Currently, there is growing support from various trials for the combination of TACE and ST as the most dominant treatment option in the first-line setting for unresectable HCC. However, in the second-line setting for advanced HCC, the clinical benefit of this combination has not yet been adequately and systematically evaluated. In this single-center case series study involving 18 patients with HCC, almost all real-life conditions were represented, including various tumor characteristics, first-line treatment protocols, and progression patterns. The combination of TACE and ST revealed promising results, with a 24-month OS observed from the date of failure of first-line ST, along with manageable complications. The TTP was achieved in 8 (44.4%) patients, with a median TTP of 3.5 months. Notably, 55.6% of patients with advanced HCC showed an objective response when treated with regorafenib combined with TACE, and 94.4% of patients achieved disease control. These preliminary outcomes indicate that patients with advanced HCC, even those facing formidable challenges, may potentially benefit from the addition of TACE to ST.
Four types of proven first-line treatment options were administrated to 14 patients in the study. Previous studies have often focused on specific subgroups with a particular treatment regimen, such as atezolizumab plus bevacizumab[29]. In terms of methodology, this study provides a general understanding of second-line therapy, whereas Shao et al. provided a more targeted understanding. The OS for second-line therapy in this study was 24 months, whereas the study by Shao et al. reported an OS of 8 months. However, the results cannot be directly compared owing to the lack of separate results for patients undergoing TACE in the latter study. The decision-making process for treatment selection is influenced by factors such as financial burden, physicians’ preferences, and patients’ choices in real-life practice. In China, physicians generally adhere to guidelines such as the BCLC guidelines or the China National Liver Cancer guidelines for HCC when making treatment-related decisions. As this study is a small case series, conducting a cross-sectional study based on a large database, such as a national platform, may yield more comprehensive epidemiological results.
Advanced HCC exhibits substantial heterogeneity in terms of progression patterns, salvage treatment patterns, and post-progression prognosis. In this study, the most common progression pattern was NIH, followed by IHG, NEH, and EHG/nVI. This finding differs from the results reported by Reig et al. and Talbot et al.[27, 28]. The differences may be attributed to the demographics of the patient cohorts, particularly the prevalence of HBV infection in the current study. In contrast, most of the patients in the other two studies had hepatitis C virus infection or no viral infection. HBV and HCV act on different stages of the carcinogenic process, with HBV initiating the process and HCV promoting its development. Consequently, in the current study, the residual normal liver tissue was more likely to develop NIH lesions in the 18 patients, while IHG was more frequent in the other two studies.
The choice of first-line ST also varies among studies (multiple types of ST vs sorafenib vs ICIs). Post-progression prognosis is influenced by specific progression patterns and salvage treatment strategies, as previously mentioned[29]. In this study, TACE combined with ST achieved a post-progression OS of 24 months, which is superior to the OS reported by previous studies and confirms the consolidative effect of subsequent treatment. Although no self-controlled analysis was conducted based on the abovementioned patterns, it is believed that the outcomes of patients in different groups would differ. There have been some suggestions regarding the design of second-line trials and clinical practice, and the addition of TACE has been highlighted as an approach that directly targets intrahepatic solid tumors.
It is worth mentioning that one patient (Patient 11) achieved successful conversion therapy after not achieving a response with lenvatinib monotherapy (Fig 5). In this case, the tumor was primarily unresectable from a surgical perspective, with risk factors including insufficient future liver remnant and a low chance of achieving R0 resection. While lenvatinib is generally effective, with a good ORR of 24.1%, it seemed ineffective for this patient. However, for some patients, lenvatinib may provide long-term tumor control and improve OS.
Currently, the combination of ICIs and MTTs seems to be a better treatment option compared to single agents alone[30]. The most important considerations in conversion therapy are ORR and mitigation, including tumor progression rate and the time, duration, and depth of remission. TACE and HAIC have shown superiority in this case, as they contribute to a lower tumor progression rate; rapid onset of response, which helps to reduce the exposure time of conversion therapy so as to reduce the incidence of adverse reactions; deeper remission, which is undoubtedly more conducive than subsequent treatment; and longer duration of remission. These factors provide a longer window period for subsequent treatment options. Numerous research studies have provided evidence for the application of locoregional treatment combined with ST in conversion therapy[31, 32].
To date, several clinical trials have been conducted to investigate the use of TACE plus regorafenib with/without ICIs as a second-line therapy for HCC[33]. These studies have demonstrated acceptable results in terms of both safety and efficacy. Similarly, the current study showed promising outcomes with no severe complications. It is important to note that when comparing the results of a single cohort with other studies, differences may be attributed to variations in evaluation criteria, sample sizes, and intervention doses.
This study has several limitations that should be acknowledged. Firstly, it is a retrospective, case series study conducted at a single center, which may limit the generalizability of the findings to other populations. The conclusions drawn from this study must be interpreted with caution and considered as preliminary evidence. Secondly, over half of the patients did not reach the study endpoints, and therefore, the outcomes may be subject to potential bias. Continued follow-up is necessary to obtain a more comprehensive understanding of the long-term outcomes. Thirdly, the TACE procedure itself is heterogeneous. The comparison between cTACE and DEB-TACE remains controversial, and the differences in the efficacy between these two techniques could introduce bias in the results. Moreover, the presence of technical bias in the TACE procedures cannot be ruled out. The lack of a control group, such as a single-agent ST group, and subgroup analysis is another limitation of the study. Considering these limitations, future trials are needed to validate the findings of our study.
In conclusion, patients with advanced HCC may potentially benefit from the addition of TACE to ST. Our results provide a basis for exploring the efficacy of the combined approach. Future research should aim to confirm these findings and assess the benefits and risks of the combined TACE and ST strategy in a larger, well-controlled trial setting.