, RF may be a safer option than surgical resection. Last but not least, it is also likely that the various treatments for early-stage multinodular HCC do not need to be mutually exclusive, but rather collaborative, adopting several methods to maximize the benefits for the patient. Thus, it remains to be explored if a “multiparametric therapeutic hierarchy” combining RF and surgery, or surgery with other locoregional treatments becoming increasingly important today (i.e., radioembolization with Yttium-90 or immunotherapy), could be the next step to explore in the treatment of early-stage multinodular HCC.

In conclusion, the methodological strength of this study highlights the superiority of LR over non-surgical treatments such as RF and CEL for patients with early multinodular HCC who are not eligible for liver transplantation. However, prospective studies with less selective exclusion criteria are needed to confirm this superiority and to develop the concept of a “treatment hierarchy”, possibly multiparametric, to personalize the management of this group of high-risk patients.

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: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2024-652/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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