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ORIGINAL ARTICLE
Year : 2022 | Volume
: 18
| Issue : 7 | Page : 1967-1972
Predictive value of hepatic venous pressure gradient and efficacy and significance of early PTVE for gastrointestinal bleeding after TACE for liver cancer
Jian Wei, Yuefeng Hu, Jianan Yu, Chao Yin, Guang Chen, Long Jin
Department of Interventional Radiography, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Correspondence Address:
Long Jin
Department of Interventional Radiography, Beijing Friendship Hospital, Capital Medical University, 95 Yong eAn Road, Xicheng District, Beijing - 100 050
China
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/jcrt.jcrt_331_22
Aims: To investigate the predictive value of hepatic venous pressure gradient (HVPG) and the efficacy and significance of early percutaneous transhepatic varices embolization (PTVE) for gastrointestinal bleeding after transcatheter arterial chemoembolization (TACE) for liver cancer.
Methods and Materials: This retrospective study enrolled 60 patients diagnosed with stage B or stage C liver cancer, according to the Barcelona Clinic Liver Cancer (BCLC) staging system, between December 2019 and October 2021. TACE and HVPG measurement (>16 mmHg or >20 mmHg) were performed on all 60 patients, who were randomized into control and experimental (PTVE) groups. All patients were followed up for 12 months.
Statistical Analysis Used: SPSS 20.0 software was used for data analysis. The two groups were compared with respect to the initial occurrence time of hemorrhage after TACE, recurrence time of hemorrhage, liver function, TACE frequency, TACE type, and tumor control.
Results: The initial hemorrhage rates at one, three, six, and 12 months after TACE were 3.2%, 12.9%, 22.6%, and 48.4%, respectively, in the control group (n = 31) and 0%, 0%, 3.4%, and 10.3%, respectively, in the PTVE group (n = 29). Differences between the groups in terms of initial hemorrhage rate at six and 12 months postoperatively were significant (P < 0.05). The recurrence rates of hemorrhage at one, three, six, and 12 months after TACE were 11.1%, 22.2%, 22.2%, and 33.3%, respectively, in 27 patients in the control group. In eight patients in the PTVE group, the corresponding rates were 0%, 0%, 0%, and 25.0%. The differences between the groups in the recurrence rate of hemorrhage at the four time points were significant (P < 0.05). At six months postoperatively, liver function recovery and remission were noted in eight (25.8%) and 18 (66.7%) patients, respectively, in the control group; these events were noted in 10 (34.5%) and 19 patients (65.5%), respectively, in the PTVE group, and the difference between the groups was not significant (P > 0.05). In the control group, TACE was performed for a total of 94 times on 31 patients within 12 months, including conventional transcatheter arterial chemoembolization (C-TACE, 75.5%) and the drug-eluting bead TACE (DEB-TACE, 24.5%); the objective response rate (ORR) was 39.3%. In the PTVE group, TACE was performed for a total of 151 times on 29 patients within 12 months, with an average of 5.21 times on each patient, including the C-TACE (57.6%) and DEB-TACE (42.4%); the ORR was 60.1%. Differences in TACE frequency, proportion of C-TACE/DEB-TACE, and ORR were significant between the two groups (P < 0.05).
Conclusion: HVPG can accurately evaluate gastrointestinal bleeding after TACE in patients with liver cancer. Early PTVE can significantly lower the risk of gastrointestinal bleeding and help TACE control tumor progression in patients with an HVPG >16 mmHg or >20 mmHg.
Keywords: Evaluation, gastrointestinal bleeding, HVPG, liver cancer, portal hypertension, PTVE, TACE
Portal hypertension (PH) is the result of decompensated cirrhosis, and its specific clinical manifestations are ascites, splenomegaly/hypersplenism, and esophageal and gastric varices. The severity of PH determines the clinical prognosis of patients with cirrhosis.[1] At present, the hepatic venous pressure gradient (HVPG) measurement is the most accurate method to evaluate PH.[2] A timely intervention can significantly reduce the risk of gastrointestinal bleeding for patients with esophageal and gastric varices and an HVPG >16 mmHg or >20 mmHg,[3],[4],[5] but PTVE is a simple and effective interventional therapy.[6] In recent years, transcatheter arterial chemoembolization (TACE) has become the primary treatment for patients with intermediate and advanced hepatocellular carcinoma.[7],[8],[9]
> Materials and MethodsGeneral information
Patients diagnosed with primary liver cancer between December 2019 and October 2021, and had stage B or stage C liver cancer, according to the BCLC staging system,[10] were included in the study. She also underwent TACE. In addition, the HVPG measurement was performed on all patients preoperatively. A total of 60 patients (with HVPG >16 mmHg or >20 mmHg)[11],[12] were enrolled in the study prospectively, and they were divided into the control group and the experimental (PTVE) group [Table 1].
Table 1: Comparison of general information of the patients between the two groupsThis study was approved by the Medical Ethics Committee of Beijing Friendship Hospital, Capital Medical University. All patients had signed the informed consent form before operations.
Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) Patients with diagnosis of primary liver cancer that met the criteria established in the BCLC staging system [stage B or C; [Figure 1]], had typical imaging features of primary liver cancer (a space-occupying lesion of the liver with a diameter >10 mm was found in the enhanced computed tomography or magnetic resonance examination, fast vascular enhancement was noted in the arterial phase, and elution was noted in the venous phase or delayed phase); (2) patients with an HVPG >16 mmHg or >20 mmHg; (3) patients with no mental or cognitive disorders; (4) patients with no severe cardiovascular or cerebrovascular diseases; and (5) patients who received only TACE and systemic treatment (sorafenib or lenvatinib).
Figure 1: A 61-year-old man was diagnosed with primary liver cancer (BCLC stage B) from an enhanced abdominal magnetic resonance imaging. (a): S5\S6 multiple nodular tumor lesions were observed in the arterial phase. (b): T2 lesions were observed to have high signal changesThe exclusion criteria were as follows: (1) Patients with severe coagulation disorders; (2) patients with uncontrollable systemic infection and vital organ failure; and (3) patients with unstable vital signs and unable to cooperate with medical workers in examinations.
Instruments and equipment
The following devices were used: 5-F/8-F vascular sheath, 0.035” super-smooth guide wire, Cobra catheter, and 5-F elbowed catheter (TERUMO, Japan); 5.5-F Fogarty balloon catheter (Edwards Lifesciences, USA); 100–300 μm Callispheres microspheres (Hengrui Pharma, China); poppy ethiodized oil injection (Hengrui Pharma, China); 8-F guiding catheter (Cordis, USA); microcoils (MWCE-18-14-8-NESTER, Cook Medical, USA), and controllable microcoils (14 mm x 30 cm/12 mm x 20 cm, Interlock, Boston Scientific, USA). GE Innova 3100-IQ flat-panel digital subtraction angiography (DSA) machine was used as the guiding device.
Operation methods
During surgery, patients received electrocardiographic monitoring in a supine position. The right femoral vein or right internal jugular vein approach was selected. Routine disinfection and placement of surgical drapes were performed, and local anesthesia was induced with 2% lidocaine. Puncture and placement of an 8-F vascular sheath were performed. The hepatic vein opening was selected using the 8-F guiding catheter and super-smooth guide wire. The 5.5-F Fogarty balloon catheter was directly inserted through the guiding catheter and placed in the right or middle hepatic vein by cooperating with the super-smooth guide wire for the measurement of HVPG [Figure 2].[3]
Figure 2: (a): An 8-F guiding catheter was placed into the right hepatic vein opening, and a 5.5-F Fogarty balloon catheter was introduced to measure the free hepatic venous pressure. (b): The wedged hepatic venous pressure was measured after balloon dilationMethod of TACE: The femoral artery was punctured with the improved Seldinger technique, and the 5-F sheath was placed to establish an arterial access. A hepatic artery catheter was inserted along the sheath and selected into the hepatic artery for angiography to identify the number of tumor lesions and corresponding feeding artery. After the exchange of microguide wire, the microcatheter was superselected into the target vessel of the tumor for angiography again to identify the location of the abnormal blood vessel. Hydroxycamptothecin 40 mg, epirubicin 60 mg, leucovorin calcium 200 mg, and fluorouracil 750 mg were slowly perfused through the microcatheter. Then, 8–15 ml of lipiodol emulsion or 1/3–1/4 of epirubicin-loaded microsphere 60 mg (100–300 μm) was used for embolization. The stump-like changes of the tumor feeding artery confirmed on angiography suggested the successful embolization. Therefore, the catheter's withdrawal and puncture point's oppression were performed to end the treatment [Figure 3].
Figure 3: (a and b): Superselective angiography and right hepatic artery embolization were performed using the microcatheter. Chemotherapy perfusion, drug-loaded microsphere, and ethiodized oil were given for embolization. (c): PTVE was followed by sequential TACE to control tumor progressionIn the PTVE group (experimental group), patients underwent the DSA-guided percutaneous transhepatic puncture of the right portal vein in a supine position. The catheter was selected into the splenic vein opening for angiography to identify the origin and trend of the gastric coronary vein. The catheter was selected to the origin of the gastric coronary vein for angiography. Dilatation and tortuosity of the gastric coronary veins and lower esophageal veins were determined; thus, the microcatheter was superselected into the distal end of the varicose vein for angiography again to identify the location of the target vessel. Microcoils were used for dense embolization of the gastric coronary veins from far to near until the adjacent opening of the gastric coronary veins. Then, the catheter was pushed to the splenic vein trunk for another angiography, which revealed that the varicose veins had disappeared [Figure 4].
Figure 4: (a): Tortuous and dilated gastric coronary veins on direct portal vein angiography. (b): The microcatheter was selected into the gastric coronary veins for angiography again to identify the embolization site. (c): Microcoils were used for dense embolization. (d): After embolization, angiography showed the disappearance of the varicose gastric coronary veins. (e): Passage for microcoil embolization and punctureFollow-up methods and observation indexes
The follow-up data of patients in the experimental group were collected from regular outpatient reexaminations, or by telephone, etc., Patients received the outpatient reexamination at one, three, six, and 12 months after surgery and were followed up closely till the end of the second year after surgery. For the clinical and follow-up data of enrolled patients collected by the review of medical records, the relevant content should be recorded in the Investigation List. Such data mainly included the gender, age, Child–Pugh score, severity of esophageal and fundic varices, bleeding history, treatment characteristics, recurrence of hemorrhage, time of the last follow-up, and enhanced abdominal magnetic resonance imaging or computed tomography, etc.
Indicators for efficacy evaluation
The indicators for efficacy evaluation were as follows: (1) Initial occurrence time of hemorrhage; (2) recurrence time of hemorrhage in the experimental group and recurrence time of hemorrhage in the control group after patients received the gastroscopy and supportive treatment for the initial hemorrhage from the Department of Internal Medicine; (3) improvement of liver function and Child–Pugh score at six months after surgery in the experimental group; and (4) frequency of TACE, TACE type, and tumor control.
Statistical analysis
Data processing was performed using the SPSS 20.0 software. Measurement data were expressed by c2 ± s and checked by t-test. Count data were expressed by % and checked by Chi-squared test. Ranking data were compared by Wilcoxon rank-sum test. Patients' postoperative survival rates between the two groups were compared by the log-rank test. The significance level was 0.05, and P < 0.05 was considered significant.
> ResultsComparison of initial hemorrhage rate
Initial hemorrhage at one, three, six, and 12 months after TACE occurred respectively in one, four, seven, and 15 patients, respectively, in the control group, and in zero, zero, two, and six patients, respectively, in the experimental group. The differences between the two groups with respect to the initial hemorrhage rate at six and 12 months after surgery were significant (P < 0.05).
Comparison of recurrence rate of hemorrhage
In the control group, 27 patients developed gastrointestinal bleeding after TACE. They received timely supportive treatment from the Department of Internal Medicine, but the hemorrhage recurred at one, three, six, and 12 months later in three, six, six, and nine patients, respectively; in the experimental group, the hemorrhage recurred at one, three, six, and 12 months (after initial hemorrhage in eight patients) in zero, zero, zero, and two patients, respectively. Differences between the two groups in the recurrence rate of hemorrhage at one, three, six, and 12 months after TACE were significant (P < 0.05).
Comparison of improvement of liver function
At six months after surgery, liver function recovery was noted in eight (30.8%) patients and remission was observed in 18 (69.2%) patients in the control group. In the PTVE group, liver function recovery was noted in 10 (34.5%) patients, and remission was observed in 19 (65.5%) patients. The difference between the two groups was not significant (P > 0.05).
Type of TACE and tumor control
In the control group, TACE was performed for a total of 94 times on 31 patients within 12 months after TACE, with an average of 3.03 times on each patient, including C-TACE on 71 patients and DEB-TACE on 23 patients, and the ORR was 39.3%. In the PTVE group, TACE was performed for a total of 151 times on 29 patients within 12 months after TACE, with an average of 5.21 times on each patient, including C-TACE on 89 patients and DEB-TACE on 64 patients, and the ORR was 60.1% (assessed according to the mRECIST criteria).[12] The differences between the two groups in the frequency of TACE, proportion of C-TACE/DEB-TACE, and ORR were significant (P < 0.05).
> DiscussionIn China, HVPG has been rarely used in stratifying risks and evaluating the efficacy of primary prevention in patients with decompensated cirrhosis, and even less in evaluating the efficacy of new drugs and noninvasive techniques. This study was conducted to stratify patients with a high risk of gastrointestinal bleeding based on the HVPG measurement and provide preventive PTVE[13] to prevent the recurrence of gastrointestinal bleeding from damaging the liver and even endangering the patient's life.
The wedged hepatic venous pressure (WHVP) can indirectly reflect the portal venous pressure.[14] Compared with the direct measurement of portal venous pressure, WHVP measurement is safer and more feasible. Moreover, HVPG is the difference between WHVP and free hepatic venous pressure, and it reflects the pressure difference between the portal vein and the intra-abdominal vena cava. HVPG has eliminated the influence of intra-abdominal pressure on the measurement result; thus, it can reflect the portal venous pressure better.[15] The normal value of HVPG ranges from 3 to 5 mmHg, and an HVPG >5 mmHg indicates the presence of PH in cirrhosis. In recent years, the status of HVPG has been rising in the clinical diagnosis and monitoring of PH in cirrhosis.[16] In 2005, it was first proposed in Baveno IV Consensus that monitoring HVPG could determine the population who would benefit from nonselective β-blockers.[17] In 2015, Baveno VI Consensus pointed out that HVPG ≥10 mmHg was the golden criteria for the diagnosis of clinically significant PH[1]; a decrease in HVPG to <12 mmHg or 20% lower than the baseline pressure could significantly reduce the risk of recurrent bleeding of the varicose veins in PH in cirrhosis. In 2016, the American Association for the Study of Liver Diseases released the consensus on the risk stratification, diagnosis, and management of portal hypertensive bleeding in cirrhosis, which once again emphasized the importance of HVPG in evaluating the stage, complication occurrence, and treatment objectives of cirrhosis.[18] However, HVPG is an invasive detection and has certain requirements on the technical skills of operators and the hospital equipment; thus, its clinical application is limited in some extent. HVPG ≥16 mmHg indicates the increased risk of death in cirrhosis patients with PH,[4],[19] and HVPG ≥20 mmHg indicates the increased failure rate of hemostatic therapy and the increased risk of death in cirrhosis patients with acute variceal bleeding.[11],[20],[21] Therefore, great attention should be paid to the above two types of PH cases, and primary preventive medication combined with secondary preventive PTVE should be performed on such patients to lower the risks of initial bleeding and recurrent bleeding.
Preventive PTVE should be performed as soon as possible on patients with HVPG ≥16 mmHg or 20 mmHg and extremely high risks of gastrointestinal bleeding and death. Therefore, people with HVPG ≥16 mmHg or 20 mmHg are selected as the research objects of this paper. In this study, the rate of initial gastrointestinal bleeding after TACE and the recurrence rate of the hemorrhage were significantly lower in the experimental group (PTVE group) than in the control group, and more evident long-term effects at six and 12 months after surgery were observed in the experimental group than in the control group. In PTVE, a percutaneous transhepatic approach is adopted for selective catheterization of the gastric coronary vein, and microcoils are then pushed in to occlude the blood vessel. The microcoils are arranged densely. The intrinsic coagulation system is activated instantaneously to form mixed thrombus in the blood vessel, thereby blocking and closing the varicose veins and reducing the blood flow. Therefore, PTVE has a good hemostatic effect. However, after all, PTVE is not effective for PH. In this study, the initial hemorrhage rate was 3.4% at six months after TACE and 10.3% at 12 months after surgery [Table 2] in the PTVE group; however, the recurrence rate of hemorrhage reached up to 25% [Table 3]. The reason remains to be the non-remission of PH. Meanwhile, embolization of the gastric coronary veins obstructs the venous return of gastric mucosa, submucosa, muscular layer, and even subserosa; arteriovenous shunts occur on the muscular layer of the gastric wall, the gastric mucosal barrier is damaged, and stagnant anoxia is worsened, thus worsening portal hypertensive gastropathy. Over time, new varicose veins and shunts of collateral veins will form gradually and cause gastrointestinal venous bleeding. TACE treatment for liver cancer is also easy to cause postoperative acute portal venous pressure increase, which is caused by embolic substances and vascular fistula entering the portal vein, leading to further increase of portal venous pressure and secondary gastrointestinal bleeding.[22] No significant difference was noted between the two groups in the improvement of liver function at six months after TACE [Table 4]. The possible reason was that the high bleeding rate in the control group worsens the damage to the liver, while TACE was performed for multiple times in the PTVE group, which also affects the liver function. Thus, no significant difference was found between the two groups with respect to liver function. Differences in the frequency of TACE, proportion of C-TACE/DEB-TACE, and ORR were significant between the two groups of patients [Table 5]. TACE was performed for a total of 151 times in the PTVE group, significantly more than that in the control group (94 times), because the control group experienced gastrointestinal bleeding after TACE and stopping of TACE. Moreover, gastrointestinal bleeding damaged the liver of patients; hence, patients received active supportive treatment to protect the liver, which also delayed the reoperation for TACE.[23] Especially, the proportion of DEB-TACE was much higher in the experimental group than in the control group, indicating that patients in the PTVE group with liver cancer also had much better liver tolerance than those in the control group. Therefore, tumor embolization had significantly better efficacy in the experimental group than in the control group. In the evaluation of short-term efficacy, the ORR was up to 60.1% in the experimental group.
Table 2: Comparison of initial hemorrhage after TACE between the two groups [n (%)]
Table 3: Comparison of recurrence of hemorrhage after TACE between the two groups [n (%)]
Table 4: Comparison of improvement of liver function after TACE between the two groups [n (%)]
Table 5: Comparison of the type of TACE and tumor control between the two groups [n (%)]HVPG monitoring is of great significance in the clinical management of patients with PH.[24],[25],[26],[27] In this study, patients with PH were randomly divided into two groups after risk stratification based on HVPG. Early PTVE was given to patients in the experimental group, and this treatment had achieved the desired objective of the study. It significantly lowered the rates of initial and recurrent gastrointestinal bleeding, and promoted TACE for the treatment of malignant liver tumors. Along with its advantages, such as small trauma, observable efficacy, and few complications, PTVE is also the preferred method of early intervention and treatment for patients with liver cancer and PH after risk stratification based on HVPG.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
> References
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