Survival time is poor once a patient enters ISPA-HCC, and the treatment at this stage seriously affects the OS. This study evaluated the efficacy of the combined treatment with sorafenib plus DEB-TACE in patients with early ISPA-HCC. We found that the combined therapy was superior to sorafenib monotherapy with respect to OS (16.3 months vs. 10.0 months) and TTP (6.7 months vs. 4.3 months). This result was similar to prospective studies of primary unresectable HCC treated with DEB-TACE combined with sorafenib, including TACE-2 (TTP 7.9 months) (Meyer et al. 2017) and SPACE (TTP 5.6 months) (Lencioni et al. 2016), and is superior to the trials of primary advanced HCC with PVTT treated with cTACE combined with sorafenib upon STAH (OS 12.8 months) (Park et al. 2019) or Zhu’s study (OS 11.0 months) (Zhu et al. 2014). According to the latest result of IMbrave150 (Finn et al. 2020; Finn et al. 2021), the median OS of patients treated with atezolizumab plus bevacizumab was 19.2 months, which is longer than our study. The participants in IMbrave150 included BCLC stage A (2%), BCLC stage B (15%), which may account for this difference. The OS and TTP of our study were calculated from the administration of sorafenib instead of the diagnosis of HCC, indicating that all patients had suffered disease progress, while all patients in IMbrave150 were treated since the diagnosis of primary HCC, making it difficult to directly compare the results. Compared to those with primary advanced HCC, patients with early ISPA-HCC normally have less tumor burden and poor liver functional reserve. However, with portal invasion, the intrahepatic tumor burden of these patients is still in the early progression stage, similar to that of HCC patients at intermediate substage B3a, as reported by Kudo et al. (Kudo et al. 2015). At this stage, local treatment to minimize liver function damage, such as super-selective TACE, could still have a high response rate in intrahepatic tumor control on the premise of systemic treatment. Therefore, early ISPA-HCC patients are most likely to benefit from selective DEB-TACE when they are refractory to cTACE.
Although the STAH trial failed to achieve a survival benefit, the results of post-hoc analysis showed that the subgroups of cTACE ≥2 could benefit from sorafenib plus TACE (Park et al. 2019). In the present study, all patients received ≥2 DEB-TACE sessions in the DTS group, and the patients who received more than two sessions of DEB-TACE had longer median OS than those who received two sessions. This suggested that for whom repeated DEB-TACE is tolerable, sorafenib combined with DEB-TACE might be more effective.
Except for the characteristics of early ISPA-HCC itself, the survival advantages in our study might be due to the mutual benefits for efficacy improvement of both DEB-TACE and sorafenib treatments. First, intrahepatic tumor burden appears to be an important predictor of survival in patients with advanced HCC. Tumor size, tumor number, and PVTT have been found to be predictors of TACE response (Vogl et al. 2011). DEB-TACE promptly reduces the tumor burden refractory to cTACE, which could further enhance sorafenib efficacy. Conversely, in our study, sorafenib was initiated before DEB-TACE, as previous studies suggested that early administration of sorafenib suppresses the post-TACE angiogenesis resulting from increased levels of vascular endothelial growth factor and other angiogenic factors after TACE (Hatooka et al. 2016; Park et al. 2012). As such, sorafenib shows marked efficacy against local tumors and extrahepatic metastases when combined with TACE. Furthermore, sorafenib can normalize the tumor blood vessels and reduce numerous bilobar HCCs simultaneously, which creates opportunities for super-selective embolization by DEB-TACE. Our sub-analyses demonstrated that DEB-TACE was more effective in patients with more advanced-stage HCC, including AFP ≥400 ng/mL, intrahepatic tumor number ≥3, and main tumor size ≥5 cm. On-demand DEB-TACE for patients could quickly reduce tumor burden, thereby protecting liver function from intrahepatic lesion progression.
AE occurrence was routinely checked prior to each TACE session. However, abnormal liver function or post-embolization syndrome was not included as part of the safety analysis, as such events are known to occur shortly after TACE. Patients from the TACE group did not experience AEs ≥grade 3. The incidence of AEs associated with sorafenib was similar to that reported by Zhu et al. and Wu et al. when treating advanced HCC with sorafenib combined with TACE (Zhu et al. 2014; Wu et al. 2017). Only two grade 3 and no grade 4 AEs were observed in this study. The most common grade 1 or 2 AEs were hand–foot syndrome, diarrhea, and fatigue. These AE results indicate that sorafenib combined with DEB-TACE is well tolerated by patients with early ISPA-HCC after cTACE-refractory.
Previous studies have suggested that DEB-TACE might be effective in cTACE refractoriness. The causes of resistance to cTACE include cTACE-induced liver function impairment (Johnson et al. 1991), heterogeneous lipiodol retention (Lee et al. 2002), and arterioportal shunt formation caused by vascular invasion (Seki and Hori 2012). HCC patients with heterogeneous lipiodol retention have poor blood supplies that are unlikely to be effectively perturbed with arterial embolization alone. In contrast, positive response to DEB-TACE may be associated with the slow release of doxorubicin from the beads in the tumor vascular plexus. Additionally, the lipiodol used during cTACE may pass through the arterioportal shunt, which would not produce embolization of the arterial blood supply to the HCC but would cause extensive ischemia in the normal liver tissue (Oh et al. 2015). However, DEB beads are inherently larger than lipiodol particles and cannot traverse arterioportal shunts; hence, shunts with diameters < 300 µm would be occluded, and continuous doxorubicin delivery would eventually kill the tumors.
There are several limitations to our study. First, as this was a retrospective study, further prospective randomized controlled studies are required to confirm our findings. Second, to date, the first-line treatments for advanced HCC include sorafenib, lenvatinib, and atezolizumab plus bevacizumab. The most suitable systemic therapy for combination with TACE remains to be explored. Last, although early detection of advanced HCC is addressed, it is difficult to define the time limit for early detection from complete cTACE resistance to early progression, and preoperative BCLC B-stage tumor burden and cTACE sessions could affect the degree of ISPA-HCC progression, all of which should be considered in further research.
In conclusion, sorafenib plus DEB-TACE is safe and effective for the treatment of early ISPA-HCC with well-preserved liver function. Combination therapy improves OS, TTP, and local tumor response and does not increase AEs compared to sorafenib monotherapy.