The effect of the number of hepatic inflow occlusion times on the prognosis of ruptured hepatocellular carcinoma patients after hepatectomy

Hepatocellular carcinoma (HCC) is one of the most serious cancers in the world and the second leading cause of death due to cancer. Rupture of hepatocellular carcinoma (HCC) is a rare and serious complication of HCC [1‐5]. In recent years, the number of ruptured HCC(rHCC) patients has been increasing year by year, especially in Asia, and the proportion of rupture is much higher than in Europe and the United States. For patients with rHCC, transcatheter arterial chemoembolization (TACE), intraperitoneal chemotherapy, and hepatectomy have been used, but recent studies have shown that two-stage delayed hepatectomy is a relatively better treatment for suitable patients [6, 7]. Although rHCC patients have a good prognosis after hepatectomy, there is still a need to pay attention to their situation because ruptured HCC patients are prone to hemodynamic instability.

Since intraoperative bleeding is the main problem in hepatectomy, and intraoperative blood transfusion may affect the postoperative prognosis of patients, researchers have introduced the method of hepatic blood flow occlusion to control bleeding. At present, the most widely used techniques are the Pringle Maneuver and Hemihepatic inflow occlusion [8, 9]. The Pringle maneuver was first described in 1908 as a method that blocks hilar vessels and achieves the effect of controlling hepatic blood flow by clamping the hepatoduodenal ligament; in 1987, a hemihepatic occlusion (HHO) technique was proposed to control hepatic blood flow [10]. In short, both methods can effectively control hepatic blood flow, but they inevitably cause hepatic hypoperfusion and ischemia–reperfusion injury, and liver dysfunction occurs at the same time [11‐13]. Patients with ruptured HCC are hemodynamically unstable on admission, and most of them have associated cirrhosis, reducing their tolerance to ischemia. Therefore, hepatic inflow occlusion can affect the liver function of the residual liver after surgery, and it may also affect the long-term prognosis of rHCC patients after surgery.

In the past, Jing-Hang Jiang et al. [14] believed that hepatic inflow occlusion did not affect the postoperative outcomes of HCC patients, while other researchers [15] found that HIO affected postoperative liver function, which in turn made the postoperative prognosis worse. However, the long-term effects of HIO on the prognosis of patients with ruptured HCC are unknown, and the effect of the number of times of HIO on prognosis is also unclear.

In this retrospective study, we aimed to assess the prognostic impact of HIO in patients with ruptured HCC. We also compared the effect of the number of HIO on the overall survival and recurrence-free survival of patients.

Rupture of liver cancer is a rare and serious complication of liver cancer with a high mortality rate. Although there are many treatment methods, such as TACE, intraperitoneal chemotherapy, surgical treatment, conservative treatment, etc., at present, the relatively better treatment is staged hepatectomy ( TACE for stage one treatment, followed by surgery as the second stage) [6]. Currently, there is an increasing number of research institutions discussing the risk factors affecting the postoperative survival of patients with ruptured HCC, hoping to find some prognostic factors to better manage rHCC patients [18‐20]. In hepatectomy for rHCC patients, we need to pay attention to the amount of bleeding during surgery, because some rHCC patients are inherently hemodynamically unstable. Surgeons usually use hepatic inflow occlusion techniques, including the Pringle Maneuver and hemihepatic vascular occlusion to control the amount of bleeding. By blocking the blood flow into the liver, intraoperative blood loss is greatly reduced and the probability of blood transfusion is also reduced [8, 9, 21‐23]. However, the adverse consequences of hepatic inflow occlusion should not be ignored. Both methods can cause postoperative liver function damage, and although some studies have indicated that HIO may not have an effect on the postoperative prognosis of HCC patients, the long-term survival rate of HIO in ruptured HCC patients is unknown, and the effect of the number of occlusion times on the prognosis is also unclear.

Previous studies have compared the Pringle Maneuver with hemihepatic blood flow occlusion, and there is still some controversy. In their meta-analysis, Wang et al. [23] found that the effects of the two techniques were not statistically different, but patients who were subjected to hemihepatic inflow occlusion had less liver injury. Similarly, Li et al. [24] and Chau et al. [15] found that hemihepatic inflow occlusion achieved similar results to the Pringle maneuver, but it had the advantage of reduced liver injury and better postoperative liver function recovery. While Yu et al. [25] concluded that the hemihepatic occlusion technique had the advantage of reduced operative time and blood loss, less injury, and better recovery when compared to the Pringle maneuver. In our study, the hepatic inflow occlusion method was selected according to the specific situation of the operator, and the blockage time was about 15 min each time. Although some studies indicated that hemihepatic blood flow blocking once could last for a longer time, considering that most patients had liver cirrhosis, the blockage time was set at about 15 min in our center. For patients with two blockages, the interval between each blockage was about 5 min.

Several previous retrospective studies [26‐29] showed that there was no significant difference in postoperative long-term survival between HIO and non-HIO groups in HCC patients. Similarly, a meta-analysis [23] compared the effect of vascular occlusion in liver surgery on postoperative HCC patients, and the results showed that HIO did not affect the postoperative overall survival. In our study, we specifically studied the effect of HIO in ruptured HCC patients after surgery, while further analyzing the effect of the number of blockages on long-term survival. Our results showed that one HIO had no effect on postoperative OS but had a negative effect on RFS in patients with rHCC; Overall, HIO negatively affected both the postoperative OS and the RFS in patients with rHCC, which is different from previous studies on patients with HCC. Ischemia during hepatic portal blood flow occlusion is one of the factors that can negatively affect the overall survival, and ischemia–reperfusion injury(IRI) after occlusion may also harm liver function [30, 31]. However, only one occlusion did not affect the OS in our study, while two occlusions were associated with a reduction in the OS. So the total number of occlusions and the composite effect of multiple ischemia–reperfusion injuries may also differently affect the OS. The main mechanisms through which HIO affects recurrence can also be summed up in two points: (1) ischemia destroys the adhesion between tumor and endothelial cells, resulting in microvascular injury, and reperfusion injury promotes metastasis and growth of tumor cells [32‐35]. (2) When in a blocked state, the pressure gradient between tumor vessels and portal vein can trigger cancer cells to detach from the main tumor, allowing tumor cells to translocate and spread.

Another point to note is why have most studies stated that HIO leads to tumor recurrence, while the conclusions for the postoperative OS of patients are very different? Lucinda Shen et al. [36] suggested that when performing HIO, they observed different blood flow responses of hepatic microvessels in different patients, which could also explain the different ischemia–reperfusion injury (IRI) effects on different patients when performing HIO, which in turn may lead to different postoperative OS’s. At the same time, it has been confirmed in some studies that changes in the circulation lead to heterogeneity in the response to IRI, and in livers with cirrhosis and fibrosis, the interaction between molecules disrupts the balance between cells and their surrounding matrix and also allows hepatic vascular remodeling. Many cells are involved in this process, including hepatic stellate cells, macrophages, and Kupffer cells. Hepatic endothelial cells are very important and help stabilize blood vessels. It is therefore necessary to develop techniques to perform intraoperative monitoring of hepatic microcirculation during hepatic inflow occlusions in the future [37].

Due to some selection or confounding bias, we also included all patient data in the multivariate Cox regression model, and the results showed that two times HIO was an independent risk factor affecting the postoperative OS of patients; HIO was an independent risk factor affecting the postoperative RFS of patients. In summary, our results suggest that HIO can affect the postoperative prognosis of ruptured HCC patients, but different blockage times will also affect the prognosis of patients differently.

This study has some limitations, namely: (1) This study is a retrospective study with some biases, and it is possible to perform a prospective study in the future to verify the conclusion. (2) The number of patients with ruptured HCC is relatively small, and the number of cases needs to be accumulated (3). Whether HIO affects postoperative complications has not been fully assessed, we need further investigation and follow-up.

In conclusion, HIO may affect the prognosis of patients with ruptured HCC, and the number of occlusion times can also affect the patients' prognosis. Although further RCTs are needed to validate this conclusion, in practical clinical work, we should consider the impact that HIO brings to patients with rHCC.