This meta-analysis is the first systematic review of the efficacy and safety of raltitrexed plus oxaliplatin in the treatment of hepatocellular carcinoma via vascular intervention, which provides a new reference for future clinical application. Since Yamada first developed Transarterial embolization (TAE) in 1977[26], Transvascular interventions became widely used in the treatment of hepatocellular carcinoma, and gradually evolved into the now commonly used TACE and HAIC. Raltitrexed, as a specific inhibitor of TS, is able to enter cells through reduced folic acid carriers, which are subsequently metabolized to polyglutamic acid form, a form that gives raltitrexed enhanced antitumor activity and prolongs its duration of action [27]。A clinical trial reported mOS of 9.6 and 8.5 months for 5-FU-based TACE and doxorubicin-based TACE, respectively, and mPFS was 4.9 months and 4.6 months, respectively [25], both were lower than the mOS (13.63 months) and mPFS (6.10 months) in the TACE group in this meta-analysis, indicating the advantage of this regimen over the currently used clinical regimens for TACE-based therapy. As for HAIC, the FOLFOX regimen has demonstrated good efficacy in several studies for different stages of HCC. A retrospective study initiated by the Center for Cancer Control of Sun Yat-sen University showed that HAIC-FOLFOX achieved mPFS and mOS of 7.4 months and 14.5 months, respectively, in patients with advanced HCC [7], another retrospective study showed comparable efficacy and safety of raltitrexed plus oxaliplatin versus FOLFOX in the treatment of intermediate to advanced HCC [28]. Raltitrexed has a longer half-life compared to 5-FU and can exert long-term effective antitumor effects [29], This may be the reason why raltitrexed plus oxaliplatin is able to exert an efficacy no less than that of the FOLFOX regimen with a shorter perfusion time. In addition, Compared to the 44–48 hours long perfusion time of 5-FU, the shorter infusion time of raltitrexed greatly improves patient comfort compared to the FOLFOX regimen and reduces the risk of intrahepatic catheter thrombosis and migration associated with prolonged infusion. [30].
According to the Guidelines for the Treatment of Primary Liver Cancer (2022 Edition), the commonly used first-line systemic therapies include atelelizumab in combination with bevacizumab (T + A), lenvatinib, sorafenib, etc. [31]. Among them, the median progression-free survival with T + A regimen was up to 6.8 months [32], while sorafenib was one of the first targeted drugs for HCC, mOS and mPFS in HCC patients treated with sorafenib in a clinical trial were only nearly 3 months longer than those treated with placebo [33]. Lenvatinib showed non-inferior median OS to sorafenib (13.6 months) in REFLECT global multicenter clinical phase III controlled study[34]. The survival results obtained from this meta-analysis suggest that the efficacy of raltitrexed plus oxaliplatin revascularization is comparable to that of first-line systemic therapy, and also suggest that the combination of drugs may lead to better survival outcomes for HCC patients. Considering that TACE and HAIC are recognized to have good tumor transformation effects, the efficacy and safety of raltitrexed plus oxaliplatin revascularization should be widely used in clinical practice.
The safety of the drug should also be focused on when administering it in the clinical setting. The results of this meta-analysis showed that the incidence of all adverse events was below half, and most of them were mild, indicating that they were tolerable and controllable in patients. A phase II clinical trial on TACE combined with bicycloplatin reported adverse events similar to this study, including decreased white blood cell count, decreased platelet count, and elevated AST, with higher levels of adverse events for TACE-bicycloplatin, TACE-bicycloplatin + epirubicin, and TACE-epirubicin than for raltitrexed plus oxaliplatin [35]. A subgroup analysis showed a higher incidence of fever, abdominal pain, and abnormal liver function (elevated AST) in patients using TACE than in those receiving arterial perfusion, similar to previously published studies[36], mainly due to the Post-TACE postembolization syndrome (PES), which is generally considered to be due to chemoembolization-induced tissue ischemia and the subsequent release of cytokines and inflammatory responses[37]. However, even though the incidence of adverse reactions was higher in the TACE group, it did not exceed the acceptable range. Considering that patients have individual differences, clinically we should still adopt different interventions according to the condition and the individual patient.
Our meta-analysis included 7 clinical trials involving 419 patients and analyzed for the first time the efficacy and safety of transplacental intervention with raltitrexed plus oxaliplatin in patients with hepatocellular carcinoma. The results of the analysis showed that raltitrexed plus oxaliplatin transvascular intervention improved OS and PFS in patients, and a subgroup analysis based on the interventional modality showed that perfusion of raltitrexed plus oxaliplatin in addition to TACE resulted in a slightly better outcome compared to the HAIC group. However, according to a previous literature summary, TACE can lead to tumor necrosis, which promotes the loss of adhesion of tumor cells to the blood. The transient hypoxic microenvironment induced by embolization can also lead to tumor progression[36], this is different from the results we obtained, probably due to the differences in tumor grade and degree of invasion in the two subgroups. Therefore, we should still choose the appropriate treatment according to the specific characteristics of the patient to achieve a better survival outcome .
There are still several limitations of this study. First, not many studies have been published on raltitrexed plus oxaliplatin transvascular intervention for hepatocellular carcinoma, and most of them were retrospective studies, some of which had small sample sizes, so we selected only mOS, mPFS, and ORR as endpoints to assess efficacy, resulting in potentially insufficient evidence for the conclusions drawn. Second, there was a high degree of heterogeneity among the results analyzed, and we only performed subgroup analyses for different interventions. Other factors such as age, baseline patient characteristics, tumor stage, and drug dose may have contributed to the high heterogeneity, but this subgroup analysis was not designed for this study because of the overall small number of patients included. It is worth noting that all seven included studies were in Chinese patients, and further validation is needed to determine whether these results are consistent in other ethnic groups. Therefore, a larger randomized controlled trial should be designed to investigate the efficacy and safety of raltitrexed plus oxaliplatin in the treatment of hepatocellular carcinoma via vascular intervention.