Letter to the editor: a commentary on “Systemic therapy plus HAIC versus systemic therapy for hepatocellular carcinoma: a systematic review and meta-analysis.”

Dear Editor,

The systematic review and meta-analysis by Lu et al^[1] provides a comprehensive assessment of the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with systemic therapy in advanced hepatocellular carcinoma (HCC). The study offers significant insights into the potential benefits of HAIC, highlighting its ability to enhance tumor control via locoregional chemotherapy delivery and induce immunogenic cell death, which amplifies the immune response to systemic therapies. This ultimately improves overall survival, progression-free survival, objective response rate, and disease control rate. Trial sequential analysis and correlation between objective response rate and overall survival further strengthen the robustness of these findings. However, several aspects warrant further discussion and refinement.

First, heterogeneity of treatment regimens is a major concern. The included studies exhibited substantial variability in the treatment regimens, with differences in HAIC agents (e.g. oxaliplatin vs. cisplatin), tyrosine kinase inhibitors (TKIs, e.g. lenvatinib, sorafenib), and immune checkpoint inhibitors (ICIs, e.g. camrelizumab, tislelizumab, sintilimab). These agents have distinct pharmacological mechanisms, immune modulation effects, and clinical efficacies^[2]. For instance, oxaliplatin can induce immunogenic cell death, potentially enhancing synergy with PD-1/PD-L1 inhibitors, while cisplatin primarily relies on DNA damage with less immune activation. Moreover, combinations of different TKIs and ICIs can exert varying degrees of modulation on the tumor microenvironment^[3]. Despite subgroup analyses, the substantial heterogeneity in treatment regimens may obscure effect estimates and affect the interpretability of pooled outcomes. We suggest that future studies consider using network meta-analysis to directly and indirectly compare the efficacy of various combinations, while improving the reporting of treatment regimens for clearer evidence regarding individualized treatment strategies.

Second, the lack of individual patient-level data is a limitation of the current analysis. Although subgroup explorations were conducted, it remains challenging to determine whether specific subgroups – such as those with Child-Pugh B liver function or extrahepatic metastases – truly benefit from HAIC-combined therapy^[4,5]. We recommend that future studies incorporate individual patient data-based meta-analyses to allow for more refined stratification and better assessment of treatment effects.

Lastly, the limited geographic and population representation in the included studies is a concern. Most studies were conducted in China and other East Asian countries, where HBV-related HCC predominates, and HAIC is more commonly practiced^[6]. However, in Western countries, HCC is more frequently associated with non-viral causes, such as non-alcoholic steatohepatitis and metabolic syndrome^[6]. These patients often have different immune microenvironment characteristics and higher comorbidity burdens, which may affect their response to combined therapies. We recommend that future studies expand their geographic scope by incorporating multicenter prospective research to include diverse ethnicities and etiologies. Conducting etiology-based subgroup analyses will help validate the broader applicability of HAIC-combined treatment strategies.

Finally, while the study provides evidence supporting the use of HAIC combined with systemic therapy in advanced HCC, we believe that future research should focus on standardizing treatment protocols, addressing population diversity, and exploring the mechanisms underlying therapeutic responses. Further studies should also consider validating these findings in real-world settings. We look forward to high-quality, multicenter trials that incorporate elements of precision medicine to optimize comprehensive treatment strategies for advanced HCC^[7].

Ethical approval

This correspondence did not require ethical approval.

Consent

Not applicable.

Sources of funding

This work did not receive any funding related to its research, authorship, or publication.

Author contributions

X.C., X.Z., and P.Y. found the question and wrote the draft. D.W., and J.W. revised the manuscript. X.C., X.Z., and P.Y. contributed equally to this work and shared the first authorship. D.W., and J.W. contributed equally to this work and share corresponding authorship. All authors have approved the letter.

Conflicts of interest disclosure

The authors declare that they have no competing interests related to this work.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Jianjun Wang.

Provenance and peer review

This paper was not invited.

Data availability statement

All data analyzed or generated during this study are included in the article.

Declaration and use of AI

No artificial intelligence tools were used in the design, execution, or writing of this study, and our article is compliant with the TITAN Guidelines 2025.