In this systematic review, we ultimately included four studies from an initial pool of 1971 identified across five databases (PubMed, ScienceDirect, Cochrane, Embase, and Scopus). After removing 145 duplicate entries, we subjected 1826 studies to further evaluation. Among these, 1820 studies were excluded after reviewing their titles, abstracts, and free access to journals. One study was excluded because did not differentiate OS for specifying in BCLC-C. One study was excluded because did not have a control group. Subsequently, we conducted a detailed assessment of the full text of 4 studies. Any study that did compare the overall survival of TACE-sorafenib and TACE-alone and studies that did not mention BCLC-C were excluded. Ultimately, four studies were found to meet the eligibility criteria. The process of creating this systematic review is visually represented in Fig. 1. PRISMA Flow Chart. Surprisingly, only one study presented the HR and CI of the Kaplan-Meier p values. None of the Kaplan-Meier data provided the number at risk or provided supplementary data so this systematic review could not perform a meta-analysis.

Flow chart. Description of reasons for including/excluding research

The quality of the study was evaluated following the Newcastle-Ottawa Scale checklist. Table 1 shows the risk of bias and applicability of the selected study. The quality of the included study was deemed to be good quality. In all investigations, the reasons for patient exclusion were explicit and appropriate. In general, however, the selected individuals were heterogeneous regarding the primary malignancy and the given sorafenib time. The treatment-response evaluation period was generally less than 3 months, indicating an early treatment-response evaluation.

This systematic review included four studies comparing the OS of patients with treatment TACE-sorafenib and TACE-alone. These studies included 401 patients with HCC BCLC-C. The features of each study are presented in detail in Table 2. All four retrospective studies were published between 2020 and 2023: China and India. All patients that were included in the studies are patients over 18 years old with HCC BCLC-C [9,10,11,12].

The inclusion criteria in these studies represent a concerted effort to establish a homogeneous patient population for research studies. Patients with advanced HCC, good liver function, and good performance status parameters are eligible for inclusion across all four studies. Most importantly, a definitive diagnosis of HCC is an essential requirement. Patients must have their HCC confirmed through various ways, such as histological examination, cytological tests, or imaging methods that adhere to established diagnostic criteria.

Patients included in the study must be at an advanced stage of the disease. They should be classified under the BCLC-C. This staging system helps ensure that the patients considered for the studies have similar disease severity. All studies mention the necessity for patients to have acceptable liver function. The Child-Pugh classification, a well-established tool in hepatology, is commonly used to assess this. The Eastern Cooperative Oncology Group (ECOG) performance status in all studies helps gauge patient’s overall health and functional capacity. The inclusion is consistent with ECOG scores of 0 or 1.

Ren et al. included all unresectable HCC cases in their study. The researchers used the PSM cohort method to match samples and minimize bias. The OS was measured HCC BCLC-C and B (matched sample and unmatched) [9]. None of the studies included patients who have undergone liver transplantation. This is a deliberate choice, as liver transplantation represents an entirely different treatment approach for patients with HCC. The exclusion of transplant recipients ensures that the study populations remain focused on the specific interventions under investigation, such as TACE and combination therapies, rather than the outcomes of transplantation.

All studies uniformly exclude patients with concurrent malignancies [9,10,11,12]. One study excluded patients with a history of resection [12]. This exclusion criterion ensures that the study’s populations comprise solely individuals with primary HCC. Excluding patients with other primary malignancies helps maintain the integrity of the research by eliminating potential confounding factors that may arise from other malignancies.

Liu, S. et al. Unlike the other studies, excluding patients with bone marrow and heart dysfunction, without specifying the cardiac issues [11]. Patidar et al. explicitly excluded patients with severe coagulopathy and demonstrated more effort to avoid bleeding risks associated with the procedure [12].

All studies administered sorafenib orally at a standard dose of 400 mg twice daily. The timing of sorafenib initiation varied slightly across the studies but was generally started within a few days to a week after TACE. All studies mentioned that dose adjustments were made based on the patient’s tolerance and the presence of side effects. Sorafenib dosage could be reduced to 200 mg twice daily or temporarily discontinued if severe adverse events occurred. Regular monitoring of patients was conducted to assess liver function, blood counts, and adverse events. Imaging studies (CT or MRI) were performed to evaluate treatment response per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria [9,10,11,12].

Two TACE techniques are practiced: conventional TACE uses lipiodol and embolic agents, while the other employs drug-loaded microsphere beads with embolic properties. Both yield similar results in tumor response, progression time, OS, and safety [13]. Most studies included in this systematic review use the technique of lipiodol and embolic agents while Patidar et al. included both techniques.

Ren et al. are using 5-Fr catheters to identify tumour-feeding arteries for TACE techniques. Subsequently, Catheterization was aimed at segmental and subsegmental tumour-feeding arteries using a 2.3-Fr to 2.8-Fr tip microcatheter. The drug regimen was chosen by the doctor’s judgement either with oxaliplatin (50–100 mg) or pirarubicin (10–40 mg) with lipiodol (2–20 mL) chosen depending on tumor size. The drug was injected into the tumour-feeding arteries through the microcatheter. Gelatin sponge or polyvinyl alcohol particles were injected for embolization if necessary. Sorafenib started within 3 to 5 days after the initial TACE procedure [9].

In the Liu, CK study, TACE was performed using the modified Seldinger method and used angiographies to locate the blood vessels supplying the tumor. A micro-catheter was inserted into the blood vessels supplying the tumor; oxaliplatin was given at doses ranging from 100 to 200 mg, and acid glycosides were provided in amounts ranging from 500 to 1000 mg. Both oxaliplatin and glycosides can be given either separately or in combination. Following this, they continued administering epirubicin (30–60 mg) with 5–25 mL of iodized oil while observing the procedure with fluoroscopic monitoring. The administration of sorafenib began between the 4th and 7th day following the TACE procedure [10].

In Liu S’s study, the TACE procedure began with the femoral artery puncture, followed by the insertion of a catheter into the hepatic artery for targeted angiography. An identified artery supplying the tumor was injected with a mixture of lobaplatin, 5-fluorouracil, and poppy ethyl iodide oil. Sorafenib treatment was initiated between the 3rd to 5th days following each TACE procedure and temporarily stopped the day before each TACE session [11].

In the Patidar study, the TACE procedure involved using the Seldinger technique to access the common femoral artery. Arterial structure and tumor vascularization were assessed by angiography. A microcatheter was used for cannulation, followed by injection, and embolized with either a combination of epirubicin and lipiodol or epirubicin-loaded drug-eluting particles [12].

In Ren et al.’s study, five individuals (8.2%) encountered delays in their treatment because of adverse effects resulting from TACE. Nonetheless, these patients initiated sorafenib therapy within a window of 6 to 14 days after concluding their TACE procedure. Additionally, 19 patients (31.1%) during treatment necessitated reductions in the prescribed sorafenib dosage, while five patients (8.2%) experienced interruptions in their medication regimen due to severe sorafenib-related adverse reactions. These adaptations were implemented to effectively manage the side effects and ensure the safety of the patients. The grading system used the National Cancer Institute Common Toxicity Criteria Adverse Events regarding severe adverse events. Fatigue was the most prevalent adverse event in the study receiving TACE-alone (19.0%). A minor percentage difference from fatigue, liver dysfunction is the second most frequent AE (18%). Conversely, in the group receiving both TACE and sorafenib, a wide range of adverse events was observed, which included hand-foot skin reactions (HFSR) as the most experienced by 75.4% of patients. Following diarrhea (47.5%) and liver dysfunction (32.8%), which ranked as the second and third most experienced. Regarding severe adverse events, they reported events that reached grade ¾ were HFSR by 18.0% of patients receiving TACE-sorafenib, followed by severe liver dysfunction in 13.1% of cases and severe diarrhea in 9.8%. Notably, no fatalities related to treatment were recorded in either of the study groups. The study findings indicated that incorporating sorafenib into the TACE therapy regimen was generally well-tolerated. Nonetheless, it is noteworthy that a significant portion of the patient population required adjustments in sorafenib dosage or experienced temporary treatment discontinuations due to adverse events [9]. Percentage of the adverse events described in Table 3.

Patidar et al. post-embolization syndrome, characterized by symptoms like fever, upper abdominal discomfort, nausea, and decreased appetite, was the most common consequence after TACE treatment. It mostly happened in the TACE-sorafenib group of patients (60%) and also in the TACE-only group, affecting (55%) of patients. Both study groups experienced transient hepatic dysfunction, as revealed by anomalies in liver function and a rise in ascites or emerging new ascites, impacting approximately 11% of the patients. Most importantly, this hepatic dysfunction gradually improved during the hospital stay following the procedure, returning to baseline levels within a week. As for sorafenib usage, the primary side effect was HFSR, seen in 54% of patients, followed by diarrhea, reported by 29.7%. Any required adjustments to sorafenib dosages were appropriately managed on an outpatient basis. Notably, neither study group encountered fatal adverse effects beyond these [12].

Liu, CK et al. conducted a comparison of both groups regarding adverse events reported in this study. Significant differences in adverse events became apparent. First, oral mucositis, characterized by mouth sores, was considerably more frequent in the TACE-sorafenib group, impacting 71.4% of patients, compared to a mere 5% in the TACE-alone group. This dissimilarity held high statistical significance (P < 0.001). Likewise, HFSR was notably more prevalent in the TACE-sorafenib group, affecting 77.1% of patients, while in the TACE-alone group, only 2.5% experienced it (P < 0.001). Moreover, hypertension was significantly more common in the TACE-sorafenib group, affecting 34.3% of patients, whereas in the TACE-alone group, only 5% of patients developed hypertension (P = 0.001) [10].

Regarding sorafenib-related adverse events, Liu CK et al. noted that eight patients had lowered the dosage of sorafenib to 200 mg twice daily because of an inability to tolerate it. Fortunately, there were no reports of severe adverse events. Significant relief of symptoms was achieved through symptomatic treatment, which aligns with what Ren et al. reported. It was also noted that 19 patients (31.1%) needed the dose to be reduced, and 5 patients (8.2%) had to temporarily stop taking the drug due to adverse events related to sorafenib [9, 10].

The Patidar report showed significantly higher OS. Whereas, the TACE-sorafenib (10.1 months) and TACE-alone (7.8 months); thus, the superiority of combination therapy in terms of OS was pointed out with a P value < 0.001). The study of Ren et al. also reported OS TACE-sorafenib group median OS was 15.8 ± 2.0 months (95% CI 11.820–19.780); meanwhile, the TACE-alone group median OS was 7.8 ± 1.1 months (95% CI 5.607–9.993). Ren et al. showed a substantial difference in median OS between the TACE-sorafenib and TACE-alone groups, both in the BCLC-B and BCLC-C subgroups, with p values of 0.027 (HR = 0.547, 95% CI = 0.317–0.943) and 0.003 (HR = 0.507, 95% CI 0.320–0.801). However, these differences remained even after propensity score matching (PSM) with P values of BCLC-B 0.041(HR = 0.620, 95% CI 0.345–1.114) and BCLC-C 0.016 (HR = 0.544, 95% CI = 0.328–0.902), which reinforced the significant survival advantage the combination therapy [9, 12].

Liu CK et al. reported findings of overall survival of TACE-sorafenib therapy (13.6 months), with significantly better survival outcomes compared to the TACE-alone group (6.5 months), as represented by a p value of less than 0.05 for OS time (P = 0.041). The study by Liu S et al. emphasized the benefit of combining sorafenib with c-TACE, with a significant difference in OS, 22.9 months in the TACE-sorafenib group and 12.1 months in the TACE-alone group (χ2 = 5.848, p = 0.016) [10, 11].

Statistically, all studies were using SPSS software. The analysis of OS involved is Kaplan-Meier (KM), and the application of a log-rank test. Surprisingly, only one study presented the HR and CI of the Kaplan-Meier p values. none of the Kaplan-Meier data provided the number at risk or provided supplementary data so this systematic review could not perform a meta-analysis [9,10,11,12].

Liu S et al. not only identified risk factors but also analyzed how factors affected patient survival in the two distinct treatment cohorts. In the TACE-sorafenib group, patients with portal vein invasion (p = 0.017), multiple TACE sessions (p = 0.021), liver cirrhosis (p = 0.040), and ascites (p = 0.013) experienced notably reduced survival rates. Similarly, in the TACE-alone group, having more than three tumors (p = 0.015), undergoing additional TACE sessions (P = 0.018), and ascites (P = 0.023) were recognized as risk factors associated with decreased survival. These findings underscore the importance of considering these factors when evaluating patient and treatment strategies.

Ren et al. also examined the BCLC-B subgroup, but this systematic review focused on BCLC-C. However, the result was also in line with the BCLC-C subgroup. Before PSM matching, the TACE-sorafenib group in BCLC-B had a median OS of 33.0 months with a confidence interval (CI) of 18.688–43.312 months, while the TACE-alone group median OS of 21.2 months with a CI of 16.696–25.704 months. After using propensity score matching (PSM), the median OS for the TACE-sorafenib group remained at 33.0 months with a CI of 18.688–43.312 months, while for the TACE-alone group, the median OS was 25.3 months with a CI of 13.135–39.465 months. Ren et al. performed multivariate analyses on the PSM cohort and discovered that treatment methods (P = 0.003), the number of nodules (P = 0.010), tumor size (P = 0.012), vascular invasion (P = 0.005), and the number of TACE procedures (P = 0.029) were all significant independent predictors of OS [9].

Moreover, Patidar et al. showed a significantly higher disease control rate (DCR) among the TACE-sorafenib therapy group (44.9%) compared to the TACE-alone group (25.8%) with a p value of 0.09, indicating better disease control in TACE-sorafenib group. Furthermore, the time-to-progression (TTP) of the TACE-sorafenib group was 4.6 months, in contrast to 3.1 months for the TACE-alone group (P = 0.001) [12].

Liu, CK et al. report TTP findings in the TACE-sorafenib group at 7.6 months which is better in comparison to the TACE-alone group at 3.4 months, with significantly better outcomes, p values of less than 0.05 for TTP (P = 0.002). One month into the treatment, tumor response was assessed using the mRECIST criteria and imaging follow-up. The combined treatment group also demonstrated a significant DCR compared to TACE-alone (P = 0.018), indicating that sorafenib enhances the effectiveness of TACE. Liu, S et al. also longer the progression-free survival (PFS) of combining sorafenib at 7.37 months with significant differences from TACE-alone at 5.97 months (p = 0.022). These combined outcomes underline the statistical significance of improved disease control and patient survival associated with the combination of sorafenib into TACE therapy across these studies [10, 11]. This indicates the superiority of combination therapy in terms of OS along with DCR, PFS, and TTP [9,10,11,12].