Letter to the editor: safety and efficacy of PD-1 inhibitor (sintilimab) combined with transarterial chemoembolization as the initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria

Abstract

[...]this is a prospective, single-arm, phase 2 clinical trial, and a detailed flowchart could clearly show the total number of subjects screened, an overview of reasons for withdrawal, and so on. [...]a figure displaying the trial profile would contribute to a clearer understanding of the selection process. According to the global cancer statistics by world region for 2022, liver cancer ranked sixth in incidence and third in mortality, rather than HCC.2 Thus, a rigorous description of the background and challenges of HCC could enhance the significance of this study. [...]it is noted that the study conducted by Kudo et al was mentioned twice in this study, primarily because patients with intermediate-stage HCC beyond the up-to-seven criteria achieved a median progression-free survival (PFS) of 3 months and an objective response rate (ORR) of 33.3%.3 Although the authors tried to demonstrate the superiority of combining sintilimab and TACE by indirectly comparing their data with Kudo et al’s, they seemed to ignore data from the experimental group, where patients treated with lenvatinib alone showed a PFS of 16 months and a 73.3% ORR, much longer and higher than the 8.4 months and 60% observed in this study.

Correspondence to Dr Bi-Cheng Wang; [email protected]

The study reported by Li and colleagues in the Journal of ImmunoTherapy of Cancer aimed to assess the safety and efficacy of combining sintilimab and transarterial chemoembolization (TACE) in patients with intermediate-stage hepatocellular carcinoma (HCC) beyond the up-to-seven criteria.¹ Although the findings of this study may provide valuable insights into intermediate-stage HCC, certain aspects warrant further clarification and discussion.

First, this is a prospective, single-arm, phase 2 clinical trial, and a detailed flowchart could clearly show the total number of subjects screened, an overview of reasons for withdrawal, and so on. Therefore, a figure displaying the trial profile would contribute to a clearer understanding of the selection process.

Second, liver cancer could be considered synonymous with HCC, as liver cancer includes five main types: HCC, cholangiocarcinoma, fibrolamellar carcinoma, angiosarcoma, and hepatoblastoma. According to the global cancer statistics by world region for 2022, liver cancer ranked sixth in incidence and third in mortality, rather than HCC.² Thus, a rigorous description of the background and challenges of HCC could enhance the significance of this study.

Third, it is noted that the study conducted by Kudo et al was mentioned twice in this study, primarily because patients with intermediate-stage HCC beyond the up-to-seven criteria achieved a median progression-free survival (PFS) of 3 months and an objective response rate (ORR) of 33.3%.³ Although the authors tried to demonstrate the superiority of combining sintilimab and TACE by indirectly comparing their data with Kudo et al’s, they seemed to ignore data from the experimental group, where patients treated with lenvatinib alone showed a PFS of 16 months and a 73.3% ORR, much longer and higher than the 8.4 months and 60% observed in this study. Additionally, in another study by Kudo and colleagues, for patients with intermediate-stage HCC beyond the up-to-seven criteria, TACE alone showed a median PFS of 9.0 months.⁴ Based on these indirect comparisons, the synergistic effect of combining sintilimab and TACE remains uncertain.

Fourth, this is a single-arm study, and no comparative analysis was conducted. Therefore, the use of the log-rank test is questionable. The description of the statistical methods was vague. The latest version of SPSS and an accurate description of the statistical methods regarding survival outcomes and response rate, along with the 95% CIs, may enhance the reliability of this study.

Fifth, considering that the median PFS was 8.4 months in this study and the median time interval between TACE treatment and subsequent sintilimab therapy was 10 days, it could be unreasonable for patients to receive only a median of 4 cycles (IQR 2–7) of sintilimab treatment (every 3 weeks).

In summary, intermediate-stage HCC beyond the up-to-seven criteria represents a population of patients who deserve further attention. Multidisciplinary teams can benefit these patients and improve their outcomes.

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

Not applicable.

Footnote

Contributors I am the sole author and the guarantor.

Funding This study was supported by the National Natural Science Foundation of China (No. 82302956 to Bi-Cheng Wang).

Competing interests No, there are no competing interests.

Provenance and peer review Not commissioned; internally peer reviewed.

References

¹ Li L, Xu X, Wang W, et al. Safety and efficacy of PD-1 inhibitor (sintilimab) combined with transarterial chemoembolization as the initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria. J Immunother Cancer 2025; 13: e010035. doi:10.1136/jitc-2024-010035

² Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024; 74: 229–63. doi:10.3322/caac.21834

³ Kudo M, Ueshima K, Chan S, 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: 1084. doi:10.3390/cancers11081084

⁴ Kudo M, Ueshima K, Ikeda M, et al. Final Results of TACTICS: A Randomized, Prospective Trial Comparing Transarterial Chemoembolization Plus Sorafenib to Transarterial Chemoembolization Alone in Patients with Unresectable Hepatocellular Carcinoma. Liver Cancer 2022; 11: 354–67. doi:10.1159/000522547