To the best our knowledge, this is the first study to explore the effectiveness and safety of the combination strategy of mFOLFOX6-HAIC and camucirumab plus rivoceranib in treating HCC with PVTT. In this multicenter retrospective study, HCC patients with PVTT received the triple therapeutic regime of HAIC combined with camucirumab and rivoceranib achieved remarkable median OS. The addition of HAIC to molecular tyrosine kinase inhibitor(TKI) plus anti-PD-1 therapy also helped further improvement in terms of PFS, ORR and DCR. Consistent survival outcomes could be observed after propensity matching except the advantages in ORR. Grade 3 or 4 TRAEs more frequently occurred in the triple combination regime(70.5% vs 62.2%), but without statistical differences between groups. In addition, the multivariate analysis revealed that the triple combination strategy was identified as an independent factor influencing OS and PFS according to multivariate analysis.
PVTT constitutes a significant influencing factor in the unfavorable prognosis of HCC, whereas there still remains controversy about standard treatment methods. Surgical resection is the preferred treatment option for PVTT, but only a minority of patients are evaluated as suitable candidates [25]. The combined approach of TACE with sorafenib or radiotherapy has shown promising outcomes, however, it remains a formidable challenge in effectively managing tumor progression [26–27]. Moreover, there is also an obvious limitation of the capability of BCLC-recommended anti-angiogenic therapy alone in the management of advanced HCC with PVTT. Besides, the updated IMbrave150 study failed to achieve positive results and reveals that the median OS for the combination therapy of bevacizumab and atezolizumab in treating PVTT is only 7.6 months[28]. Currently, the RESCUE phase II trial[15] (median PFS of 5.7 months and 5.5 months in the first-line treatment and in the second-line treatment, respectively)and CARES-310 phase III trial[16] (median OS of 22.1 months), aimed to compare the efficacy of camucirumab plus rivoceranib to sorafenib, both achieved positive results in first-line treating advanced HCC. The CARES-310 trial, encompassing a substantial proportion of patients with PVTT, has documented the longest recorded median overall survival thus far and demonstrated promising potential in terms of favorable survival benefits within the portal vein involvement subtype. Up to now, the application of camucirumab plus rivoceranib in HCC with PVTT was only reported in a multicenter retrospective study, with a median OS of 14.8 months, which significantly further extended around 9–10 months of median OS on the basis of sorafenib[17]. By contrast, the results in our study are less superior, and the relatively unfavorable prognosis in terms of median OS is mainly because of the higher tumor burden and a higher proportion of metastasis in the patients included in this study, which makes it more difficult to shrink intrahepatic tumor lesions.
According to the outcomes in several phase III trials[19, 29], the advantages of Folfox-HAIC not only exhibited in long-term survival but also in tumor responses in comparison to TACE and sorafenib, which are widely recognized as primary options in the treatment of HCC. In spite of the insufficient efficacy of Folfox-HAIC monotherapy in repressing tumor progression for advanced HCC, Folfox-HAIC-based combination treatment has shown promising outcomes especially in the cases with PVTT. The integration of HAIC and irradiation is identified as an efficacious therapeutic strategy for PVTT, as stated in the Japanese guidelines. Onishi et al performed a retrospective study and reported a better median OS of 12.4 months with a 45% objective response of those who received HAIC in combination with irradiation than 5.7 months observed in the HAIC monotherapy group[30]. Moreover, Four clinical trials compared the survival benefits between HAIC plus sorafenib and sorafenib monotherapy in the treatment of HCC patients with major PVTT and received three positive results. Among them, the randomized trial by Zheng et al reported that the HAIC-sorafenib combination group obtained a best median OS of 16.3 months, which is significantly superior to the 6.5 months in the sorafenib monotherapy group for major PVTT[21]. Additionally, another propensity-matching study showed the combination of TACE-HAIC with tyrosine kinase inhibitors and PD-1 inhibitors. The median PFS was 14.8 months with an ORR of 49.6% and well-tolerated adverse events in the entire cohort, but the median OS was unreached[31]. However, it still remains unclear whether the incomplete devascularization of TACE directly affects the administration of Folfox-HAIC. Therefore, the potential survival benefits of TACE-HAIC over HAIC are yet to be determined, despite existing evidence that suggests TACE-HAIC may extend survival more effectively than TACE. Relatively, the triple combination therapy implies an increased occurrence of adverse events, while it has been reported that the control of adverse reactions in HAIC monotherapy is significantly better than that in TACE or TACE-HAIC. In comparison to TACE-HAIC or TACE, the application of HAIC in systemic treatment may be more prudent and reliable for PVTT. As reported in the 2022 ASCO conference, the first-line treatment of BCLC C stage HCC with HAIC combined with camucirumab and rivoceranib demonstrated a highly remarkable ORR of 70.96%. In this study, when HAIC combined with camucirumab and rivoceranib, the triple regime led to an encouraging mOS of 19.6 months with an ORR of 55.5% for PVTT in the entire cohort. With regard to safety, the incorporation of HAIC resulted in a rise in the incidence of adverse events, but overall, these reactions remained controllable.
Such remarkable survival outcomes may be attributed to the reciprocal regulatory reaction and synergistic effect of chemotherapy agents, anti-angiogenic therapy, and the blockade of the PD-1/PD-L1 pathway. On the one hand, The inhibitors of VEGFR can not only facilitate the restructuring of tumor blood vessels, promoting vascular normalization and consequently enhancing the efficacy and resistance to chemotherapy and anti-PD-1/PD-L1 treatment[31], but also exhibit the capability to suppress the immune inhibitory myeloid cell recruitment induced by VEGF-A. This inhibition effectively counteracts the immunosuppressive effects exerted by aberrant myeloid populations and improves the tumor immune microenvironment, thus enhancing the resistance to immunotherapy[32–33]. On the other hand, within the mFOLFOX regimen-based HAIC, oxaliplatin assumes a crucial role by facilitating immunogenic cell death, thus promoting immune activation and augmenting the antigenicity of tumor cells in the tumor cell microcirculation. Besides, immunogenic cell death can also improve the antigenicity of tumors to sensitize “off-target” cells in the tumor microenvironment to inhibit the proliferation and migration of tumor cells[34–38]. As a result, these three factors collectively exhibit a synergistic effect and, to a certain extent, compensate for their individual deficiencies, for fully unleashing their anti-tumor effects.
In this study, the overall tumor response, ORR, and DCR of the H-C-R group in the entire cohort were significantly higher than those of the C-R group. However, in the propensity score-matched cohort, there was no statistical difference in ORR between the groups. This discrepancy may be associated with the deviation introduced by excluding crucial cases through PSM adjustment, highlighting the need for further randomized controlled trials to rectify the limitation. Furthermore, multivariate analyses identified CTP stage A, ALBI grade 1, tumor number ≤ 3 and treatment regime as risk factors influencing OS, while AFP level, tumor number, metastasis, and treatment regime were considered as risk factors affecting PFS. Among them, CTP stage and ALBI grade are established criteria for assessing liver function, and ALBI grading eliminates the subjective impact of ascites and hepatic encephalopathy, making it a more objective reference standard. Additionally, the existing medical evidence has already confirmed that AFP dynamically reflect tumor activity and indirectly reflect the tumor progression capability. As for subgroup comparison, the triple combination regime showed effective management in HCC patients with high tumor burden. Patients exhibiting the traits of being aged ≤ 65y, ECOG PS 0, tumor size > 7 cm, with HBV infection and metastasis are more suitable for adding HAIC to the administration of camucirumab and rivoceranib regarding profitable OS and PFS. but age, ECOG PS 0 and HBV infection-related ineffectiveness of the triple combination regime may be primarily due to insufficient sample size within these subgroups.
This study still has some inherent limitations that should be acknowledged. Firstly, due to its retrospective nature, it inherently introduces unavoidable selection bias. While we employed propensity score matching to minimize between-group differences, endogenous differences may still exist. Thus, there is a need for additional prospective randomized controlled trials to enhance the level of evidence and further validate our findings. Secondly, the relatively small sample size in certain subgroups underscores the importance of expanding the study population and conducting larger-scale research to enhance the reliability of the findings. Then, this study incorporated multicenter data, thereby potentially introducing variations in treatment approaches across different centers that could impact the findings of this study. Finally, it is noteworthy that a significant portion of patients encompassed in this study exhibit viral hepatitis, engendering potential incongruity with the comprehensive demographic of globally encompassed unresectable HCC patients. Hence, further validation through larger international trials is warranted.