Early Mortality After Emergency Transarterial Embolization/Chemoembolization for Spontaneous Rupture of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis

Hepatocellular carcinoma (HCC) is a highly vascular tumor and one of the most common cancer types around the world (1). It can rapidly develop and directly invade the surrounding parenchyma and capsule, resulting in spontaneous rupture. The incidence of spontaneous HCC rupture is reportedly less than 3% in the Western population, while the highest rate is 26% in Asian countries (2-4). Generally, it is a serious and life-threatening complication, which ranks the third among the causes of HCC deaths (4-6). Although the incidence of spontaneous HCC rupture has decreased with the improvement of early diagnosis in recent years, the 30-day mortality rate is still as high as 17 - 71% (2, 3, 7-10).

Patients with spontaneous HCC rupture usually experience shock, hypoperfusion, and multiple organ dysfunction. The primary treatment goal for these patients is to achieve a stable hemodynamic state and save their lives. In previous studies, the safety and efficacy of transarterial embolization/chemoembolization (TAE/TACE) have been fully demonstrated for critically ill patients with spontaneous HCC rupture (4, 8, 10, 11). Nevertheless, the clinical outcomes of emergency TAE/TACE in patients with spontaneous HCC rupture remain unpredictable. Despite successful embolization for bleeding termination, a significant number of patients still have a short survival. In previous studies, the 30-day mortality rate of patients with spontaneous HCC rupture significantly differs following emergency TAE/TACE (7.7%~75%), and the influential factors for mortality are inconsistent (1, 4, 6, 9, 12-31). Therefore, it is necessary to conduct a meta-analysis of 30-day mortality data after emergency TAE/TACE for patients with spontaneous HCC rupture.

This study aimed to conduct a comprehensive quantitative evaluation of early mortality after emergency TAE/TACE for spontaneous HCC rupture and to perform an overall analysis of risk factors to obtain more representative data.

Spontaneous HCC rupture is one of the most common emergency complications in advanced HCC, with a commonly poor prognosis (36). In the event of spontaneous HCC rupture, the main goal is to achieve rapid and effective hemostasis, which is the most important factor in determining early mortality (37).

Today, the main hemostatic methods for patients with spontaneous HCC rupture include conservative treatment, partial hepatectomy, and TAE/TACE. There are also some less commonly used hemostatic methods, such as perihepatic packing, suturing and folding of hemorrhagic tumors, absolute alcohol injection, and hepatic artery ligation (3). The results of conservative treatment alone are usually poor. In a multi-center study by Zhong et al. on patients with spontaneous HCC rupture, the 30-day survival was much higher after partial hepatectomy or TAE compared to conservative treatment (88.2% vs. 8.6%; P < 0.001) (1). In another study by Shinmura et al., the prognosis of TAE was better than that of conservative treatment (median survival time, 28 vs. 16 days; 30-day survival rate, 39% vs. 63%), although no significant difference was found in the overall survival rate between the two groups (18).

Currently, it is believed that conservative treatment should be only applied for dying patients with decompensation of liver function and progressive tumor, for which TAE/TACE or hepatic resection is not feasible. Hepatic resection is also one of the effective treatment options for ruptured HCC. However, relative to TAE/TACE, it is not suitable for patients with an unstable hemodynamic status or severe liver cirrhosis and coagulation dysfunction (2). Although in some previous studies, no significant difference was found in the efficacy or safety of emergency TAE/TACE and surgical resection in patients with spontaneous HCC rupture (3, 23, 37), a recent meta-analysis of the efficacy and safety of TAE/TACE and emergency surgery for spontaneous HCC rupture reported that the incidence of complications in the TAE/TACE group was only one-third of the emergency surgery group (odds ratio (OR): 0.36; P < 0.0001). The in-hospital mortality rate in this group was also half the rate reported in the emergency surgery group (OR: 0.52; P = 0.03) (38).

In previous research, the success rate of emergency TAE/TACE hemostasis in patients with spontaneous HCC rupture was as high as 53 - 100% (2, 37), and the early postoperative mortality rate was 7.7 - 75% (1, 4, 6, 9, 12-31). After combining the results of previous studies, the 30-day mortality of patients with spontaneous HCC rupture after emergency TAE/TACE was 29.0% (95% CI: 23.7 - 34.5%), which is significantly lower than the previously reported rate in these patients undergoing emergency open surgery (28 - 75%) (8).

In the present study, the 30-day mortality following TAE/TACE treatment for spontaneous HCC rupture has decreased significantly in the past two years compared to earlier years (19.1% in 2020 - 2021 vs. 31.6% in 2001 - 2010); apparently, the mortality rate is about 12% lower than earlier years, which is clinically important. This finding may be related to the following phenomena. First, development of magnetic resonance imaging (MRI), enhanced computed tomography (CT) scan, contrast-enhanced ultrasonography (CEUS), and other techniques has made the diagnosis of ruptured tumors more rapid, and it is now simpler to identify the location of ruptured tumors more accurately and achieve successful embolization. Second, with the development of interventional instruments and technologies, many previously inaccessible microvessels can now be successfully entered for more precise embolization (39, 40). Finally, with the progress of intensive care management, active initial resuscitation, effective correction of hypovolemic shock, and increased awareness of the importance of preventing decompensated liver failure in patients with potential liver cirrhosis, early mortality after TAE/TACE can be reduced.

The factors contributing to early mortality after emergency TAE/TACE in patients with spontaneous HCC rupture vary greatly in previous studies. In the current study, liver cirrhosis was an important factor affecting the early mortality of TAE/TACE in patients with spontaneous HCC rupture. HCC has always been recognized as the leading cause of death in patients with liver cirrhosis. Regardless of the stage of liver cirrhosis, 1 - 8% of patients develop HCC every year (41, 42). Zhu et al. found that liver cirrhosis is an independent predictor of spontaneous HCC rupture (43). Following cirrhosis, the liver microenvironment undergoes a series of changes. Through changes in the biomechanical properties of the liver, secretion of specific cytokines, and activation of various signaling pathways, tumor growth can be stimulated, and resistance to chemotherapy drugs can be developed (44); these characteristics may reduce the efficacy of TAE/TACE (44, 45).

In TAE/TACE, polyvinyl alcohol (PVA), embosphere, gelatin sponge particles, lipiodol, or chemotherapeutic agents emulsified with lipiodol are usually used to block the ruptured tumor blood supply artery to achieve the purpose of hemostasis and induce tumor ischemic necrosis. When liver cirrhosis occurs, the production of endothelin-1 increases, the sensitivity of its receptors enhances, and the production of nitric oxide decreases (46). After acting on hepatic stellate cells (HSC), they cause vascular remodeling in the hepatic sinusoid (contraction of HSC), which increases vascular resistance (46); consequently, embolic agents may not reach more distant and thinner blood vessels of the liver tumor, thereby reducing the effect of TAE/TACE.

Additionally, patients with liver cirrhosis often have poorer liver functional reserves, a higher risk of infection, potential coagulation disorders, and pancytopenia (due to portal hypertension and hypersplenism) (26, 27, 47). The combined effects of these factors may be also an important reason for the high early mortality rate after TAE/TACE in patients with spontaneous HCC rupture in liver cirrhosis (26, 27, 46). Tan et al. found that liver cirrhosis was an important factor, affecting the increase in 30-day mortality in patients with spontaneous HCC rupture (30). Moreover, in a multicenter study by Zhong et al., liver cirrhosis was an independent factor influencing the overall survival rate of patients with spontaneous HCC rupture (1).

In the current study, bilobar tumor distribution was an important factor affecting early mortality after TAE/TACE in patients with spontaneous HCC rupture. First, bilobar tumor distribution indicates a poor liver functional reserve (16), resulting in greater susceptibility to ischemic injury by TAE/TACE, which is closely linked to early liver failure (12). Second, bilobar tumor distribution suggests that a larger embolization area may be needed during TAE/TACE (both left and right hepatic arteries need to be entered, selective embolization should be carried out, and sometimes, the embolization scope is inevitably expanded), while the probability of post-embolization syndrome, liver failure, liver abscess/biloma, and other complications of large-scale embolization is greatly increased (9, 48). In some studies, extensive bilobar tumor involvement is even considered an absolute contraindication for TACE (48, 49). In an early study by Shin et al., bilobar tumor distribution affected the poor prognosis of patients with spontaneous HCC rupture after TAE/TACE (26). In another retrospective study, bilobar tumor distribution was an independent predictor of increased 30-day mortality after TAE in patients with spontaneous HCC rupture (OR = 29.6; P < 0.001) (16), which is consistent with the results of the present study.

In our subgroup analysis, based on the comparison of the TAE group with the TACE group, the P-value was 0.01 between the subgroups. However, the CIs of the two data groups overlapped. In the regression analysis, no significant difference was found between the TAE and TACE groups; based on the results, TACE and TAE do not appear to have different effects on the patients’ 30-day mortality. In some early studies, it was believed that TAE should be performed for hemodynamically unstable patients, while TACE is feasible for patients with a relatively stable status (4, 6, 25-31). However, in recent years, this view has not been widely accepted. Some studies suggest that for hemodynamically unstable patients with an apparent continuous hemorrhage, TACE can be considered if the liver functional reserve is not very poor (3, 17). Many centers also choose emergency TACE for patients with shock (14, 15). Nevertheless, compared to TAE, the use of chemotherapy drugs may cause further damage to the liver function. Our findings also suggest that hepatic failure is the most common cause of 30-day mortality after the procedure.

In most recent studies, TAE is still used more commonly than TACE in relatively “critically ill” patients, especially those with a poor liver function (1, 18-20, 22). Clinically, it is unclear whether TAE or TACE is superior for patients with spontaneous HCC rupture. The type of embolization agents used during TAE/TACE is important regardless of whether chemotherapeutic agents are used, but is not accurately described in most papers (Tables 1-4), and we were unable to conduct further subgroup and regression analyses. Also, there is no literature directly comparing the efficacy of these interventional strategies for patients with spontaneous HCC rupture; these questions warrant further analysis. In the current study, no detailed subgroup or regression analysis was performed. Nonetheless, the number of papers in many subgroups was limited after stratification, which can be considered a limitation. Also, this may be the reason why many other factors proposed in other papers, possibly contributing to an increase in early mortality after TAE/TACE, were not significant in our study; these factors can be also significant if the number of studies was large enough. We can simply divide the mentioned factors into three categories.

The first category includes indicators of poor liver functional reserve, including the model for end-stage liver disease (MELD) score, Child-Pugh classification, and bilirubin level (9, 12, 13, 17, 18, 24, 26, 29, 30). In many studies, the MELD score was an independent predictor of increased 30-day mortality after TAE/TACE in patients with spontaneous HCC rupture (9, 12, 17). However, the optimal critical value remains controversial. In some studies using the Child-Pugh classification, a Child-Pugh score ≥ 8 was significantly associated with poor prognosis following TAE/TACE in patients with spontaneous HCC rupture (12, 13, 18, 24, 26, 29, 30). Meanwhile, compared to conservative treatment, patients with spontaneous HCC rupture and Child-Pugh scores of 12/13 showed no significant advantage for TAE/TACE (19). Regarding the bilirubin level, although it has been included in the Child-Pugh score, there are still many studies analyzing bilirubin level as a separate influential factor. Despite the fact that the total serum bilirubin level is the main factor affecting early mortality after TAE/TACE, the optimal critical value is still unclear (12, 14, 16, 26, 27, 29).

The second category includes indicators of bleeding severity after HCC rupture, including shock on admission, hemoglobin level, albumin level, and blood transfusion volume (4, 13, 22, 24, 25, 27, 29). During hemorrhagic shock, the function of oxygen transport decreases, tissue perfusion reduces, and cell hypoxia causes serious damage to important organs. Moreover, hemorrhagic shock makes the liver function more fragile than usual, and coagulation dysfunction of patients with impaired liver function can further increase the risk of shock death. Kim et al. found that the 30-day postoperative mortality rate of TACE was 16.7% in patients with ruptured HCC, and a higher preoperative hemoglobin level was an independent influential factor reducing the postoperative mortality rate (P = 0.036) (24).

Kung et al. analyzed the prognosis of 167 patients with spontaneous HCC rupture, accompanied by hemodynamic instability after TAE and found that patients who died early had lower hemoglobin and albumin levels and more blood transfusions (P < 0.05 for all) (29). Additionally, in a retrospective study by Li et al., the early death of patients with spontaneous HCC rupture treated with TAE was associated with a low hemoglobin level, low serum albumin level, and prolonged prothrombin time (27). Serum creatinine level is also an important index reflecting the systemic hemodynamic status of critically ill patients. The significant increase in serum creatinine level usually represents greater blood loss. In the study by Kung et al., along with lower hemoglobin and albumin levels and higher transfusion volume, a serum creatinine level ≥ 1.5 mg/dL was an independent predictor of increased 30-day mortality (29).

Finally, the third category includes large tumor diameter, high alpha-fetoprotein (AFP) level, portal vein tumor thrombus formation, distant metastasis, and absence of tumor capsule, all of which suggested a significant increase of tumor load (12, 17-19, 22, 26, 28-30). In a retrospective study by Zhang et al., in addition to the MELD score, AFP ≥ 1000 ng/mL, maximum tumor diameter ≥ 10 cm, and absence of capsules around tumors were independent risk factors for 30-day mortality after TACE (17). Shinmura et al. found that distant metastasis is an independent prognostic factor for TAE and conservative treatment in patients with spontaneous HCC rupture (P = 0.023) (18). In patients without distant metastasis, the formation of portal vein tumor thrombus is an important prognostic factor (P = 0.015) (18). These important influential factors should be considered by clinicians before TAE/TACE treatment for patients with spontaneous HCC rupture.

This study had some limitations. First, there are relatively few high-quality studies on early mortality after TAE/TACE for spontaneous HCC rupture in this meta-analysis. Many studies did not include complete confounding factors; therefore, some factors proposed in many other studies, which might have contributed to an increase in early mortality after TAE/TACE, were not found significant in our study. Second, the number of studies in many subgroups was very small after stratification; consequently, the statistical efficiency of the estimated mortality in some subgroups may be insufficient. Third, the current study was not registered, and there may be small bias; nevertheless, we strictly adhered to the PRISMA guidelines. It is necessary to conduct prospective large-scale randomized clinical trials to further investigate the effect of TAE/TACE and other methods on the early mortality of spontaneous HCC rupture.

In conclusion, in recent years, the early mortality rate following emergency TAE/TACE for spontaneous HCC rupture has been significantly lower than before, but it is still not negligible. Before TAE/TACE, it is necessary for clinicians to predict the adverse outcomes, along with the patients' risk factors and disease-related factors, and to formulate appropriate intervention measures.