Abstract
Background
Spontaneously ruptured hepatocellular carcinoma (rHCC) is a life-threatening condition. Transarterial chemoembolization (TACE) is a widely accepted treatment; however, it can lead to serious complications, especially liver failure. We sought to identify preoperative predictors of liver failure in patients with rHCC undergoing TACE.
Methods
Patients with rHCC who received TACE as the initial therapy were retrospectively studied at our institution between January 2016 and December 2021. Based on the occurrence of liver failure after TACE, the patients were divided into liver failure and no-liver failure groups. Predictors of liver failure after TACE were analyzed using univariate and multivariate regression analyses. The predictive performance was assessed using the area under the curve (AUC). Delong's test was used to compare predictive efficiency.
Results
Sixty patients (19 and 41 in the liver failure and non-liver failure groups, respectively) were included. Multivariate analysis showed that preoperative prothrombin activity (PTA) level (odds ratio [OR], 0.956; 95% confidence interval [CI], 0.920–0.994; P = 0.024) and Child-Pugh grade B (OR, 6.419; 95% CI, 1.123–36.677; P = 0.037) were independent predictors of liver failure after TACE in patients with rHCC. The AUCs of the preoperative PTA levels and Child-Pugh grade B for predicting liver failure after TACE in patients with rHCC were 0.783 and 0.764, respectively.
Conclusion
Preoperative PTA level and Child-Pugh grade B were significant independent risk factors for liver failure after TACE in patients with rHCC. These can be used to predict liver failure after TACE in patients with rHCC for individual decision-making regarding treatment planning.
Keywords: Hepatocellular carcinoma, Spontaneous rupture, Transarterial chemoembolization, Liver failure
1. Introduction
Hepatocellular carcinoma (HCC) is the sixth most common cancer and leads to the fourth most common cancer-related death worldwide, with more than one million people developing HCC every year by 2025.1 Spontaneously ruptured HCC (rHCC) is a rare fatal complication that occurs in less than 3% of patients with HCC in the Western world and as high as 12%–14% in Asian patients with HCC.2 rHCC is defined by the American Joint Committee on Cancer/Union for International Cancer Control as a T4 lesion and is staged similar to tumors with vascular or bile duct invasion; the mortality rate of rHCC in the acute stage is as high as 25%–75% due to massive intraperitoneal hemorrhage. The median survival of rHCC is short, approximately 7–21 weeks, making it the third most common cause of death from liver cancer, except for cancer progression and liver failure.3 Moreover, rHCC may produce a spillage of tumor cells in the peritoneal surface with possible seeding and multiple nodule growth.
A well-accepted treatment of choice for most patients with rHCC is a non-surgical approach, particularly the transarterial embolization (TAE)/transarterial chemoembolization (TACE). However, the clinical outcomes of rHCC after TAE/TACE remain unpredictable and a significant proportion of patients succumb early despite successful embolization. Liver failure is the most important complication leading to early death in patients with rHCC after TAE/TACE, the incidence of liver failure after TAE/TACE can reach 12%–34%.4,5
Although TAE/TACE can block most of the blood supply to the tumor and inhibit swelling and tumor growth, allowing for easier secondary surgical treatment, it is controversial whether TAE/TACE would cause further deterioration of liver function in patients with rHCC. Several reports have shown the factors associated with liver failure after TACE in patients with HCC,6 such as tumor diameter and albumin levels. To date, very little attention has been paid to the complications of TACE in patients with rHCC. Thus, in the absence of significant data, this study aimed to identify the predictive factors for liver failure in patients with rHCC after TACE.
2. Methods
2.1. Patient selection
Data of patients with newly diagnosed rHCC who initially underwent TACE were collected from January 2016 to December 2021 at The Second Affiliated Hospital of Chongqing Medical University. HCC was diagnosed according to the diagnostic guidelines issued by the American Association for the Study of Liver Diseases.7 rHCC was identified by contrast-enhanced computed tomography (CT) with typical findings, including HCC with a surrounding high-attenuation perihepatic hematoma, protrusion of the hepatic contour, focal discontinuity of the hepatic surface, and active extravasation of the contrast medium. Abdominal paracentesis was performed in some patients, but it was not necessary to diagnose rHCC. The exclusion criteria were 1) incomplete clinical data, 2) severe comorbidities that could affect life expectancy, such as a history of severe cardiac disorders, 3) liver failure before TACE, 4) traumatic and iatrogenic HCC rupture, and 5) Child-Pugh grade C.
This study was approved by the Ethics Committee of The Second Affiliated Hospital of Chongqing Medical University (Chongqing, China). The requirement for written informed consent was waived, considering the retrospective nature of this study, and the study was performed in compliance with the Declaration of Helsinki.
2.2. TACE procedure
First, active fluid resuscitation, blood transfusion, and other supportive treatments, including correction of coagulopathy, were instituted in hemodynamically unstable patients. Premedications for analgesia and sedation were administered to all the patients before the procedure. TACE was performed by experienced interventional radiologists in our angiography suite (all with >10 years of clinical practice). Standard Seldinger access of the right common femoral artery was performed, and a 5-Fr micropuncture catheter sheath (COOK, Bloomington, Indiana, USA) using a short guide wire was inserted. A 5-Fr angiography catheter (COOK, Bloomington, Indiana, USA) was inserted into the abdominal trunk and common hepatic artery to visualize the HCC blood supply and identify the point of bleeding. In patients without active contrast agent extravasation from the HCC on selective right or left hepatic angiograms, the embolization site was determined based on CT or magnetic resonance (MR) imaging to localize the rupture in the HCC. A 2.7-Fr angiography microcatheter (COOK, Bloomington, Indiana, USA) was super selectively inserted into the tumor nutrient artery and the bleeding site through the microguide wire.
Two embolization strategies have been approved and are commonly used at our institution. The conventional TACE group (C-TACE) was administered 10–20 mL lipiodol (Guerbet, Villepinte, Seine Saint-Denis, France) combined with 350 μm gelatin sponge particles (Alicon, Hangzhou, Zhejiang, China) mixed with 20–40 mg epirubicin (Shenzhen Main Luck Pharmaceuticals Inc., Shenzhen, Guangdong, China) as chemoembolization agents; the drug-eluting beads TACE group (DEB-TACE) was administered 10–20 mL lipiodol combined with CalliSpheres microsphere (Jiangsu Hengrui Medicine Co. Ltd, Lianyungang, Jiangsu, China) embolization. CalliSpheres microsphere with a diameter of 100–300 μm was used to load 80 mg epirubicin as a chemoembolization agent.
The actual dose was determined according to the size and number of tumors and liver function of the patients. The endpoint of both embolization strategies was complete flow stasis in the target vessels of the ruptured tumor. Regarding other multiple tumor lesions, the magnitude of embolization was performed depending on the patient's condition, such as liver function and tumor volume.
The technical success of embolization was flow stasis in the tumor-feeding arteries, absence of active contrast extravasation, and preservation of peripheral normal liver parenchyma blood supply. The clinical success of TACE was determined by the stabilization of vital signs and serum hemoglobin levels after the cessation of supportive measures.
2.3. Data collection
We analyzed preoperative clinical data, including age, sex, hepatitis B virus (HBV) surface antigen positivity, history of hypertension, hemorrhagic shock, time from admission to TACE, embolic agents of TACE, Child-Pugh grade, albumin-bilirubin (ALBI) score, model for end-stage liver disease (MELD) score, and model for end-stage liver disease with sodium (MELD-Na) score. Laboratory data included hemoglobin, platelet count, serum creatinine, serum sodium (Na), prothrombin activity (PTA), international standardized ratio (INR), prothrombin time (PT), albumin (ALB), total bilirubin, alanine aminotransferase (ALT), glutamate transaminase (AST), and alpha-fetoprotein. The radiological characteristics included cirrhosis, portal hypertension, maximum tumor diameter, tumor number, portal vein invasion, hepatic vein invasion, and extrahepatic metastasis.
2.4. Follow-up and liver failure assessment
Post-TACE follow-up was performed in the surgical ward. Further treatment was performed in the intensive care unit (ICU) if necessary. Post-TACE liver failure was diagnosed according to the definition of acute-on-chronic liver failure (ACLF) of the 2019 Asian Pacific Association for the Study of the Liver (APASL).8 The diagnostic criteria were jaundice (serum total bilirubin ≥85 mmol/L) and coagulopathy (INR ≥1.5 or PTA <40%) complicated within 4 weeks by clinical ascites and/or hepatic encephalopathy.
2.5. Statistical analysis
Continuous data were described as mean ± standard deviation or median (interquartile range), and between-group comparisons were evaluated using unpaired Student's t-tests or Mann–Whitney U test. Categorical data were described as frequency (percentage), and the Pearson χ2 test, correction χ2 test, and Fisher's exact test were applied to analyze the differences between the two groups. Univariate and multivariate analyses were performed using logistic regression models. Variables that achieved statistical significance (P < 0.05) or those close to significance (P < 0.1) on univariate analysis were subsequently included in the multivariate analysis. Receiver operating characteristic (ROC) analysis was used to evaluate the predictive value of some predictors of liver failure after TACE in patients with rHCC. Delong's test was applied to compare the performance of predictors using MedCalc® Statistical Software version 20.010 (MedCalc Software Ltd, Ostend, West Flanders, Belgium). All statistical analyses were performed using IBM SPSS Statistics ver. 26.0 (IBM, Armonk, NY, USA). Statistical significance was determined by two-tailed tests and considered statistically significant at P < 0.05.
3. Results
3.1. Clinical characteristics
The characteristics of the 60 patients with rHCC treated with TACE are shown in Table 1. This study included 50 men and 10 women with a mean age of 55.35 years (range, 16–83 years). The patients were divided into a liver failure group (19 cases) and a no-liver failure group (41 cases) according to the occurrence of liver failure after TACE. The incidence rate of liver failure was 31.7% (19/60). Preoperative hemorrhagic shock occurred more frequently in the liver failure group than in the non-liver failure group (42.1% vs. 14.6%, P = 0.044). The liver failure group had significantly lower hemoglobin, PTA, and ALB levels and significantly higher INR, PT, ALT, and AST levels. No patients had Child-Pugh grade C in this study; 28 (46.7%) patients had Child-Pugh grade A liver function, while 32 (53.3%) had Child-Pugh grade B. Preoperative Child-Pugh grade B was more prevalent in the liver failure group (89.5% vs. 36.6%, P < 0.001). Additionally, significantly increased ALBI, MELD, and MELD-Na scores were observed in the liver failure group.
Table 1.
Clinical characteristics of 60 patients with rHCC undergoing TACE.
| Variables | Total (n = 60) | Liver failure (n = 19) | No-Liver failure (n = 41) | P value |
|---|---|---|---|---|
| Age (years), mean ± SD | 55.35 ± 13.82 | 59.16 ± 11.59 | 53.59 ± 14.53 | 0.148 |
| Sex (male/female) | 50(83.3%)/10(16.7%) | 14(73.7%)/5(26.3%) | 36(87.8%)/5(12.2%) | 0.321 |
| HBV (positive/negative) | 50(83.3%)/10(16.7%) | 16(84.2%)/3(15.8%) | 34(82.9%)/7(17.1%) | 1 |
| Hypertension (yes/no) | 9(15.0%)/51(85.0%) | 4(21.1%)/15(78.9%) | 5(12.2%)/36(87.8%) | 0.613 |
| Cirrhosis (yes/no) | 37(61.7%)/23(38.7%) | 11(57.9%)/8(42.1%) | 26(63.4%)/15(36.6%) | 0.682 |
| Portal hypertension (yes/no) | 29(48.3%)/31(51.7%) | 8(42.1%)/11(57.9%) | 21(51.2%)/20(48.8%) | 0.511 |
| Hemorrhagic shock (yes/no) | 14(23.3%)/46(76.7%) | 8(42.1%)/11(57.9%) | 6(14.6%)/35(85.4%) | 0.044 |
| Hb (g/L), mean ± SD | 95.78 ± 25.69 | 82.42 ± 23.18 | 101.98 ± 24.66 | 0.005 |
| PLT (109/L), median (IQR) | 182.00(101.75–239.75) | 181.00(99.00–263.00) | 183.00(109.00–238.50) | 0.893 |
| Scr (μmol/L), median (IQR) | 68.80(62.20–84.20) | 75.10(65.90–110.70) | 67.60(60.65–78.20) | 0.133 |
| Na (mmol/L), median (IQR) | 137.35(135.35–138.98) | 138.10(136.40–140.90) | 137.10(135.00–138.90) | 0.203 |
| PTA (%), mean ± SD | 77.70 ± 21.29 | 61.68 ± 21.92 | 85.12 ± 16.56 | <0.001 |
| INR, median (IQR) | 1.15(1.05–1.29) | 1.45(1.14–1.71) | 1.11(1.03–1.20) | <0.001 |
| PT (s), median (IQR) | 14.80(13.80–16.78) | 18.50(14.70–22.80) | 14.40(13.60–15.25) | <0.001 |
| ALB (g/L), median (IQR) | 34.60(30.15–37.48) | 30.90(28.00–33.30) | 35.50(33.40–38.20) | 0.006 |
| TB (μmol/L), median (IQR) | 16.55(10.18–24.28) | 18.80(12.60–28.20) | 14.10(9.25–23.25) | 0.094 |
| ALT (U/L), median (IQR) | 50.00(30.00–97.00) | 80.00(39.00–153.00) | 44.00(26.00–79.50) | 0.041 |
| AST (U/L), median (IQR) | 110.00(64.25–249.50) | 202.00(144.00–447.00) | 84.00(63.00–152.50) | 0.011 |
| AFP (<200 ng/mL/≥200 ng/mL) | 23(38.3%)/37(61.7%) | 7(36.8%)/12(63.2%) | 16(39%)/25(61%) | 0.872 |
| Diameter (cm), mean ± SD | 10.10 ± 4.34 | 10.68 ± 3.50 | 9.82 ± 4.69 | 0.436 |
| Number (single/multiple) | 23(38.3%)/37(61.7%) | 4(21.1%)/15(78.9%) | 19(46.3%)/22(53.7%) | 0.061 |
| Portal vein invasion (yes/no) | 27(45.0%)/33(55.0%) | 9(47.4%)/10(52.6%) | 18(43.9%)/23(56.1%) | 0.802 |
| Hepatic vein invasion (yes/no) | 17(28.3%)/43(71.3%) | 7(36.8%)/12(63.2%) | 10(24.4%)/31(75.6%) | 0.319 |
| Extrahepatic metastasis (yes/no) | 14(23.3%)/46(76.7%) | 1(5.3%)/18(94.7%) | 13(31.7%)/28(68.3%) | 0.054 |
| Time (<24 h/≥24 h) | 33(55.0%)/27(45.0%) | 8(42.1%)/11(57.13%) | 25(61.0%)/16(39.0%) | 0.172 |
| Embolic agents (C/DEB) | 47(78.3%)/13(21.7%) | 15(78.9%)/4(21.1%) | 32(78.0%)/9(22.0%) | 1 |
| Child-Pugh grade (A/B) | 28(46.7%)/32(53.3%) | 2(10.5%)/17(89.5%) | 26(63.4%)/15(36.6%) | <0.001 |
| ALBI score, median (IQR) | −2.06(-2.40–1.75) | −1.75(-1.99–1.54) | −2.29(-2.48–1.98) | <0.001 |
| MELD score, mean ± SD | 5.68 ± 6.37 | 9.54 ± 8.36 | 3.89 ± 4.26 | 0.011 |
| MELD-Na score, median (IQR) | 4.99(1.60–10.75) | 10.99(2.31–16.79) | 4.31(1.36–8.46) | 0.031 |
rHCC, spontaneously ruptured hepatocellular carcinoma; TACE, transcatheter arterial chemoembolization; Hb, hemoglobin; PLT, platelet count; Scr, serum creatinine; Na, serum sodium; PTA, prothrombin activity; INR, international standardized ratio; PT, prothrombin time; ALB, albumin; TB, total bilirubin; ALT, alanine aminotransferase; AST, glutamate transaminase; AFP, alpha-fetoprotein; ALBI, albumin-bilirubin; MELD, model for end-stage liver disease; MELD-Na, model for end-stage liver disease with sodium; SD, standard error; IQR, interquartile range; C, conventional; DEB, drug-eluting beads.
3.2. Predictors of liver failure after TACE in patients with rHCC
Liver failure was evaluated according to the definition of ACLF of the 2019 APASL.8 19 cases (31.7%) had liver failure during hospitalization. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of liver failure (Table 2). Univariate analysis revealed that 11 variables were significantly associated with liver failure: hemorrhagic shock, hemoglobin, prothrombin activity, international standardized ratio, prothrombin time, albumin, extrahepatic metastasis, Child-Pugh grade, ALBI score, MELD score, and MELD-Na score. Multivariate analysis further indicated that preoperative PTA level (odds ratio [OR], 0.956; 95% confidence interval [CI], 0.920–0.994; P = 0.024) and Child-Pugh grade B (OR, 6.419; 95% CI, 1.123–36.677; P = 0.037) were independent risk factors for liver failure after TACE in patients with rHCC.
Table 2.
Univariate and multivariate analyses of factors associated with liver failure after TACE.
| Univariate analysis |
Multivariate analysis |
||||
|---|---|---|---|---|---|
| Variables | OR (95%CI) | P value | OR (95%CI) | P value | |
| Age (years) | 1.033 (0.988, 1.080) | 0.151 | |||
| Sex (female) | 2.571 (0.644, 10.270) | 0.181 | |||
| HBV (positive) | 1.098 (0.251, 4.810) | 0.901 | |||
| hypertension (yes) | 1.920 (0.452, 8.154) | 0.377 | |||
| Cirrhosis (yes) | 0.793 (0.261, 2.408) | 0.683 | |||
| Portal hypertension (yes) | 0.693 (0.231, 2.076) | 0.512 | |||
| Hemorrhagic Shock (yes) | 4.242 (1.207, 14.908) | 0.024 | NS | ||
| Hb (g/L) | 0.968 (0.945, 0.992) | 0.009 | NS | ||
| PLT (109/L) | 1 (0.996, 1.004) | 0.983 | |||
| Scr (μmol/L) | 1.021 (0.999, 1.043) | 0.064 | NS | ||
| Na (mmol/L) | 1.1 (0.938, 1.29) | 0.24 | |||
| PTA (%) | 0.937 (0.902, 0.972) | 0.001 | 0.956 (0.920, 0.994) | 0.024 | |
| INR | 46.311 (3.609, 594.254) | 0.003 | NS | ||
| PT (s) | 1.683 (1.232, 2.3) | 0.001 | NS | ||
| ALB (g/L) | 0.863 (0.759, 0.981) | 0.024 | NS | ||
| TB (μmol/L) | 1.033 (0.996, 1.071) | 0.083 | NS | ||
| ALT (U/L) | 1.005 (0.999, 1.011) | 0.133 | |||
| AST (U/L) | 1.002 (1, 1.004) | 0.122 | |||
| AFP (<200 ng/mL) | 0.911 (0.296, 2.804) | 0.872 | |||
| Diameter (cm) | 1.047 (0.923, 1.188) | 0.477 | |||
| Number (multiple) | 3.239 (0.917, 11.443) | 0.068 | NS | ||
| Portal vein invasion (yes) | 1.15 (0.386, 3.426) | 0.802 | |||
| Hepatic vein invasion (yes) | 1.808 (0.559, 5.847) | 0.322 | |||
| Extrahepatic metastasis (yes) | 0.12 (0.014, 0.995) | 0.049 | NS | ||
| Time (≥24 h) | 2.148 (0.711, 6.493) | 0.175 | |||
| Embolic agents (DEB) | 0.948 (0.251, 3.577) | 0.937 | |||
| Child-Pugh grade (B) | 14.733 (2.983, 72.759) | 0.001 | 6.419 (1.123, 36.677) | 0.037 | |
| ALBI score | 13.916 (2.435, 79.547) | 0.003 | NS | ||
| MELD score | 1.17 (1.051, 1.303) | 0.004 | NS | ||
| MELD-Na score | 1.117 (1.025, 1.217) | 0.012 | NS | ||
TACE, transcatheter arterial chemoembolization; Hb, hemoglobin; PLT, platelet count; Scr, serum creatinine; Na, serum sodium; PTA, prothrombin activity; INR, international standardized ratio; PT, prothrombin time; ALB, albumin; TB, total bilirubin; ALT, alanine aminotransferase; AST, glutamate transaminase; AFP, alpha-fetoprotein; ALBI, albumin-bilirubin; MELD, model for end-stage liver disease; MELD-Na, model for end-stage liver disease with sodium; DEB, drug-eluting beads; OR, odds ratio; CI, confidence interval; NS, not significant.
3.3. Comparison of predictors for liver failure after TACE in patients with rHCC
We used ROC curve analysis to quantify the predictive power of Child-Pugh grade, ALBI score, MELD score, MELD-Na score, and PTA (Fig. 1 and Table 3). The area under the ROC curve (AUC) of the ALBI score for predicting liver failure after TACE in patients with rHCC was greater than that of any other predictor (AUC, 0.795). For the ALBI score, the best cut-off level of −2.035 showed a sensitivity and specificity of 84.2% and 70.7%, respectively. For Child-Pugh grade A/B, the AUC was 0.764, with a sensitivity of 89.5% and a specificity of 63.4%. Similarly, the AUC of the PTA level was 0.783, and the best cut-off level was 60, with a best sensitivity of 97.6% and a specificity of 57.9%. In addition, comparisons of the AUCs of the predictors were performed using Delong's test, which showed no statistical difference (all P > 0.05, Table 4).
Fig. 1.
Receiver operating characteristic (ROC) curves of Child-Pugh grade, ALBI score, MELD score, MELD-Na score, and PTA for predicting liver failure after TACE in patients with rHCC.
Table 3.
Results of ROC analysis shows the predictive ability of Child-Pugh grade, ALBI score, MELD score, MELD-Na score and PTA for liver failure after TACE in patients with rHCC.
| AUC | 95% CI | Standard error | P | Youden's index | Optimal cut-off | Sensitivity (%) | Specificity (%) | |
|---|---|---|---|---|---|---|---|---|
| Child-Pugh grade | 0.764 | 0.640–0.889 | 0.064 | 0.001 | 0.529 | A/B | 89.5 | 63.4 |
| ALBI score | 0.795 | 0.664–0.925 | 0.067 | <0.001 | 0.549 | −2.035 | 84.2 | 70.7 |
| MELD score | 0.698 | 0.531–0.866 | 0.085 | 0.014 | 0.428 | 8.62 | 52.6 | 90.2 |
| MELD-Na score | 0.674 | 0.507–0.840 | 0.085 | 0.031 | 0.404 | 10.51 | 52.6 | 87.8 |
| PTA | 0.783 | 0.649–0.918 | 0.0697 | <0.001 | 0.555 | 60 | 97.6 | 57.9 |
AUC, area under the ROC curve; CI, confidence interval; PTA, prothrombin activity; ALBI, albumin-bilirubin; MELD, model for end-stage liver disease; MELD-Na, model for end-stage liver disease with sodium.
Table 4.
Pairwise comparison of ROC curves.
| Difference between areas | Standard errora | 95% CI | Z statistic | P value | |
|---|---|---|---|---|---|
| MELD-Na score vs. MELD score | 0.0244 | 0.0154 | −0.0602 | 1.589 | 0.1121 |
| MELD-Na score vs. Child-Pugh grade | 0.0905 | 0.0919 | −0.3606 | 0.985 | 0.3248 |
| MELD-Na score vs. PTA | 0.109 | 0.0712 | −0.2794 | 1.533 | 0.1253 |
| MELD-Na score vs. ALBI score | 0.121 | 0.106 | −0.4162 | 1.138 | 0.2552 |
| MELD score vs. Child-Pugh grade | 0.0661 | 0.0945 | −0.37 | 0.7 | 0.4842 |
| MELD score vs. PTA | 0.0847 | 0.0727 | −0.2847 | 1.166 | 0.2436 |
| MELD score vs. ALBI score | 0.0963 | 0.11 | −0.43 | 0.878 | 0.3797 |
| Child-Pugh grade vs. PTA | 0.0186 | 0.0649 | −0.255 | 0.287 | 0.7741 |
| Child-Pugh grade vs. ALBI score | 0.0302 | 0.069 | −0.27 | 0.437 | 0.662 |
| PTA vs. ALBI score | 0.0116 | 0.0914 | −0.359 | 0.126 | 0.8994 |
CI, confidence interval; PTA, prothrombin activity; ALBI, albumin-bilirubin; MELD, model for end-stage liver disease; MELD-Na, model for end-stage liver disease with sodium.
DeLong et al., 1988.
4. Discussion
rHCC is a common and serious complication of HCC and is characterized by rapid disease progression and high mortality. For patients with rHCC, TAE/TACE has become the initial treatment of choice to achieve hemostasis and stabilize the patient, with emergency hepatic resection reserved for only a limited number of highly selected patients.9 A recent study showed that TAE/TACE therapy is safe and effective in treating rHCC.10 TAE/TACE techniques have proven to be highly effective in controlling life-threatening hemorrhage, even for hemostasis of rHCC in patients with unstable hemodynamic conditions. Once initial hemostasis after TAE/TACE is achieved, the patient will have a chance to undergo staged hepatectomy, which can often help patients achieve better long-term survival than emergency hepatectomy.11 Furthermore, there are many clinical reports12,13 that the therapeutic effect on staged hepatectomies after TAE/TACE hemostasis can be comparable to those procedures with these kinds of elective liver resection in patients with non-rHCC. Recent changes in surgical management trends are moving away from emergency hepatectomies and toward TAE/TACE followed by staged hepatectomies, which is the best and most radical approach for patients with rHCC.14 Therefore, it is very important to prevent post-TAE/TACE complications for further treatment, especially liver failure.
PTA level and Child-Pugh grade B were independent risk factors for post-TACE liver failure. The incidence of liver failure after TACE in patients was related to the state of basic liver function. Lee et al. reported that high serum bilirubin and low serum albumin levels were associated with the risk of early mortality in patients with rHCC after TAE.9 Both bilirubin and albumin are included in the Child-Pugh grade. According to a previous study,15 patients with rHCC with Child-Pugh grade A/B liver function were preferable for interventional therapy, and patients with Child-Pugh grade C could receive only the best supportive care. We speculate that patients with rHCC with worse Child-Pugh grades have impaired liver reserves, leaving them more susceptible to ischemic injury to TAE/TACE and postoperative liver failure.
PTA was calculated using PT, which is a method of normalizing PT values. A previous report16 has shown that PTA is the most suitable expression form of PT in patients with advanced viral hepatitis. In our study, most patients (83.3%) had hepatitis B virus infection. Most coagulation factors involved in bleeding and hemostasis, including anticoagulant and procoagulant factors, are synthesized in the liver. Thus, coagulation function plays a non-negligible role in judging the synthetic function of the liver. A significant decrease in PTA not only indicates that the liver has an insufficient ability to synthesize coagulation factors but also indirectly reflects that the liver cells are in a severely damaged state. Decreased PTA is common in liver dysfunction and can predict liver failure.17 For patients with rHCC, their liver function is often unsatisfactory because of advanced tumors, and decreasing the ability to synthesize coagulation factors leads to lower PTA. Moreover, tumor rupture and hemorrhage activate the coagulation system, and excessive consumption of coagulation factors also reduces PTA.
ALBI, MELD, and MELD-Na scores, and Child-Pugh grade are clinically recognized as important indicators for the evaluation of liver function.18 It has been reported that19 the ALBI score is a good predictor of ACLF after TACE in patients with HCC. According to ROC curve analysis, ALBI also showed the best prediction performance (AUC = 0.795). However, we ultimately found no difference in the predictive value of these predictors using the Delong's test (all P > 0.05). The ALBI score is reliable and objective because it is based on an analysis of a large sample of clinical data. The Child-Pugh grade includes subjective indices of ascites and hepatic encephalopathy. It has defects, especially in patients with rHCC, because it is difficult to determine whether ascites is due to deterioration of liver function or hemorrhage in rHCC. In addition, an altered mental status secondary to hypovolemic shock is common. Accurate determination of the Child-Pugh score in patients with rHCC can be challenging. In contrast, identifying Child-Pugh grade A or B is easier.
In our study, the rate of liver failure after TACE in patients with rHCC was 31.7%, which deserved further investigation. The incidence was high even though TACE is safe and this is possibly because the APASL diagnostic criteria for ACLF, including patients with transient liver function damage after TACE, were selected. Furthermore, our hospital is a tertiary referral center, and a significant proportion of patients are referred after the initial treatment has failed, which is a serious disease.
Additionally, for postoperative liver failure, a well-established definition of post-hepatectomy liver failure has been widely accepted,20 while the definition of post-TACE liver failure is still not proposed. This has led to some confusion regarding the feasibility of interventional treatment for liver cancer, especially in patients with very poor liver function.
Based on our results, we recommend close surveillance of patients with rHCC undergoing TACE who are at risk of liver failure because of the high risk of mortality. Protective measures of liver and coagulation function should be actively taken, such as supplementation of coagulation factors through plasma transfusion, particularly by patients with Child-Pugh grade B or PTA <60 before TACE.
This study had some limitations. First, the retrospective nature of this study renders it susceptible to selection bias. Second, because of the low incidence of rHCC, our sample size was relatively small and, hence, prone to type 2 errors. Third, given that this was a single-center study, the study population was limited to Chinese patients with rHCC, and the dominant etiology of the liver disease was HBV, which is different from that seen in Western countries. Further multicenter studies with larger sample sizes are required. A quantitative score containing several variables, such as Child-Pugh grade and PTA levels, may be very helpful for probability calculation and decision making in the future.
In conclusion, preoperative PTA level and Child-Pugh grade B were significant independent risk factors for liver failure after TACE in patients with rHCC. Therefore, they can be used to predict liver failure after TACE in patients with rHCC. These findings are important, especially for institutions initially adopting TAE/TACE toward patients with rHCC, and suggest that protection of liver function and supplementation of coagulation factors should be considered before TAE/TACE.
Declaration of competing interest
There are no conflicts of interest to declare.
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