The development of early ascites is associated with shorter overall survival in patients with hepatocellular carcinoma treated with drug-eluting embolic chemoembolization

doi:10.21203/rs.2.19067/v1

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The development of early ascites is associated with shorter overall survival in patients with hepatocellular carcinoma treated with drug-eluting embolic chemoembolization

https://doi.org/10.21203/rs.2.19067/v1

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published 01 Jun, 2020

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Background: A single-centre cohort study was performed to identify the independent factors associated withthe overall survival (OS) of hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization with drug-eluting beads (DEB-TACE).

Methods: A total of 216 HCC patients who underwent DEB-TACE from October 2008 to October 2015 at a tertiary hospital were consecutively recruited. The analysis of prognostic factors associated with DEB-TACE complications was performed.

Results: The objective response (OR) rate (Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria) to the first DEB-TACE (DEB-TACE-1) was 70.3%; the median OS from DEB-TACE-1 was 27 months (95% confidence interval (CI), 24-30). In the multivariate analysis, basal Barcelona Clinic Liver Cancer (BCLC) stage and serum alkaline phosphatase were independent factors for survival following DEB-TACE-1. The most important clinical event associated with poor survival was the development of early ascites after DEB-TACE-1 (median OS, 17 months), which was closely related to the history of ascites, albumin and hemoglobin but not to tumour load or to response to therapy.

Conclusions: Early ascites post-DEB-TACE is associated with the survival of patients despite adequate liver function and the use of a supra-selective technical approach. History of ascites, albumin and hemoglobin are major determinants of the development of early ascites post-DEB-TACE.

Gastroenterology & Hepatology

Oncology

hepatocellular carcinoma

DEB-TACE

ascites

response

survival

Ethics approval: The protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ethics Committee of the Hospital Universitario Central de Asturias (Approval No. 120/19).

Consent to participate (provide consent): yes. All patients provided signed consent to perform the DEB-TACE and the follow-up CT scan. No specific individual consent was obtained regarding the publication of data.

Consent to publish: not applicable

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests: Pipa-Muñiz M, Sanmartino S, Mesa A, Cadahía V, Rodríguez JE, Vega F, and Costilla-García SM: none. Álvarez Navascués C: speaking fees and advisory roles for Gilead, Abbvie, and Intercept. González-Dieguez ML: speaker fees from Gilead, Abbvie and Novartis and consultancy fees from Gilead. Manuel Rodríguez M: speaking fees and advisory fees from Gilead, Abbvie, Intercept, and MSD. Varela M: speaker fees from Bayer and Gilead; consultancy fees from Roche, Bristol-Myers-Squibb, SIRTEX, Bayer, IPSEN, and BTG-Boston.

Funding: none

Authors' Contributions: Concept and design of the study: M Varela and M Pipa; data collection: M Pipa, S Sanmartino, A Mesa, C Alvarez-Navascués, ML González-Diéguez, V Cadahía, JE Rodríguez, F Vega; statistical analysis: M Pipa, M Rodríguez, M Varela; analysing the results and writing of article: M Pipa, S Sanmartino, A Mesa, JE Rodríguez, SM Costilla-García, M Rodríguez and M Varela. All authors approved the last version of the manuscript.

Acknowledgements: Susana Díaz-Coto and Pablo Martínez-Camblor (statistical support).

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and is the fourth-leading cause of cancer-related mortality^{1, 2.} According to the European and American guidelines^3,4, transarterial chemoembolization (TACE) is the first-line treatment for asymptomatic patients with Barcelona Clinic Liver Cancer (BCLC) B stage disease (which includes multinodular HCC beyond the Milan criteria, without portal invasion or extrahepatic disease) and compensated liver function. TACE is performed not only in BCLC-B patients but also in early-stage patients if resection, ablation or liver transplantation is not feasible. Thus, TACE candidates represent a heterogeneous group of patients with variable tumour burden and liver function^5.

TACE is an image-guided transcatheter tumour therapy that has an ischaemic and cytotoxic effect on tumour tissue. The use of drug-eluting embolic chemoembolization (DEB-TACE) is safe and effective^6,7. However, an improvement in the overall survival (OS) of DEB-TACE compared to that of conventional TACE has not been confirmed^8,9.

Considering the heterogeneity of TACE candidates, patient selection must be carefully carried out. Underlying chronic liver disease is exacerbated by this procedure, especially in patients with diminished liver reserve^10. Several algorithms have been recently reported to predict HCC prognosis in an attempt to optimize chemoembolization treatments, but few data have been obtained from DEB-TACE procedures^11–13. Moreover, there is also scarce information about the influence of post-DEB-TACE events on OS and hepatic decompensation.

A prior meta-analysis of untreated patients in randomized clinical trials for HCC reported that ascites is strongly linked to a worse outcome in intermediate/advanced BCLC stages^14.

Some authors have suggested that a time-dependent covariate analysis that includes all the rounds of DEB-TACE, clinically relevant events and subsequent therapies is needed to properly evaluate the factors that influence the survival of patients.

The aim of our study was to identify predictive factors for survival in HCC patients treated with DEB-TACE, taking into account the basal characteristics, the procedure, the response to treatment and the impact of events after the first DEB-TACE (DEB-TACE–1), in a time-dependent covariate analysis.

Patients:

From October 2008 to October 2015, patients with HCC diagnosed according to the European Association for the Study of the Liver (EASL) guidelines who were selected for DEB-TACE were referred to a tertiary academic university hospital and were prospectively registered.

The inclusion criteria were as follows: 1) HCC that was diagnosed in the early stage but was not eligible for resection, ablation or liver transplant; 2) HCC with an intermediate BCLC stage; 3) compensated cirrhosis with normal or mildly altered liver function, without ascites or encephalopathy at the time of DEB-TACE; 4) an asymptomatic status, with an ECOG performance status 0; and 5) approval for DEB-TACE after evaluation by the multidisciplinary tumour board. Portal thrombosis, impaired liver function, decompensated cirrhosis, performance status > 0, extrahepatic disease and contraindication or impossibility for catheterization or chemoembolization were considered exclusion criteria. Patients included in clinical trials or awaiting liver transplantation for whom DEB-TACE was used as a bridge therapy were excluded.

We defined clinically significant portal hypertension (CSPH) as the presence of prior cirrhosis decompensation, oesophageal or gastric varices or low platelet counts (lower than 100x10⁹/mm³)¹⁵. Early ascites was defined as the appearance of ascites after the first round of DEB-TACE.

Clinical, biochemical and radiological examinations were performed at baseline and prior to every DEB-TACE procedure. No general sedation was used, and no antibiotic prophylaxis was indicated, except in patients with prior endoscopic retrograde cholangiopancreatography. If the prothrombin rate was lower than 50% or if the platelet count was less than 50x10⁹/mm³, fresh-frozen plasma was administered and/or platelet infusion was performed. Pain during the procedure was individually managed, and patients were discharged 24 hours later, unless complications were observed.

DEB-TACE procedure:

Drug-eluting beads® were loaded with doxorubicin following the manufacturer’s instructions the day before the procedure. Particles that were 300-500 microns (µm) were used until March 2013, when these particles were replaced by 100-300-µm beads to further penetrate the tumour¹⁶. If embolization was not completely achieved unloaded microspheres were employed to complete the artery obstruction.

Selective angiography of the common hepatic artery was carried out as well as of the right and left hepatic arteries. A supraselective approach for tumour vessels was achieved by using a Progreat 2.7 (Terumo®) microcatheter with 0.21, 0.16 or 0.14 Terumo® microwires, and DC-Beads® were then injected. After angiographic control, the 4F catheter and the introducer were removed, and manual compression was applied.

Starting in February 2015, Cone-Beam-Computed-Tomography software (CBCT, Syngo DynaCT, Siemens®) with contrast injection was employed to help during vascular catheterization, especially if the nodule was not visible at basal angiography or was in intersegmental nodules, when lesions were proximal to the diaphragm and when extrahepatic vascularization was evaluated. Once the procedure was finished, CBCT without intraarterial contrast was used to evaluate embolization.

Follow-up:

All patients received a clinical, analytical and radiological follow-up 6 weeks after each DEB-TACE procedure. Response to treatment was evaluated by contrast-enhanced computed tomography (CT) according to the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria¹⁷, and results were presented to the multidisciplinary tumour board. If partial response, stable disease or treatable progression were observed, a subsequent DEB-TACE was planned¹⁸. Patients with untreatable progression were evaluated for systemic therapy. Objective response (OR) was defined as the sum of complete response and partial response. The disease control rate (DCR) was defined as the OR as well as the stable disease rate.

Statistical analysis:

Quantitative variables are expressed as the median and interquartile range, and categorical variables are expressed as the count and proportion. Continuous quantitative variables were categorized according to the median value for the analysis. Differences between subgroups were evaluated with a Chi-squared test, Fisher’s exact test and a Student’s T-test, depending on the type of variable. A conventional p-value of less than 0.05 was considered significant.

Patient survival probability was estimated using the Kaplan-Meier method. OS was calculated from DEB-TACE-1 to death or to the end of follow-up for two periods: from baseline (t₀), taking into account clinical, demographic and radiological data prior to DEB-TACE-1, and from 6 weeks after DEB-TACE-1 (t₁), also considering complications and the radiological response to treatment. Variables with univariate significance (p<0.10) and clinical relevance were included in the Cox proportional hazards model for the multivariable analysis with the forward selection method.

The factors associated with the development of early ascites were analysed, bearing in mind the baseline characteristics, the response to treatment and other complications. The time was censored at ascites development, death or the second DEB-TACE (DEB-TACE-2).

All calculations were performed with SPSS version 23 (SPSS Inc., Chicago, IL).

An additional time-dependent covariate analysis was performed by using R (www.r-project.org) to identify factors associated with mortality. A backward method based on the Akaike information criteria was employed.

The protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ethics Committee of the Hospital Universitario Central de Asturias (Approval No. 120/19).

From October 2008 to October 2015, 242 consecutive patients with HCC who were diagnosed according to EASL guidelines were referred for DEB-TACE, but only 216 of these patients met the inclusion criteria. Table 1 summarizes the baseline characteristics. The predominant aetiology of liver disease was alcohol (45%), followed by hepatitis C virus infection (36%). Most of the patients were BCLC-B (59.7%) and Child-Pugh class A 5 (64%). Sixty-one percent had oesophageal varices, 32% were on a low-salt diet and / or diuretic and 73% presented CSPH.

The median number of DEB-TACE sessions was 2 (IQR, 1-3), and a total of 443 procedures were performed (Figure 1).

The median follow-up was 26.5 months, and follow-up was censored at death, loss to follow-up or the last visit (April 1, 2019).

Response to treatment:

According to the mRECIST criteria at week 6 after DEB-TACE-1, complete response was achieved in 25.5% of patients, partial response was achieved in 45% and stable disease was achieved in 11%; in contrast, 35 patients presented progressive disease after DEB-TACE-1 (69% BCLC-B and 31% BCLC-C).

Follow-up and post-DEB-TACE events:

During the follow-up, DEB-TACE was discontinued in 71 patients after the first session. Figure 1 shows the different causes for the discontinuation of DEB-TACE after the first or subsequent rounds. Post-procedure events within the first 90 days after DEB-TACE-1 are described in Supplementary table 1. A total of 73 of 216 patients experienced post-DEB-TACE-1 events (33.7%): 23 patients (31.5%) experienced radiological events, 41 patients (56.2%) experienced clinical events and 9 patients (12.3%) experienced both clinical and radiological events. Ascites was the most frequent adverse event and was present in 27 patients.

At the end of follow-up, 27 patients were alive; 70 patients had moved to sorafenib and 9 to second-line regorafenib.

Overall Survival:

The median OS from DEB-TACE-1 was 27 months (95% confidence interval (CI), 24.193-29.807) (Figure 2). The cumulative survival rates were 82%, 58%, 32% and 16% at 1, 2, 3 and 5 years, respectively.

Univariate and multivariate analyses prior to DEB-TACE-1 (t₀) and at 6 weeks after DEB-TACE-1 (t₁) are shown in Tables 2 and 3. The independent factors associated with OS at t₀were BCLC stage and alkaline phosphatase, and the independent factors associated with OS at t₁were albumin, BCLC stage, alkaline phosphatase and ascites. A second model with the independent factors of survival in the t₁ period was constructed that included the liver function, as estimated by the Child-Pugh score, and DCR, as estimated by mRECIST, after DEB-TACE-1.

Post-DEB-TACE events:

The most important clinical event associated with shorter survival was the presence of ascites after DEB-TACE-1 (Figure 3). Patients with ascites (n=27) had a median OS of 17 months (95% CI, 8.566-25.434; p< 0.05); in contrast, patients without ascites had a median OS of 28 months (95% CI, 25.519-30.481). Cumulative survival rates at 1, 2, 3 and 5 years are shown in Figure 3.

Baseline characteristics associated with the development of ascites are shown in Supplementary table 2. History of ascites decompensation, hemoglobin and albumin were independently related to the development of early ascites (Table 4). The development of ascites after DEB-TACE was independent of the radiological response (the OR rate was similar in patients who developed ascites, indicating that this was not related to tumour progression, p=0.13). The median time from DEB-TACE-1 to the onset of early ascites was 40 days (interquartile range (IQR), 33-57), and the median time between DEB-TACE-1 and DEB-TACE-2 was 140 days (IQR, 81 -177). Lastly, 9 patients recovered from hepatic decompensation and received DEB-TACE-2.

In the time-dependent covariate analysis, the variables that were independently associated with survival were basal alpha-fetoprotein (HR 1.66; 95% CI, 1.31-2.10; p< 0.001), time-dependent bilirubin (HR 4.47; 95% CI, 1.80-11.09; p< 0.001) and time-dependent alkaline phosphatase (HR 1.68; 95% CI, 1.41-2.01; p< 0.001) (Supplementary tables 3 and 4 and Supplementary figure 1).

Several publications have described the safety of DEB-TACE^6–9, but an in-depth analysis of the impact of adverse events on patient progression has not been examined. Our study determined that the development of early ascites was negatively related to the overall survival of compensated patients treated with DEB-TACE. This finding was related to low albumin, low hemoglobin and prior episodes of clinical ascites. The presence of significant portal hypertension and/or worse liver function might suggest that patients are predisposed to complications in chemoembolization procedures and to the consequent impairment in OS. Currently, the presence of CSPH precludes patients from undergoing surgical resection for HCC¹⁹, but less attention has been paid to other loco-regional therapies. However, two studies have recently reported that CSPH is a major negative prognostic factor in patients treated with DEB-TACE^10,20.

It should be noted that the OS of this cohort was lower than that at other sites^21–29(Supplementary table 5),, despite similar patient selection, supra-selective procedures and response to therapy. We speculate that although alcohol aetiology is not an independent predictor of survival, alcohol consumption can impair liver function due to acute-on-chronic liver failure³⁰ or alcoholic hepatitis^{31, 32.} The poor prognosis of alcohol-related HCC has been specifically observed in some French cohort studies^{33, 34} and in patients treated with Y⁹⁰-radioembolization in the SORAMIC study^35. Indeed, these patients had more comorbidities than those affected by hepatitis C, and in some cases, refused to undergo additional sessions of DEB-TACE. In our series, 6 patients presented a second primary tumour after DEB-TACE (1 pyriform sinus, 1 bladder, 1 colorectal and 3 lung cancers), and 13% of patients died from other causes that were not related to tumour progression or cirrhosis decompensation. Finally, some post-DEB-TACE events were handled out of the tertiary hospital, and the suboptimal care of cirrhosis complications could have influenced the survival of our patients.

This study had several weaknesses. This was an observational cohort study that was performed over many years, during which changes in the state-of-the-art technology occurred. However, the multidisciplinary core team and the main interventional radiologists did not change over the course of the study. Furthermore, nor the change in the DEB particles size (March 2103) nor the introduction of CBCT (February 2015) have influenced the objective response rate or the global overall survival (data not shown).

The second weakness was that no clinical events were identified in the time-dependent covariate analysis.

In contrast, the main advantage of this study was the prospective collection of a large number of patients who were treated with a homogeneous protocol and the collection of adverse effects after DEB-TACE, including asymptomatic radiological abnormalities.

In conclusion, adverse events reduce OS following DEB-TACE, especially when ascites is present. Although compensated chronic liver disease is a requirement for loco-regional therapy, the appearance of early ascites seems to be related to the history of prior ascites, lower hemoglobin levels and lower albumin. These factors could be relevant for properly select the best candidates for DEB-TACE when different therapeutic options are available.

BCLC: Barcelona Clinic Liver Cancer

CBCT: cone-beam computed tomography

CI: Confidence interval

CT: Computed tomography

CR: Complete response

CSPH: clinically significant portal hypertension

CDR: disease control rate

DEB-TACE: drug-eluting embolic chemoembolization

EASL: European Association for the Study of the Liver

HCC: Hepatocellular carcinoma

HR: Hazard ratio

IQR: interquartile range

mRECIST: modified Response Evaluation Criteria in Solid Tumors

OR: objective response

OS: overall survival

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Table 1: Baseline characteristics of the patients (n=216).

Age (yr), median (IQR)	70 (63-76)
Gender (Male/Female), n	180/36
Alcohol/HCV/other etiologies, n	97/ 78/ 41
Prior radiological ascites (no / yes), n	198 / 18
Diuretic treatment (no/yes), n	67 / 84
Esophageal varices (yes/no/not available), n	72/131/13
Child-Pugh (A5/A6/B/ not available), n	139/39/18/20
BCLC-B (0/A/B), n	10/77/129
Bilirubin (mg/dL), median (IQR)	1 (0.93-1.33)
Albumin, (g/L), median (IQR)	40 (36-43)
AFP (ng/mL), median (IQR)	12.8 (4.9-60.3)
Cr (mg/dL), median (IQR)	0.84 (0.72-0.99)
Sodium (mEq/L), median (IQR)	141 (138-142)
AST (IU/L), median (IQR)	50 (32-84)
ALT (IU/L), median (IQR)	38 (25-76.5)
GGT (IU/L), median (IQR)	120 (67-212)
AP (IU/L), median (IQR)	108 (86.5-138.5)
PT (%), median (IQR)	84 (75-94)
Platelets (x 10⁹/mL), median (IQR)	113 (79-159)
Hemoglobin (g/dL), median (IQR)	13.6 (12.4-14.9)
Clinically Significant Portal Hypertension (yes/no), n	157/ 59
Main nodule diameter (mm), median (IQR)	35 (23-48)
Previous treatment (ablation/resection), n	44/8
ALBI 1/2/3/not available, n	81/96/1/38
Beads size 300-500 mm/ 100-300 mm, n	187 / 29
Use of Cone Beam CT (no/yes), n	135 / 81
Dose of doxorubicin (mg), median (IQR)	90 (70-140)

Yr: year; IQR: interquartile range; HCV: hepatitis C virus; BCLC: Barcelona Clinic Liver Cancer; AFP: alpha-fetoprotein; Cr: serum creatinine; AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: gamma-glutamyl-transpeptidase; AP: alkaline phosphatase; PT: prothrombin time.

Table 2. Predictors of overall survival from DEB-TACE-1 (period t₀) with pre-DEB-TACE variables (n=216) based on multivariate Cox regression.

			Univariate analysis			Multivariate analysis
Variable	Categories	n =216	Overall survival (months)		p-value	HR	HR 95% CI	p-value
			median	median 95% CI
Esophageal varices	No varices	72	30	22.795 - 37.205	0.025
	Varices	131	25	21.219 - 28.781
> 3 nodules	No	180	27	23.853 - 30.147	0.029
	Yes	33	23	18.632 - 27.368
Tumor size ^Ɨ	< 36.5 mm	128	30	26.946 - 33.054	0.025
	> 36.5 mm	84	22	17.509 - 26.491
AFP pre-TACE 1	< median	105	30	25.759 - 34.241	0.008
	> median	105	23	19.244 - 26.756
Bil pre-TACE 1	< median	130	28	24.174 - 31.826	0.052
	> median	79	25	21.332 - 28.668
Alb pre-TACE1	< median	110	24	20.271 - 27.729	0.112
	> median	98	28	24.344 - 31.656
AP preTACE-1	< median	105	32	28.016 - 35.984	< 0.001	0.649	0.471 - 0.893	0.008
	> median	105	24	20.771 - 27.229
Hb pre-TACE1	< median	108	24	19.020 - 28.980	0.155
	> median	105	28	25.661 - 30.339
Ascites preTACE-1	No	197	27	24.361 - 29.639	0.068
	Yes	19	21	16.985 - 25.015
BCLC-preTACE-1	BCLC-0/A	90	33	28.931- 37.069	0.001	0.661	0.484 - 0.903	0.009
	BCLC-B	126	23	19.826 - 26.174
CSPH	No	59	30	22.482 - 37.518	0.045
	Yes	157	26	22.257 - 29.743

AFP pre-TACE 1 median value 12,95 ng/mL; Bil pre-TACE 1 median value 1,00 mg/dL; Alb preTACE-1 median value 40 g/L; AP preTACE-1 median value 108,50 IU/L; Hb preTACE-1 median value 13.5 g/dL; Other variables evaluated in the multivariate analysis: sex (p=0.156), etiology (0.197); diabetes (p=0.929); AST (p=0.340); ALT (p= 0.791); GGT (p=0.289); Creatinine (p=0.847); Na (P=0.944);

^ƗTumor size (cut-off estimated by AUROC); platelets (p=0.611); DynaCT use (p=0.495); DEB size (p=0.283).

Table 3. Predictors of overall survival in the t₁ period (from DEB-TACE-1 assessment) including pre and post-procedure variables (n=216) based on multivariate Cox regression.

			Univariate analysis			Multivariate analysis
Variable	Categories	n =216	Overall survival, months		p-value	HR	HR 95% CI	p-value
			Median	Median 95% CI
BCLC-stage pre-DEB-TACE	BCLC 0/A	88	33	29.461 -36.539	<0.001	0.624	0.452 - 0.860	0.004
	BCLC-B	123	22	18.190 - 25.810
CSPH	No	58	29	19.055 - 38.945	0.046
	Yes	153	25	21.645 - 28.346
Post-TACE 1 events	No	142	27	24.308 - 29.692	0.026
	Yes	69	22	15.090 - 28.910
Albumin post-TACE1	< median	106	21	18.519 - 23.481	< 0.001	2.064	1.483 - 2.872	< 0.001
	> median	100	34	29.103 - 38.897
AFP post-TACE 1	< median	105	28	23.406 - 32.594	0.021
	> median	104	22	18.450 - 25.550
Bilirubin post-TACE 1	< median	138	28	24.296 - 31.704	0.009
	> median	71	23	19.909 - 26.071
AP post-TACE 1	< median	103	32	28.409 - 35.591	< 0.001	0.698	0.507 - 0.961	0.028
	> median	99	23	20.156 - 25.844
Ascites post-TACE 1	No	180	28	24.835 -31.165	< 0.001	0.504	0.315 - 0.806	0.004
	Yes	28	16	9.650 - 22.350
ALBI post-TACE 1	1	76	33	26.161 - 39.839	<0.001
	2	124	22	19.407- 24.593
	3	6	20	6.797 - 33.203
Child post-TACE 1	A5	122	29	24.525 - 33.479	< 0.001	0.574	0.414 - 0.796	0.001
	Other	71	21	18.178 - 23.822
MELD post-TACE 1	< 8	99	28	22.981 - 33.019	0.013
	> 8	97	23	20.131- 25.869
Progressive disease to TACE-1 (mRECIST)	Yes	35	21	18.241 - 23.759	0.062	0.602	0.395 - 0.918	0.018
	No	176	27	24.473 - 29.527

CI: confidence interval; HR: hazard ratio; TACE: transarterial chemoembolization; BCLC: Barcelona Clinic Liver Cancer; CSPH: clinically significant portal hypertension.; AFP: alphafetoprotein; Bil: bilirubin; Alb: albumin; AP: alkaline phosphatase; Hb: Hemoglobin. Alb posTACE1 median value 38 g/L; AFP posTACE 1 median value 8.5 ng/mL; Bil posTACE 1 median value 1.00 mg/dL; AP post-TACE 1 median value 128 IU/L; MELD posTACE 1 median value 8.

Multivariate analysis model 1: includes BCLC-stage, albumin, alkaline phosphatase, ascites. Multivariate analysis model 2: includes Child-Pugh and response to treatment.

Table 4: Predictors of development of early ascites based on multivariate Cox regression, censoring the time of follow-up at death, early ascites, or second DEB-TACE.

	p-value	Exp(B)	Exp(B) 95% CI
	p-value	Exp(B)	Lower	Higher
CSPH (yes/no)	0.348	0.366	0.045	2.995
Esophageal varices (yes/no)	0.430	0.607	0.175	2.100
BCLC 0/ A (yes/no)	0.201	1.804	0.730	4.459
Bilirubin	0.152	1.529	0.855	2.735
Hemoglobin	0.007	0.666	0.497	0.893
Child A5 (yes / no)	0.001	0.217	0.089	0.528
Albumin	0.029	0.313	0.110	0.885
Ascites prior to DEB-TACE	0.000	0.116	0.042	0.322

CSPH: clinically significant portal hypertension.

Model 1: Child A 5 plus Hemoglobin; Model 2: Hemoglobin plus prior ascites plus albumin.

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The development of early ascites is associated with shorter overall survival in patients with hepatocellular carcinoma treated with drug-eluting embolic chemoembolization

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