Discussion
headaches, blindness, toxicity, 2022.BCLC stage C, SD, PVTT, PD, portal vein tumor thrombus, HCC, headache, hematological tumors
SECONDARY, SIDE EFFECT, BLINDNESS
To our knowledge, this study represents the first published clinical trial on the treatment of HCC patients with EHM using a combination therapy of FOLFOX4 and ATRA. The treatment showed significant clinical benefits to this group of HCC patients compared with FOLFOX4-placebo. This study also verified the results of our previously published retrospective study. The median OS was 16.2 months in the FOLFOX4-ATRA group, which was significantly higher than that in the FOLFOX4-placebo group. Furthermore, the secondary endpoints, including a median PFS of 7.2 months, ORR of 24.5%, and DCR of 50.9%, were also very encouraging. The toxicity in this study was consistent with our previous experience with FOLFOX4 in treating HCC patients. The results of this study provide a safe and effective treatment for HCC patients with EHM.In recent years, immunotherapy for advanced HCC has made great progress. In addition to the IMbrave150 study and HIMALAYA trial, the ORIENT-32 study (sintilimab plus a bevacizumab biosimilar as first-line therapy) and the Keynote-394 study (pembrolizumab as second-line therapy) both disclosed encouraging results in 2021 and 2022.BCLC stage C includes HCC patients with EHM and/or portal vein tumor thrombus (PVTT). The staging and treatment of PVTT have made steady progress.ATRA is an antiproliferative and cytodifferentiating agent rather than a cytotoxic agent. ATRA was first used in the treatment of hematological tumors, and it has become a standard treatment for APL, resulting in high CR rates of over 90%.Differential proteins in patients with various responses prior to treatment in the FOLFOX4-ATRA group were analyzed to identify protein indicators that could predict patient prognosis prior to treatment. Using the pre-treatment proteome data in plasma, markers in CR, PR, and SD patients were identified, which showed significant and specifically high expression in each group prior to treatment. The results suggested that when future studies employ these markers in predicting prognosis (CR, PR, or SD), different combinations of these proteins should be considered (SOD3, TTR, SSC5D, GP5, IGKV1D-33 combination for CR and TGFB1, GSS, IGHV5-10-1 combination for PR). In addition, functional enrichment analysis of these markers revealed that patients with CR, PR, and SD have unique, highly expressed proteins in different biological pathways. Complement- and coagulation-related proteins were highly expressed in all these pathways, although different proteins were involved. Among these, alpha 2-antiplasmin (SERPINF2) and Ficolin 3 (FCN3) were significantly expressed in CR, F8, and C4A in PR, and Factor XI (F11) and complement Factor H-related protein 2 (CFHR2) in SD. In vivo and in vitro trials conducted as early as the 1990s have shown ATRA corrects the activities of pro-coagulant and fibrinolytic agents.Several studiesOur study has limitations. First, as headache is a peculiar side effect of ATRA, it could affect the effect of double blindness clinically. The medical care and follow-up may have differed for patients who developed headaches, which could have affected the results. However, the incidence of headaches was only ~20%, and all data in the study were collected and analyzed by masked experts to minimize biases. Second, concomitant therapies were inevitable, especially for patients who were assessed to have PD. Although different treatments were given according to different conditions, there were no significant differences in postchemotherapeutic treatments given to these two groups of patients. Third, our study included both first-line and second-line patients, which would make the enrolled population heterogeneous, but the subgroup analysis revealed that ATRA-FOLFOX is efficient both for first-line and second-line patients. Last, due to the differences in the actual patient enrollment rates among the different centers, there are indeed differences in the number of patients enrolled in each center, which could affect the results slightly.