- Email: [email protected]
Albumin-Bilirubin Score: An Accurate Predictor of Hepatic Decompensation in High-Risk Patients Undergoing Transarterial Chemoembolization for Hepatocellular Carcinoma
CLINICAL STUDY
Albumin-Bilirubin Score: An Accurate Predictor of Hepatic Decompensation in High-Risk Patients Undergoing Transarterial Chemoembolization for Hepatocellular Carcinoma Mohammed A. AbdelRazek Mohammed, MD, Mohamed H. Khalaf, MD, Tie Liang, EdD, David S. Wang, MD, Matthew P. Lungren, MD, Jarret Rosenberg, PhD, and Nishita Kothary, MD
ABSTRACT Purpose: To evaluate validity of albumin-bilirubin (ALBI) grade as a predictor of acute-on-chronic liver failure (ACLF) after transarterial chemoembolization for hepatocellular carcinoma (HCC) in patients with baseline moderate to severe liver dysfunction. Materials and Methods: In this retrospective study, serum albumin and bilirubin levels measured before chemoembolization were used to calculate ALBI score in 123 patients treated with 187 high-risk chemoembolizations. Procedures were considered high risk if Child-Turcotte-Pugh score before chemoembolization was 8. ACLF was objectively measured using chronic liver failure–sequential organ failure assessment score at 30 and 90 d. The 30-day mortality and morbidity from new or worsening ascites and/or hepatic encephalopathy (HE) were assessed. Univariate and multivariate analyses were used to identify clinical and procedural predictors of ACLF in this high-risk population. Results: ACLF occurred after 15 (8%) high-risk chemoembolizations within 30 days and an additional 9 (5%) procedures between 30 and 90 days. Overall 30-day mortality was 2.7%. New or worsened ascites and/or HE occurred after 52 (28%) procedures within 30 days. Significant prognosticators of ACLF at 90 days revealed by univariate analysis were bilirubin (P ¼ .004), albumin (P ¼ .007), and ALBI score (P ¼ .002), with ALBI score remaining statistically significant on multivariate regression analysis (OR ¼ 3.99; 95% CI, 1.70–9.40; P ¼ .002). Conclusions: Chemoembolization for HCC can be performed safely in patients with moderate to severe liver dysfunction. ALBI score before chemoembolization provides objective prognostication for ACLF after chemoembolization in this cohort and may be used for risk stratification.
ABBREVIATIONS ACLF ¼ acute-on-chronic liver failure, ALBI ¼ albumin-bilirubin, BCLC ¼ Barcelona Clinic Liver Cancer, CI ¼ confidence interval, CTP ¼ Child-Turcotte-Pugh, HCC ¼ hepatocellular carcinoma, HE ¼ hepatic encephalopathy, MELD ¼ Model for End-Stage Liver Disease, OR ¼ odds ratio
Risk stratification before transarterial chemoembolization for patients with hepatocellular carcinoma (HCC) and hepatic impairment owing to underlying cirrhosis is challenging. The Child-Turcotte-Pugh (CTP) classification
system is commonly used in clinical practice to identify patients at risk for chemoembolization-related liver decompensation (1), but it was not originally designed for this clinical purpose (2). Its utility is further limited by its
From the Division of Interventional Radiology (M.A.A.M., M.H.K., D.S.W., M.P.L., N.K.), Department of Radiology (T.L., J.R.), Stanford University School of Medicine, 300 Pasteur Drive, H3630, Stanford, CA 94305-5642. Received March 6, 2018; final revision received June 11, 2018; accepted June 21, 2018. Address correspondence to N.K.; E-mail: [email protected]
Appendices A and B can be found by accessing the online version of this article on www.jvir.org and clicking on the Supplemental Material tab.
M.A.A.M. and M.H.K. contributed equally to this study.
https://doi.org/10.1016/j.jvir.2018.06.016
N.K. is a paid advisor for Siemens Healthcare (Erlangen, Germany). None of the other authors have identified a conflict of interest.
© SIR, 2018 J Vasc Interv Radiol 2018; ▪:1–8
2 ▪ ALBI: Predictor of Decompensation after Chemoembolization
reliance, in part, on subjective variables. The Barcelona Clinic Liver Cancer (BCLC) staging system is based on tumor burden and the CTP class as a guideline for treatment options for HCC, but it provides limited insight into the patient’s ability to tolerate liver-directed therapies, offering only palliation in patients with CTP class C (3). In 2015, Johnson et al (4) introduced a model for objective assessment of liver function based on a logarithmic ratio of albumin and bilirubin referred to as the albumin-bilirubin (ALBI) grade. This metric has been validated extensively across geographically diverse patient populations with various liver disease etiologies as a clinically accurate measure of liver dysfunction (5). Recent studies evaluated the prognostic performance of ALBI grade in patients who underwent transarterial therapies for HCC (6,7). However, these studies were limited to the ability of ALBI grade to predict survival. The occurrence of acute-onchronic liver failure (ACLF) after chemoembolization can result in further hepatic decompensation, emergent transplantation, or procedure-related mortality. Thus, the purpose of this study was 2-fold: (i) to identify clinical, laboratory, or procedural predictors of ACLF and (ii) to specifically evaluate the validity of ALBI grade as a predictor of chemoembolization-related ACLF in an at-risk cohort of patients with existing moderate or severe hepatic impairment.
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Table 1. Patient Characteristics (N ¼ 123 Patients) Characteristic Age, y, mean ± SD (range) Sex, male/female
Value 60 ± 6 (48–74) 81 (65.9)/42 (34.1)
Race White
42 (34.1)
Hispanic
38 (30.9)
Asian
13 (10.6)
African American Other Etiology Hepatitis C
4 (3.3) 26 (21.1) 59 (48)
Alcohol
25 (20.3)
Hepatitis C and alcohol
17 (13.8)
Hepatitis B
4 (3.3)
NASH
11 (8.9)
Other
7 (5.6)
Transplantation eligibility Waiting list Ineligible
92 (74.8) 31 (25.2)
Transarterial chemoembolization history Chemotherapy naïve
53 (40.7)
Prior chemoembolization
70 (59.3)
Note–All values except age are number (%). NASH ¼ nonalcoholic steatohepatitis.
MATERIALS AND METHODS This retrospective study was approved by the institutional review board and was compliant with the Health Insurance Portability and Accountability Act.
Patients Consecutive patients with unresectable HCC who underwent chemoembolization between January 2006 and August 2016 were identified using the institutional data archiving system. The dataset was further substratified to identify all patients with decompensated liver function defined by a CTP score 8, as described in prior studies (6). Transarterial liver-directed therapy, including chemoembolization, was considered to be high risk in these patients, and thus they were included in the study. Based on this definition, 187 high-risk chemoembolizations were performed in 123 patients during the study period (65.9% male, mean age 60 y). Of patients, 53 (40.7%) were chemotherapy-naïve, whereas the rest had undergone at least 1 prior chemoembolization (mean ± SD, 3 ±1.3; range, 2–8). Baseline patient demographics are summarized in Table 1.
Preprocedural and Procedural Details The decision to perform a high-risk chemoembolization procedure was made by a multidisciplinary team after considering tumor burden, tumor location, performance status, absence of venous invasion, and liver transplantation waiting list status. Patients were counseled on the risks for ACLF before the procedure. In addition, patients on the
waiting list for liver transplantation were counseled on the possibility of emergent transplantation. Procedures were performed at a single tertiary center by 1 of 5 boardcertified interventional radiologists, with 4–17 years of experience and with particular expertise in interventional oncology. Tumor burden was characterized as focal when within University of California San Francisco criteria (8). Superselective chemoembolization (defined as embolization at a subsegmental or higher order level) was performed in patients with focal disease, whereas sublobar or lobar chemoembolization was performed in patients with tumor burden that exceeded the University of California San Francisco criteria. Complete stasis or the previously described “tree-in-winter” appearance in tumor feeding arteries was used as the embolization endpoint depending on the tumor burden (9). Operator preference and drug availability determined the use of conventional transarterial chemoembolization or chemoembolization with drug-eluting microspheres. Conventional transarterial chemoembolization was performed using 5 mg/mL doxorubicin dissolved in iohexol (Omnipaque 300; GE Healthcare, Waukesha, Wisconsin), emulsified in a 1:1 volume ratio with ethiodized oil (Lipiodol; Guerbet LLC, Bloomington, Indiana) for a maximum delivered dose of 50 mg doxorubicin and 10 mL ethiodized oil. Drug-eluting microspheres (100–300 μm and/or 300–500 μm LC Bead; Biocompatibles/BTG, Farnham, United Kingdom) were reconstituted in iopamidol (Isovue; Bracco Diagnostics Inc., Monroe
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Township, New Jersey) for a maximum delivered dose of 150 mg of doxorubicin.
Data Collection and Outcomes Baseline laboratory data were obtained within 21 days before the procedure. Laboratory values recorded included serum bilirubin, serum albumin, international normalized ratio, platelet count, serum creatinine, and serum sodium. ALBI scores before chemoembolization were calculated using the previously published formula (Appendix A [on the article's Supplemental Material page at www.jvir.org]) (4). ALBI grades were assigned as follows: grade 1, 2.60; grade 2, > 2.60 but 1.39; and grade 3, > 1.39. In addition, CTP class/score, BCLC stage, and MELD score were determined. The presence and severity of chemoembolization-related ACLF were objectively measured using chronic liver failure–sequential organ failure assessment, an algorithm developed by the European Association for the Study of the Liver for systematic grading of ACLF (Appendix B [on the article's Supplemental Material page at www.jvir.org]) (10). The incidence of ACLF was reported at 30 days and at 90 days using laboratory data closest to the 30-day (median, 31 d; SD ± 26) and 90-day (median, 86 d; SD ± 26) time points. Outcomes were analyzed per procedure rather than per patient, as the primary goal of the study was to examine the potential impact of predictors before and during chemoembolization that may vary between individual procedures. However, statistical methods described further on were used to correct any within-patient correlation. Electronic medical records were queried for follow-up clinic visits, emergency department visits, and readmissions and/or admissions to another medical facility (documented by primary physicians or hepatologists). Worsening or new-onset ascites and/or hepatic encephalopathy (HE) within 30 days of the procedure that did not meet ACLF criteria were recorded. Laboratory toxicity, outside of toxicities included for ACLF, was defined as new-onset grade 3 or 4 toxicity for serum bilirubin or international normalized ratio based on the Common Terminology Criteria for Adverse Events (11). Finally, the number of patients listed for liver transplantation successfully bridged to transplantation or remaining on the waiting list was assessed.
Statistical Analysis Descriptive statistics were used to summarize the incidence of ACLF at 30 days and at 90 days. Univariate logistic regression analyses were performed to identify predictors of ACLF and new-onset/worsening ascites and/or HE. As ACLF can occur after any given individual procedure, the analysis was performed on a per-procedure level rather than per patient. However, any within-patient correlation was statistically addressed with clustering. Odds ratios (OR), confidence interval (CI), and significance level were reported for each predictor. The prognostic value of ALBI for prediction of ACLF was visually assessed on a prediction curve
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generated from the logistic regression model and quantitatively assessed by the area under the curve on a receiver operator characteristic curve, in addition to the sensitivity and specificity at a given cutoff point. All statistical analyses were done using Stata Release 15.0 (StataCorp LP; College Station, Texas). P < .05 was set as the significance level.
RESULTS Summary demographics, tumor characteristics, laboratory data, and procedural details are provided in Tables 1 and 2. Superselective chemoembolization was used in 94.1% of the procedures (n ¼ 176). Conventional chemoembolization was performed in 72% (n ¼ 187) of procedures, whereas drug-eluting microspheres were used in the remaining 28% (n ¼ 53). The mean CTP score before the procedure was 9.2 (range, 8–13, SD ± 1.3) with 32% of the procedures performed in CTP class C patients. The mean serum bilirubin level was 2.4 mg/dL (range, 0.6–12.9 mg/dL) and was > 3 mg/dL for 32% of the procedures. Stratification by ALBI grade before chemoembolization identified 62 (33.2%) chemoembolizations performed in 49 patients with an ALBI grade of 2 and 125 (66.8%) procedures performed in 87 patients with an ALBI grade of 3. There were no patients with an ALBI grade of 1. Of note, 79 (64%) patients who underwent 123 (65.7%) chemoembolizations had ascites before the procedure. Similarly, 71 (58%) patients who underwent 109 (58.2%) chemoembolizations had baseline grade 1 or 2 encephalopathy. Nine patients after 9 chemoembolizations were lost to follow-up, 1 at < 30 days and 8 between 30 and 90 days. Of the 178 chemoembolizations with 90-day follow-up, laboratory data at 30 and 90 days were not available for 4 and 6 procedures, respectively.
ACLF, Mortality, and Morbidity Table 3 summarizes all ACLF events and outcomes. The 30-day ACLF rate, per high-risk chemoembolization, was 8% (n ¼ 15 procedures in 15 patients). Delayed-onset ACLF occurred between 30 and 90 days after an additional 9 chemoembolizations (5%). The 30-day mortality rate from all causes was 2.7% (5 chemoembolizations) in 5 patients (4.1%) and increased to 7.8% at 90 days (in an additional 9 patients, total n ¼ 14 chemoembolizations in 14 patients). Contributing causes of death were ACLF (8 patients), sepsis (2 patients with intact sphincter of Oddi), variceal bleeding (1 patient), multiorgan failure (1 patient); and undetermined cause (2 patients). New or worsening ascites and/or HE was subjectively observed after 52 chemoembolizations (28%) in 44 (36%) patients within 30 days. New-onset grade 3 or 4 Common Terminology Criteria for Adverse Events bilirubin toxicity was noted after 34 chemoembolizations (18.1%), and grade 3 international normalized ratio toxicity was noted after 6 (3.2%) chemoembolizations. A scatter plot of baseline serum bilirubin levels and changes after chemoembolization is illustrated in Figure 1. Finally, of the 92 patients eligible for liver
4 ▪ ALBI: Predictor of Decompensation after Chemoembolization
Table 2. Clinical, Laboratory, and Procedural Variables per High-Risk Chemoembolization (N ¼ 187) Characteristic Tumor burden (%) Focal disease Tumor diameter, cm, mean ± SD Median tumor number Multifocal disease
Value 177 (95) 3.3 ± 1.5 1 10 (5)
Type of embolization (%) Superselective Sublobar or lobar Total serum bilirubin, mg/dL, mean ± SD (range)
2 75 (40)
Median < 3.5 (%) Sodium, mmol/L, mean ± SD (range) Median INR, mean ± SD (range) Median Creatinine, mg/dL, mean ± SD (range) Median CTP score/class, mean ± SD (range) Median Class (%)
61 (32) 2.7 ± 0.41 (1.3–3.7) 3 180 (96) 136 ± 4 (121–145) 137 1.43 ± 0.3 (0.9–4.2) 1.4 1.06 ± 0.4 (0.4–3.6) 1 9.2 ± 1.3 (8–13) 9
A
0 (0)
B
128 (68)
C
59 (32)
BCLC stage (%) 0
0
A
62 (33)
B C
66 (35) 0
D
59 (32)
Calculated MELD score, mean ± SD (range) Median Calculated ALBI score, mean ± SD (range) Median Grade (%)
14.7 ± 3.7 (8–31) 14 1.215 ± 0.399 (2.119 to 0.123) 1.184
1
0 (0)
2
62 (33.2)
3
125 (66.8)
Ascites (%) Absent Present
Characteristic Drug delivery method (%) Conventional chemoembolization Drug-eluting microspheres
Value 134 (72) 53 (28)
ALBI ¼ albumin-bilirubin; BCLC ¼ Barcelona Clinic Liver Cancer; CTP ¼ Child-Turcotte-Pugh; INR ¼ international normalized ratio; MELD ¼ Model for End-Stage Liver Disease.
11 (5.9) 2.4 ± 1.3 (0.6–12.9)
2 (%) 3 (%)
Table 2. Clinical, Laboratory, and Procedural Variables per High-Risk Chemoembolization (N ¼ 187) (continued)
176 (94.1)
Median
Albumin, g/dL, mean ± SD (range)
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64 (34) 123 (66)
Encephalopathy (%) Absent
78 (42)
Present
109 (58) continued
transplant (74.8%), 48 (52%) were successfully bridged to transplantation, 1 patient remains on the waiting list, and an additional 5 patients were successfully maintained on the waiting list for at least 1 year after high-risk chemoembolization (mean, 543 d; range, 400–993 d). Table 4 presents the univariate analysis for predictors of ACLF and new-onset/worsening ascites and/or HE at 90 days. Significant prognosticators of ACLF at 90 days revealed by univariate analysis were bilirubin (OR ¼ 1.52; 95% CI, 1.14–2.03; P ¼ .004), albumin (OR ¼ 0.11; 95% CI, 0.02–0.54; P ¼ .007), and ALBI grade (OR ¼ 3.99; 95% CI, 1.70–9.40; P ¼ .002); however, on multivariate analysis, only the ALBI grade remained statistically significant (P ¼ .002) with an OR of 3.99 (95% CI, 1.70–9.40). The OR for CTP score was 1.07 (95% CI, 0.75–1.54; P ¼ .7). Significant prognosticators for worsening HE and/or ascites included serum albumin (OR ¼ 0.19; 95% CI 0.07–0.48, P < .001), CTP class (OR ¼ 1.88; 95% CI, 1.32–2.67; P < .001), BCLC stage D versus A (OR ¼ 4.95; 95% CI, 1.90– 12.89; P ¼ .001), and the ALBI grade (OR ¼ 2.35; 95% CI, 1.43–3.86; P ¼ .001). Although both CTP score and ALBI grade remained statistically significant on multivariate analysis (P¼0.00 and 0.001, respectively), OR for ALBI score was 2.35 (95% CI, 1.43–3.86) compared with 1.88 for CTP score (95% CI, 1.32–2.67). Figure 2 demonstrates the prediction curve from the logistic regression model for ACLF at 90 days using ALBI scores. The risk of ACLF is low for ALBI scores of < 1.5, increases minimally when the ALBI score reaches 1.39 (ALBI grade 3), and increases rapidly as the ALBI score nears 0. Using a cutoff score of 1.39 (ALBI grade 3), the area under the curve for ACLF was 0.69 (95% CI, 0.65–0.73) with a sensitivity of 1.00 (95% CI, 0.77–1.00) and specificity of 0.38 (95%CI, 0.31–0.47). Approaching a cutoff ALBI value of 1, the area under the curve for ACLF prediction improved to 0.75 (95% CI, 0.62–0.88) with a sensitivity of 0.64 (95% CI, 0.35–0.87) and specificity of 0.73 (95% CI, 0.66–0.80) (Figure 3).
DISCUSSION These results underscore the value of the ALBI score as a prognostic tool for liver failure after chemoembolization for
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Table 3. ACLF Events and Outcomes (n ¼ 24 events) Patient
ACLF Grade
Type of Embolization
BCLC Stage
CTP Class
Child Pugh Score
Preprocedure ALBI Score
Preprocedure ALBI Grade
Outcome
ACLF at 30 d 1
2
Selective
D
C
10
0.921
3
Death
2
1
Selective
A
B
9
1.006
3
Death
3
3
Selective
D
C
13
0.382
3
Emergent liver transplant 0.5 month after procedure
4
2
Selective
D
C
10
1.740
2
Emergent liver transplant 0.5 month after procedure
5
3
Selective
D
C
10
0.261
3
Persisted to 90 d
6
2
Selective
B
B
9
1.157
3
Persisted to 90 d, death
7
1
Selective
A
B
8
0.660
3
Persisted to 90 d, death
8 9
1 1
Selective Selective
B D
B C
10 9
1.377 0.884
3 3
Persisted to 90 d Persisted to 90 d, death
10
3
Selective
B
B
9
0.408
3
Persisted to 90 d, death
11
1
Selective
A
B
9
1.479
2
Recovered 1.5 months after procedure
12
1
Selective
D
C
10
0.867
3
Recovered, transplanted 1 month after procedure Recovered 2 months after procedure
13
2
Selective
D
C
10
0.674
3
14
1
Selective
A
B
8
0.745
3
Recovered 1.5 months after procedure
15
3
Selective
D
C
11
0.669
3
Recovered 1 month after procedure
Delayed-onset ACLF 30–90 d 1
2
Selective
B
B
9
0.453
3
Death
2 3
1 1
Selective Selective
D B
C B
11 8
0.596 0.812
3 3
Death Progressed to end-stage liver disease
4
1
Selective
D
C
11
0.493
3
Progressed to end-stage liver disease
5
1
Selective
B
B
9
0.859
3
Persisted, progressed to end-stage liver disease
6
3
Sublobar/lobar
A
B
9
0.456
3
Persisted, progressed to end-stage liver disease
7
3
Selective
D
C
10
0.405
3
8
3
Selective
A
B
9
0.362
3
Recovered, transplanted 4 months after procedure Recovered 3.5 months after procedure
9
1
Selective
B
B
8
0.321
3
Recovered 4 months after procedure
ACLF ¼ acute-on-chronic liver failure; ALBI ¼ albumin-bilirubin; BCLC ¼ Barcelona Clinic Liver Cancer; CTP ¼ Child-Turcotte-Pugh.
patients with HCC and underlying liver disease. In line with prior studies, this study demonstrates that chemoembolization in patients with baseline moderate or severe hepatic impairment carries an acceptable risk of ACLF and 30-day mortality (7,12,13). By confirming the safety of superselective chemoembolization in this high-risk cohort, this study highlights its role as a bridge to liver transplanation, even in the presence of moderate or severe liver impairment, an important consideration in regions with long waiting periods owing to organ shortage. Patients with HCC and moderate to severe liver dysfunction are a challenging population. The BCLC staging system integrates CTP class and tumor burden to provide an algorithmic guide for treatment options (3). However, in this capacity, the BCLC staging system is
limited for patients with moderate to severe liver dysfunction. CTP class C patients are assigned BCLC stage D, restricted to palliation, regardless of the tumor burden. Furthermore, the use of BCLC staging and/or CTP class to predict chemoembolization-related ACLF extends both beyond their primary purposes. Finally, the use of interrelated variables and the subjective nature of 2 of the CTP variables (ascites and HE) are limitations of the CTP system. In short, prognostication of chemoembolization-related ACLF and decompensation is especially difficult in this high-risk patient population. However, as demonstrated in this study, an approach that integrates ALBI grade provides greater insight than individual laboratory tests. In fact, the results of this study demonstrate that even in patients with ALBI grade 3, the risk for ACLF after chemoembolization
6 ▪ ALBI: Predictor of Decompensation after Chemoembolization
Mohammed et al ▪ JVIR
Figure 1. Scatter plot of baseline serum bilirubin levels and change in levels after chemoembolization at 90 days.
Table 4. Univariate Analysis for ACLF and Worsening or New-Onset Ascites/HE at 90 Days ACLF
New or Worsening Ascites/HE
OR
95% CI
P Value
OR
95% CI
Prior chemoembolization
0.68
0.43–1.08
.105
0.95
0.72–1.25
P Value .701
Type of embolization (selective vs sublobar/lobar)
1.24
0.14–11.21
.849
1.03
0.31–3.49
.956
Serum bilirubin
1.52
1.14–2.03
.004
1.23
0.94–1.61
.131
Serum albumin
0.11
0.02–0.54
.007
0.19
0.07–0.48
< .001
Serum sodium
0.95
0.83–1.09
.497
0.93
0.85–1.01
.089
INR
0.88
0.24–3.24
.843
1.36
0.25–7.45
.724
Creatinine CTP score/class
0.95 1.07
0.28–3.23 0.75–1.54
.938 .700
0.85 1.88
0.37–1.95 1.32–2.67
.689 < .001
BCLC stage B vs A
2.15
0.52–8.84
.288
1.07
0.50–2.29
.860
BCLC stage D vs A
2.21
0.49–9.87
.299
4.95
1.90–12.89
.001
MELD score
1.07
0.94–1.22
.312
1.02
0.92–1.13
.686
ALBI score
3.99
1.70–9.40
.002
2.35
1.43–3.86
.001
Drug delivery method (conventional vs drug-eluting beads)
1.14
0.33–3.88
.834
1.12
0.53–2.38
.770
ACLF ¼ acute-on-chronic liver failure; ALBI ¼ albumin-bilirubin; BCLC ¼ Barcelona Clinic Liver Cancer; CI ¼ confidence interval; CTP ¼ Child-Turcotte-Pugh; HE ¼ hepatic encephalopathy; INR ¼ international normalized ratio; MELD ¼ Model for End-Stage Liver Disease; OR ¼ odds ratio.
increases substantially only beyond an ALBI score > 1, allowing clinicians to offer chemoembolization to patients who would otherwise be denied the procedure using current risk stratification systems or laboratory values alone. The validity of the ALBI grade for providing more granularity has been demonstrated in multiple datasets (4,5). Improved risk stratification with ALBI in patients undergoing transarterial therapies for HCC has also been reported (6,7). In a cohort of all-comers, Hickey et al (6) demonstrated that the ALBI grade provided a greater level of discriminatory ability than the current prognosticators, as evidenced by the distinct survival curves in that population. In another study, Hansmann et al (7) reported the
performance of ALBI grade in predicting overall survival in high-risk patients undergoing conventional transarterial chemoembolization for HCC. Their results similarly indicated that ALBI grade provided an accurate metric of survival, outperforming CTP and BCLC. The present study further broadens the potential role of ALBI grade not only as a useful predictor of overall survival but also as an accurate predictor of chemoembolization-induced ACLF. Although laboratory toxicity is not uncommon after chemoembolization, liver function tests return to baseline within 6 weeks in most instances (14). In contrast to transient transaminitis, ACLF after chemoembolization, often owing to collateral injury to the adjacent, nontumorous liver, carries a
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Figure 2. Prediction curve from logistic regression model for ACLF at 90 days using ALBI scores showing the risk of ACLF is negligible for ALBI scores < 1.5, increases minimally when the ALBI score reaches 1.39 (ALBI grade 3), and increases rapidly as the ALBI score nears 0.
Figure 3. Receiver operator characteristic (ROC) curve showing the area under the curve for ACLF using ALBI score is 0.69 (95% CI, 0.65–0.73) with a sensitivity of 1.00 (95% CI, 0.77–1.00) and specificity of 0.38 (95% CI, 0.31–0.47) for a cutoff value of 1.39 corresponding to ALBI grade 3.
mortality risk of 2%–8% (12–15). In an effort to identify laboratory values obtained before chemoembolization that could serve as predictors of ACLF, this study tested individual
variables, such as serum bilirubin, serum albumin, serum creatinine, and serum sodium. However, similar to prior studies (7,12,13), the results reported here demonstrate that as stand-alone factors, these variables are an inaccurate measure of this outcome. The ability to safely perform chemoembolization in a highrisk population has far-reaching implications. Constrained by the scarcity of donor organs and further limited by uneven geographical distribution of the available organs, wait times for patients listed for orthotopic liver transplantation continue to increase (16). Based on published literature on the role of chemoembolization in impeding tumor progression while awaiting transplantation (17), one could reasonably infer the growing demand for chemoembolization for bridging despite moderate or severe hepatic impairment in regions with long waiting periods for transplantation. Furthermore, even in the absence of transplantation, chemoembolization could provide a survival benefit in carefully selected patients. In the study by Kothary et al, the median survival in patients with limited tumor burden was 623 days compared with 127 days in patients with multifocal disease or extensive tumor burden (13). Thus, treatment decisions based on tumor burden and ALBI grade could help identify patients in whom chemoembolization would carry minimal risk and provide maximal oncologic benefit. This study has limitations. First, it has the limitations of a single-center, retrospective study. Second, observational studies such as this one are limited by operator biases that include choice of agent and technique. Third, this study uses CTP score to stratify risk and to identify the at-risk cohort.
8 ▪ ALBI: Predictor of Decompensation after Chemoembolization
One can argue that differentiating between preserved and decompensated liver function along CTP scores is arbitrary; however, a transition point of CTP score > 8 has been used in prior studies (6) and was used in a similar capacity in this study. Although other variables have been used to identify at-risk groups, these have lacked consensus. Finally, this study excluded patients with ALBI grade 1 and/or preserved liver function (CTP score < 8), thus limiting a comprehensive analysis of factors that lead to chemoembolizationinduced ACLF in all-comers. In conclusion, despite the above-mentioned limitations, the use of the ALBI score can provide an additional layer of risk analysis. This study illustrates that the ALBI score can predict chemoembolization-related ACLF in patients with moderate to severe liver dysfunction and should be used routinely for improved risk stratification.
REFERENCES 1. Brown DB, Fundakowski CE, Lisker-Melman M, et al. Comparison of MELD and Child-Pugh scores to predict survival after chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2004; 15:1209–1218. 2. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60:646–649. 3. Bruix J, Sherman M, American Association for the Study of Liver Disease. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53:1020–1022. 4. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach—the ALBI grade. J Clin Oncol 2015; 33:550–558. 5. Toyoda H, Lai PB, O’Beirne J, et al. Long-term impact of liver function on curative therapy for hepatocellular carcinoma: application of the ALBI grade. Br J Cancer 2016; 114:744–750.
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6. Hickey R, Mouli S, Kulik L, et al. Independent analysis of albuminbilirubin grade in a 765-patient cohort treated with transarterial locoregional therapy for hepatocellular carcinoma. J Vasc Interv Radiol 2016; 27:795–802. 7. Hansmann J, Evers MJ, Bui JT, et al. Albumin-bilirubin and plateletalbumin-bilirubin grades accurately predict overall survival in high-risk patients undergoing conventional transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2017; 28: 1224–1231.e2. 8. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001; 33:1394–1403. 9. de Baere T, Arai Y, Lencioni R, et al. Treatment of liver tumors with Lipiodol TACE: technical recommendations from experts opinion. Cardiovasc Intervent Radiol 2016; 39:334–343. 10. Kim TY, Kim DJ. Acute-on-chronic liver failure. Clin Mol Hepatol 2013; 19: 349–359. 11. National Cancer Institute. Common Terminology Criteria for Adverse Events v4.03. Available at: https://ctep.cancer.gov/protocolDevelopment/ electronic_applications/docs/CTCAE_4.03.xlsx. Accessed August 20, 2018. 12. Kiely JM, Rilling WS, Touzios JG, et al. Chemoembolization in patients at high risk: results and complications. J Vasc Interv Radiol 2006; 17: 47–53. 13. Kothary N, Weintraub JL, Susman J, Rundback JH. Transarterial chemoembolization for primary hepatocellular carcinoma in patients at high risk. J Vasc Interv Radiol 2007; 18:1517–1526; quiz 1527. 14. Chan AO, Yuen MF, Hui CK, Tso WK, Lai CL. A prospective study regarding the complications of transcatheter intraarterial lipiodol chemoembolization in patients with hepatocellular carcinoma. Cancer 2002; 94: 1747–1752. 15. Katsushima S, Inokuma T, Oi H, et al. Acute hepatic failure following transcatheter arterial embolization for the treatment of hepatocellular carcinoma. Digestion 1997; 58:189–195. 16. Yi Z, Mayorga ME, Orman ES, Wheeler SB, Hayashi PH, Barritt AST. Trends in characteristics of patients listed for liver transplantation will lead to higher rates of waitlist removal due to clinical deterioration. Transplantation 2017; 101:2368–2374. 17. Graziadei IW, Sandmueller H, Waldenberger P, et al. Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome. Liver Transpl 2003; 9:557–563.
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APPENDIX A. ALBUMIN-BILIRUBIN (ALBI) SCORE EQUATION The equation to calculate ALBI score is as follows (4): ALBI score ¼ (log10 bilirubin 0.66) þ (albumin 0.085), where bilirubin is in μmol/L and albumin in g/L.
APPENDIX B. CHRONIC LIVER FAILURE– SEQUENTIAL ORGAN FAILURE ASSESSMENT Liver failure was defined by a serum bilirubin level 12.0 mg/dL. Kidney failure was defined by a serum creatinine level 2.0 mg/dL or the use of renal replacement therapy. Cerebral failure was defined by grade III or IV HE, according to the West Haven classification. Coagulation failure was defined by an international normalized ratio > 2.5 and/or a platelet count of 20 109/L. Circulatory failure was defined by the use of dopamine, dobut-
8.e1
amine, or terlipressin. Respiratory failure was defined by a ratio of arterial oxygen partial pressure to fractional inspired oxygen 200 or a ratio of oxygen saturation to fraction of inspired oxygen 200. Based on these criteria, ACLF grades were defined as follows (10): No ACLF—includes the following 3 subgroups: (a) patients with no organ failure; (b) patients with a single nonkidney organ failure (ie, single failure of liver, coagulation, circulation, or respiration) who had a serum creatinine level < 1.5 mg/dL and no HE; and (c) patients with single cerebral failure who had a serum creatinine level < 1.5 mg/dL. ACLF grade 1—includes the following 3 subgroups: (a) single kidney failure; (b) single liver, coagulation, circulatory, or lung failure associated with serum creatinine between 1.5 and 2 mg/dL and/or HE grades 1 or 2; or (c) single cerebral failure with serum creatinine between 1.5 and 2 mg/dL. ACLF grade 2—2 organ failures. ACLF grade 3—3 organ failures.
Albumin-Bilirubin Score: An Accurate Predictor of Hepatic Decompensation in High-Risk Patients Undergoing Transarterial Chemoembolization for Hepatocellular Carcinoma Mohammed A. AbdelRazek Mohammed, MD, Mohamed H. Khalaf, MD, Tie Liang, EdD, David S. Wang, MD, Matthew P. Lungren, MD, Jarret Rosenberg, PhD, and Nishita Kothary, MD
ABSTRACT Purpose: To evaluate validity of albumin-bilirubin (ALBI) grade as a predictor of acute-on-chronic liver failure (ACLF) after transarterial chemoembolization for hepatocellular carcinoma (HCC) in patients with baseline moderate to severe liver dysfunction. Materials and Methods: In this retrospective study, serum albumin and bilirubin levels measured before chemoembolization were used to calculate ALBI score in 123 patients treated with 187 high-risk chemoembolizations. Procedures were considered high risk if Child-Turcotte-Pugh score before chemoembolization was 8. ACLF was objectively measured using chronic liver failure–sequential organ failure assessment score at 30 and 90 d. The 30-day mortality and morbidity from new or worsening ascites and/or hepatic encephalopathy (HE) were assessed. Univariate and multivariate analyses were used to identify clinical and procedural predictors of ACLF in this high-risk population. Results: ACLF occurred after 15 (8%) high-risk chemoembolizations within 30 days and an additional 9 (5%) procedures between 30 and 90 days. Overall 30-day mortality was 2.7%. New or worsened ascites and/or HE occurred after 52 (28%) procedures within 30 days. Significant prognosticators of ACLF at 90 days revealed by univariate analysis were bilirubin (P ¼ .004), albumin (P ¼ .007), and ALBI score (P ¼ .002), with ALBI score remaining statistically significant on multivariate regression analysis (OR ¼ 3.99; 95% CI, 1.70–9.40; P ¼ .002). Conclusions: Chemoembolization for HCC can be performed safely in patients with moderate to severe liver dysfunction. ALBI score before chemoembolization provides objective prognostication for ACLF after chemoembolization in this cohort and may be used for risk stratification.
ABBREVIATIONS ACLF ¼ acute-on-chronic liver failure, ALBI ¼ albumin-bilirubin, BCLC ¼ Barcelona Clinic Liver Cancer, CI ¼ confidence interval, CTP ¼ Child-Turcotte-Pugh, HCC ¼ hepatocellular carcinoma, HE ¼ hepatic encephalopathy, MELD ¼ Model for End-Stage Liver Disease, OR ¼ odds ratio
Risk stratification before transarterial chemoembolization for patients with hepatocellular carcinoma (HCC) and hepatic impairment owing to underlying cirrhosis is challenging. The Child-Turcotte-Pugh (CTP) classification
system is commonly used in clinical practice to identify patients at risk for chemoembolization-related liver decompensation (1), but it was not originally designed for this clinical purpose (2). Its utility is further limited by its
From the Division of Interventional Radiology (M.A.A.M., M.H.K., D.S.W., M.P.L., N.K.), Department of Radiology (T.L., J.R.), Stanford University School of Medicine, 300 Pasteur Drive, H3630, Stanford, CA 94305-5642. Received March 6, 2018; final revision received June 11, 2018; accepted June 21, 2018. Address correspondence to N.K.; E-mail: [email protected]
Appendices A and B can be found by accessing the online version of this article on www.jvir.org and clicking on the Supplemental Material tab.
M.A.A.M. and M.H.K. contributed equally to this study.
https://doi.org/10.1016/j.jvir.2018.06.016
N.K. is a paid advisor for Siemens Healthcare (Erlangen, Germany). None of the other authors have identified a conflict of interest.
© SIR, 2018 J Vasc Interv Radiol 2018; ▪:1–8
2 ▪ ALBI: Predictor of Decompensation after Chemoembolization
reliance, in part, on subjective variables. The Barcelona Clinic Liver Cancer (BCLC) staging system is based on tumor burden and the CTP class as a guideline for treatment options for HCC, but it provides limited insight into the patient’s ability to tolerate liver-directed therapies, offering only palliation in patients with CTP class C (3). In 2015, Johnson et al (4) introduced a model for objective assessment of liver function based on a logarithmic ratio of albumin and bilirubin referred to as the albumin-bilirubin (ALBI) grade. This metric has been validated extensively across geographically diverse patient populations with various liver disease etiologies as a clinically accurate measure of liver dysfunction (5). Recent studies evaluated the prognostic performance of ALBI grade in patients who underwent transarterial therapies for HCC (6,7). However, these studies were limited to the ability of ALBI grade to predict survival. The occurrence of acute-onchronic liver failure (ACLF) after chemoembolization can result in further hepatic decompensation, emergent transplantation, or procedure-related mortality. Thus, the purpose of this study was 2-fold: (i) to identify clinical, laboratory, or procedural predictors of ACLF and (ii) to specifically evaluate the validity of ALBI grade as a predictor of chemoembolization-related ACLF in an at-risk cohort of patients with existing moderate or severe hepatic impairment.
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Table 1. Patient Characteristics (N ¼ 123 Patients) Characteristic Age, y, mean ± SD (range) Sex, male/female
Value 60 ± 6 (48–74) 81 (65.9)/42 (34.1)
Race White
42 (34.1)
Hispanic
38 (30.9)
Asian
13 (10.6)
African American Other Etiology Hepatitis C
4 (3.3) 26 (21.1) 59 (48)
Alcohol
25 (20.3)
Hepatitis C and alcohol
17 (13.8)
Hepatitis B
4 (3.3)
NASH
11 (8.9)
Other
7 (5.6)
Transplantation eligibility Waiting list Ineligible
92 (74.8) 31 (25.2)
Transarterial chemoembolization history Chemotherapy naïve
53 (40.7)
Prior chemoembolization
70 (59.3)
Note–All values except age are number (%). NASH ¼ nonalcoholic steatohepatitis.
MATERIALS AND METHODS This retrospective study was approved by the institutional review board and was compliant with the Health Insurance Portability and Accountability Act.
Patients Consecutive patients with unresectable HCC who underwent chemoembolization between January 2006 and August 2016 were identified using the institutional data archiving system. The dataset was further substratified to identify all patients with decompensated liver function defined by a CTP score 8, as described in prior studies (6). Transarterial liver-directed therapy, including chemoembolization, was considered to be high risk in these patients, and thus they were included in the study. Based on this definition, 187 high-risk chemoembolizations were performed in 123 patients during the study period (65.9% male, mean age 60 y). Of patients, 53 (40.7%) were chemotherapy-naïve, whereas the rest had undergone at least 1 prior chemoembolization (mean ± SD, 3 ±1.3; range, 2–8). Baseline patient demographics are summarized in Table 1.
Preprocedural and Procedural Details The decision to perform a high-risk chemoembolization procedure was made by a multidisciplinary team after considering tumor burden, tumor location, performance status, absence of venous invasion, and liver transplantation waiting list status. Patients were counseled on the risks for ACLF before the procedure. In addition, patients on the
waiting list for liver transplantation were counseled on the possibility of emergent transplantation. Procedures were performed at a single tertiary center by 1 of 5 boardcertified interventional radiologists, with 4–17 years of experience and with particular expertise in interventional oncology. Tumor burden was characterized as focal when within University of California San Francisco criteria (8). Superselective chemoembolization (defined as embolization at a subsegmental or higher order level) was performed in patients with focal disease, whereas sublobar or lobar chemoembolization was performed in patients with tumor burden that exceeded the University of California San Francisco criteria. Complete stasis or the previously described “tree-in-winter” appearance in tumor feeding arteries was used as the embolization endpoint depending on the tumor burden (9). Operator preference and drug availability determined the use of conventional transarterial chemoembolization or chemoembolization with drug-eluting microspheres. Conventional transarterial chemoembolization was performed using 5 mg/mL doxorubicin dissolved in iohexol (Omnipaque 300; GE Healthcare, Waukesha, Wisconsin), emulsified in a 1:1 volume ratio with ethiodized oil (Lipiodol; Guerbet LLC, Bloomington, Indiana) for a maximum delivered dose of 50 mg doxorubicin and 10 mL ethiodized oil. Drug-eluting microspheres (100–300 μm and/or 300–500 μm LC Bead; Biocompatibles/BTG, Farnham, United Kingdom) were reconstituted in iopamidol (Isovue; Bracco Diagnostics Inc., Monroe
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Township, New Jersey) for a maximum delivered dose of 150 mg of doxorubicin.
Data Collection and Outcomes Baseline laboratory data were obtained within 21 days before the procedure. Laboratory values recorded included serum bilirubin, serum albumin, international normalized ratio, platelet count, serum creatinine, and serum sodium. ALBI scores before chemoembolization were calculated using the previously published formula (Appendix A [on the article's Supplemental Material page at www.jvir.org]) (4). ALBI grades were assigned as follows: grade 1, 2.60; grade 2, > 2.60 but 1.39; and grade 3, > 1.39. In addition, CTP class/score, BCLC stage, and MELD score were determined. The presence and severity of chemoembolization-related ACLF were objectively measured using chronic liver failure–sequential organ failure assessment, an algorithm developed by the European Association for the Study of the Liver for systematic grading of ACLF (Appendix B [on the article's Supplemental Material page at www.jvir.org]) (10). The incidence of ACLF was reported at 30 days and at 90 days using laboratory data closest to the 30-day (median, 31 d; SD ± 26) and 90-day (median, 86 d; SD ± 26) time points. Outcomes were analyzed per procedure rather than per patient, as the primary goal of the study was to examine the potential impact of predictors before and during chemoembolization that may vary between individual procedures. However, statistical methods described further on were used to correct any within-patient correlation. Electronic medical records were queried for follow-up clinic visits, emergency department visits, and readmissions and/or admissions to another medical facility (documented by primary physicians or hepatologists). Worsening or new-onset ascites and/or hepatic encephalopathy (HE) within 30 days of the procedure that did not meet ACLF criteria were recorded. Laboratory toxicity, outside of toxicities included for ACLF, was defined as new-onset grade 3 or 4 toxicity for serum bilirubin or international normalized ratio based on the Common Terminology Criteria for Adverse Events (11). Finally, the number of patients listed for liver transplantation successfully bridged to transplantation or remaining on the waiting list was assessed.
Statistical Analysis Descriptive statistics were used to summarize the incidence of ACLF at 30 days and at 90 days. Univariate logistic regression analyses were performed to identify predictors of ACLF and new-onset/worsening ascites and/or HE. As ACLF can occur after any given individual procedure, the analysis was performed on a per-procedure level rather than per patient. However, any within-patient correlation was statistically addressed with clustering. Odds ratios (OR), confidence interval (CI), and significance level were reported for each predictor. The prognostic value of ALBI for prediction of ACLF was visually assessed on a prediction curve
3
generated from the logistic regression model and quantitatively assessed by the area under the curve on a receiver operator characteristic curve, in addition to the sensitivity and specificity at a given cutoff point. All statistical analyses were done using Stata Release 15.0 (StataCorp LP; College Station, Texas). P < .05 was set as the significance level.
RESULTS Summary demographics, tumor characteristics, laboratory data, and procedural details are provided in Tables 1 and 2. Superselective chemoembolization was used in 94.1% of the procedures (n ¼ 176). Conventional chemoembolization was performed in 72% (n ¼ 187) of procedures, whereas drug-eluting microspheres were used in the remaining 28% (n ¼ 53). The mean CTP score before the procedure was 9.2 (range, 8–13, SD ± 1.3) with 32% of the procedures performed in CTP class C patients. The mean serum bilirubin level was 2.4 mg/dL (range, 0.6–12.9 mg/dL) and was > 3 mg/dL for 32% of the procedures. Stratification by ALBI grade before chemoembolization identified 62 (33.2%) chemoembolizations performed in 49 patients with an ALBI grade of 2 and 125 (66.8%) procedures performed in 87 patients with an ALBI grade of 3. There were no patients with an ALBI grade of 1. Of note, 79 (64%) patients who underwent 123 (65.7%) chemoembolizations had ascites before the procedure. Similarly, 71 (58%) patients who underwent 109 (58.2%) chemoembolizations had baseline grade 1 or 2 encephalopathy. Nine patients after 9 chemoembolizations were lost to follow-up, 1 at < 30 days and 8 between 30 and 90 days. Of the 178 chemoembolizations with 90-day follow-up, laboratory data at 30 and 90 days were not available for 4 and 6 procedures, respectively.
ACLF, Mortality, and Morbidity Table 3 summarizes all ACLF events and outcomes. The 30-day ACLF rate, per high-risk chemoembolization, was 8% (n ¼ 15 procedures in 15 patients). Delayed-onset ACLF occurred between 30 and 90 days after an additional 9 chemoembolizations (5%). The 30-day mortality rate from all causes was 2.7% (5 chemoembolizations) in 5 patients (4.1%) and increased to 7.8% at 90 days (in an additional 9 patients, total n ¼ 14 chemoembolizations in 14 patients). Contributing causes of death were ACLF (8 patients), sepsis (2 patients with intact sphincter of Oddi), variceal bleeding (1 patient), multiorgan failure (1 patient); and undetermined cause (2 patients). New or worsening ascites and/or HE was subjectively observed after 52 chemoembolizations (28%) in 44 (36%) patients within 30 days. New-onset grade 3 or 4 Common Terminology Criteria for Adverse Events bilirubin toxicity was noted after 34 chemoembolizations (18.1%), and grade 3 international normalized ratio toxicity was noted after 6 (3.2%) chemoembolizations. A scatter plot of baseline serum bilirubin levels and changes after chemoembolization is illustrated in Figure 1. Finally, of the 92 patients eligible for liver
4 ▪ ALBI: Predictor of Decompensation after Chemoembolization
Table 2. Clinical, Laboratory, and Procedural Variables per High-Risk Chemoembolization (N ¼ 187) Characteristic Tumor burden (%) Focal disease Tumor diameter, cm, mean ± SD Median tumor number Multifocal disease
Value 177 (95) 3.3 ± 1.5 1 10 (5)
Type of embolization (%) Superselective Sublobar or lobar Total serum bilirubin, mg/dL, mean ± SD (range)
2 75 (40)
Median < 3.5 (%) Sodium, mmol/L, mean ± SD (range) Median INR, mean ± SD (range) Median Creatinine, mg/dL, mean ± SD (range) Median CTP score/class, mean ± SD (range) Median Class (%)
61 (32) 2.7 ± 0.41 (1.3–3.7) 3 180 (96) 136 ± 4 (121–145) 137 1.43 ± 0.3 (0.9–4.2) 1.4 1.06 ± 0.4 (0.4–3.6) 1 9.2 ± 1.3 (8–13) 9
A
0 (0)
B
128 (68)
C
59 (32)
BCLC stage (%) 0
0
A
62 (33)
B C
66 (35) 0
D
59 (32)
Calculated MELD score, mean ± SD (range) Median Calculated ALBI score, mean ± SD (range) Median Grade (%)
14.7 ± 3.7 (8–31) 14 1.215 ± 0.399 (2.119 to 0.123) 1.184
1
0 (0)
2
62 (33.2)
3
125 (66.8)
Ascites (%) Absent Present
Characteristic Drug delivery method (%) Conventional chemoembolization Drug-eluting microspheres
Value 134 (72) 53 (28)
ALBI ¼ albumin-bilirubin; BCLC ¼ Barcelona Clinic Liver Cancer; CTP ¼ Child-Turcotte-Pugh; INR ¼ international normalized ratio; MELD ¼ Model for End-Stage Liver Disease.
11 (5.9) 2.4 ± 1.3 (0.6–12.9)
2 (%) 3 (%)
Table 2. Clinical, Laboratory, and Procedural Variables per High-Risk Chemoembolization (N ¼ 187) (continued)
176 (94.1)
Median
Albumin, g/dL, mean ± SD (range)
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64 (34) 123 (66)
Encephalopathy (%) Absent
78 (42)
Present
109 (58) continued
transplant (74.8%), 48 (52%) were successfully bridged to transplantation, 1 patient remains on the waiting list, and an additional 5 patients were successfully maintained on the waiting list for at least 1 year after high-risk chemoembolization (mean, 543 d; range, 400–993 d). Table 4 presents the univariate analysis for predictors of ACLF and new-onset/worsening ascites and/or HE at 90 days. Significant prognosticators of ACLF at 90 days revealed by univariate analysis were bilirubin (OR ¼ 1.52; 95% CI, 1.14–2.03; P ¼ .004), albumin (OR ¼ 0.11; 95% CI, 0.02–0.54; P ¼ .007), and ALBI grade (OR ¼ 3.99; 95% CI, 1.70–9.40; P ¼ .002); however, on multivariate analysis, only the ALBI grade remained statistically significant (P ¼ .002) with an OR of 3.99 (95% CI, 1.70–9.40). The OR for CTP score was 1.07 (95% CI, 0.75–1.54; P ¼ .7). Significant prognosticators for worsening HE and/or ascites included serum albumin (OR ¼ 0.19; 95% CI 0.07–0.48, P < .001), CTP class (OR ¼ 1.88; 95% CI, 1.32–2.67; P < .001), BCLC stage D versus A (OR ¼ 4.95; 95% CI, 1.90– 12.89; P ¼ .001), and the ALBI grade (OR ¼ 2.35; 95% CI, 1.43–3.86; P ¼ .001). Although both CTP score and ALBI grade remained statistically significant on multivariate analysis (P¼0.00 and 0.001, respectively), OR for ALBI score was 2.35 (95% CI, 1.43–3.86) compared with 1.88 for CTP score (95% CI, 1.32–2.67). Figure 2 demonstrates the prediction curve from the logistic regression model for ACLF at 90 days using ALBI scores. The risk of ACLF is low for ALBI scores of < 1.5, increases minimally when the ALBI score reaches 1.39 (ALBI grade 3), and increases rapidly as the ALBI score nears 0. Using a cutoff score of 1.39 (ALBI grade 3), the area under the curve for ACLF was 0.69 (95% CI, 0.65–0.73) with a sensitivity of 1.00 (95% CI, 0.77–1.00) and specificity of 0.38 (95%CI, 0.31–0.47). Approaching a cutoff ALBI value of 1, the area under the curve for ACLF prediction improved to 0.75 (95% CI, 0.62–0.88) with a sensitivity of 0.64 (95% CI, 0.35–0.87) and specificity of 0.73 (95% CI, 0.66–0.80) (Figure 3).
DISCUSSION These results underscore the value of the ALBI score as a prognostic tool for liver failure after chemoembolization for
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5
Table 3. ACLF Events and Outcomes (n ¼ 24 events) Patient
ACLF Grade
Type of Embolization
BCLC Stage
CTP Class
Child Pugh Score
Preprocedure ALBI Score
Preprocedure ALBI Grade
Outcome
ACLF at 30 d 1
2
Selective
D
C
10
0.921
3
Death
2
1
Selective
A
B
9
1.006
3
Death
3
3
Selective
D
C
13
0.382
3
Emergent liver transplant 0.5 month after procedure
4
2
Selective
D
C
10
1.740
2
Emergent liver transplant 0.5 month after procedure
5
3
Selective
D
C
10
0.261
3
Persisted to 90 d
6
2
Selective
B
B
9
1.157
3
Persisted to 90 d, death
7
1
Selective
A
B
8
0.660
3
Persisted to 90 d, death
8 9
1 1
Selective Selective
B D
B C
10 9
1.377 0.884
3 3
Persisted to 90 d Persisted to 90 d, death
10
3
Selective
B
B
9
0.408
3
Persisted to 90 d, death
11
1
Selective
A
B
9
1.479
2
Recovered 1.5 months after procedure
12
1
Selective
D
C
10
0.867
3
Recovered, transplanted 1 month after procedure Recovered 2 months after procedure
13
2
Selective
D
C
10
0.674
3
14
1
Selective
A
B
8
0.745
3
Recovered 1.5 months after procedure
15
3
Selective
D
C
11
0.669
3
Recovered 1 month after procedure
Delayed-onset ACLF 30–90 d 1
2
Selective
B
B
9
0.453
3
Death
2 3
1 1
Selective Selective
D B
C B
11 8
0.596 0.812
3 3
Death Progressed to end-stage liver disease
4
1
Selective
D
C
11
0.493
3
Progressed to end-stage liver disease
5
1
Selective
B
B
9
0.859
3
Persisted, progressed to end-stage liver disease
6
3
Sublobar/lobar
A
B
9
0.456
3
Persisted, progressed to end-stage liver disease
7
3
Selective
D
C
10
0.405
3
8
3
Selective
A
B
9
0.362
3
Recovered, transplanted 4 months after procedure Recovered 3.5 months after procedure
9
1
Selective
B
B
8
0.321
3
Recovered 4 months after procedure
ACLF ¼ acute-on-chronic liver failure; ALBI ¼ albumin-bilirubin; BCLC ¼ Barcelona Clinic Liver Cancer; CTP ¼ Child-Turcotte-Pugh.
patients with HCC and underlying liver disease. In line with prior studies, this study demonstrates that chemoembolization in patients with baseline moderate or severe hepatic impairment carries an acceptable risk of ACLF and 30-day mortality (7,12,13). By confirming the safety of superselective chemoembolization in this high-risk cohort, this study highlights its role as a bridge to liver transplanation, even in the presence of moderate or severe liver impairment, an important consideration in regions with long waiting periods owing to organ shortage. Patients with HCC and moderate to severe liver dysfunction are a challenging population. The BCLC staging system integrates CTP class and tumor burden to provide an algorithmic guide for treatment options (3). However, in this capacity, the BCLC staging system is
limited for patients with moderate to severe liver dysfunction. CTP class C patients are assigned BCLC stage D, restricted to palliation, regardless of the tumor burden. Furthermore, the use of BCLC staging and/or CTP class to predict chemoembolization-related ACLF extends both beyond their primary purposes. Finally, the use of interrelated variables and the subjective nature of 2 of the CTP variables (ascites and HE) are limitations of the CTP system. In short, prognostication of chemoembolization-related ACLF and decompensation is especially difficult in this high-risk patient population. However, as demonstrated in this study, an approach that integrates ALBI grade provides greater insight than individual laboratory tests. In fact, the results of this study demonstrate that even in patients with ALBI grade 3, the risk for ACLF after chemoembolization
6 ▪ ALBI: Predictor of Decompensation after Chemoembolization
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Figure 1. Scatter plot of baseline serum bilirubin levels and change in levels after chemoembolization at 90 days.
Table 4. Univariate Analysis for ACLF and Worsening or New-Onset Ascites/HE at 90 Days ACLF
New or Worsening Ascites/HE
OR
95% CI
P Value
OR
95% CI
Prior chemoembolization
0.68
0.43–1.08
.105
0.95
0.72–1.25
P Value .701
Type of embolization (selective vs sublobar/lobar)
1.24
0.14–11.21
.849
1.03
0.31–3.49
.956
Serum bilirubin
1.52
1.14–2.03
.004
1.23
0.94–1.61
.131
Serum albumin
0.11
0.02–0.54
.007
0.19
0.07–0.48
< .001
Serum sodium
0.95
0.83–1.09
.497
0.93
0.85–1.01
.089
INR
0.88
0.24–3.24
.843
1.36
0.25–7.45
.724
Creatinine CTP score/class
0.95 1.07
0.28–3.23 0.75–1.54
.938 .700
0.85 1.88
0.37–1.95 1.32–2.67
.689 < .001
BCLC stage B vs A
2.15
0.52–8.84
.288
1.07
0.50–2.29
.860
BCLC stage D vs A
2.21
0.49–9.87
.299
4.95
1.90–12.89
.001
MELD score
1.07
0.94–1.22
.312
1.02
0.92–1.13
.686
ALBI score
3.99
1.70–9.40
.002
2.35
1.43–3.86
.001
Drug delivery method (conventional vs drug-eluting beads)
1.14
0.33–3.88
.834
1.12
0.53–2.38
.770
ACLF ¼ acute-on-chronic liver failure; ALBI ¼ albumin-bilirubin; BCLC ¼ Barcelona Clinic Liver Cancer; CI ¼ confidence interval; CTP ¼ Child-Turcotte-Pugh; HE ¼ hepatic encephalopathy; INR ¼ international normalized ratio; MELD ¼ Model for End-Stage Liver Disease; OR ¼ odds ratio.
increases substantially only beyond an ALBI score > 1, allowing clinicians to offer chemoembolization to patients who would otherwise be denied the procedure using current risk stratification systems or laboratory values alone. The validity of the ALBI grade for providing more granularity has been demonstrated in multiple datasets (4,5). Improved risk stratification with ALBI in patients undergoing transarterial therapies for HCC has also been reported (6,7). In a cohort of all-comers, Hickey et al (6) demonstrated that the ALBI grade provided a greater level of discriminatory ability than the current prognosticators, as evidenced by the distinct survival curves in that population. In another study, Hansmann et al (7) reported the
performance of ALBI grade in predicting overall survival in high-risk patients undergoing conventional transarterial chemoembolization for HCC. Their results similarly indicated that ALBI grade provided an accurate metric of survival, outperforming CTP and BCLC. The present study further broadens the potential role of ALBI grade not only as a useful predictor of overall survival but also as an accurate predictor of chemoembolization-induced ACLF. Although laboratory toxicity is not uncommon after chemoembolization, liver function tests return to baseline within 6 weeks in most instances (14). In contrast to transient transaminitis, ACLF after chemoembolization, often owing to collateral injury to the adjacent, nontumorous liver, carries a
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7
Figure 2. Prediction curve from logistic regression model for ACLF at 90 days using ALBI scores showing the risk of ACLF is negligible for ALBI scores < 1.5, increases minimally when the ALBI score reaches 1.39 (ALBI grade 3), and increases rapidly as the ALBI score nears 0.
Figure 3. Receiver operator characteristic (ROC) curve showing the area under the curve for ACLF using ALBI score is 0.69 (95% CI, 0.65–0.73) with a sensitivity of 1.00 (95% CI, 0.77–1.00) and specificity of 0.38 (95% CI, 0.31–0.47) for a cutoff value of 1.39 corresponding to ALBI grade 3.
mortality risk of 2%–8% (12–15). In an effort to identify laboratory values obtained before chemoembolization that could serve as predictors of ACLF, this study tested individual
variables, such as serum bilirubin, serum albumin, serum creatinine, and serum sodium. However, similar to prior studies (7,12,13), the results reported here demonstrate that as stand-alone factors, these variables are an inaccurate measure of this outcome. The ability to safely perform chemoembolization in a highrisk population has far-reaching implications. Constrained by the scarcity of donor organs and further limited by uneven geographical distribution of the available organs, wait times for patients listed for orthotopic liver transplantation continue to increase (16). Based on published literature on the role of chemoembolization in impeding tumor progression while awaiting transplantation (17), one could reasonably infer the growing demand for chemoembolization for bridging despite moderate or severe hepatic impairment in regions with long waiting periods for transplantation. Furthermore, even in the absence of transplantation, chemoembolization could provide a survival benefit in carefully selected patients. In the study by Kothary et al, the median survival in patients with limited tumor burden was 623 days compared with 127 days in patients with multifocal disease or extensive tumor burden (13). Thus, treatment decisions based on tumor burden and ALBI grade could help identify patients in whom chemoembolization would carry minimal risk and provide maximal oncologic benefit. This study has limitations. First, it has the limitations of a single-center, retrospective study. Second, observational studies such as this one are limited by operator biases that include choice of agent and technique. Third, this study uses CTP score to stratify risk and to identify the at-risk cohort.
8 ▪ ALBI: Predictor of Decompensation after Chemoembolization
One can argue that differentiating between preserved and decompensated liver function along CTP scores is arbitrary; however, a transition point of CTP score > 8 has been used in prior studies (6) and was used in a similar capacity in this study. Although other variables have been used to identify at-risk groups, these have lacked consensus. Finally, this study excluded patients with ALBI grade 1 and/or preserved liver function (CTP score < 8), thus limiting a comprehensive analysis of factors that lead to chemoembolizationinduced ACLF in all-comers. In conclusion, despite the above-mentioned limitations, the use of the ALBI score can provide an additional layer of risk analysis. This study illustrates that the ALBI score can predict chemoembolization-related ACLF in patients with moderate to severe liver dysfunction and should be used routinely for improved risk stratification.
REFERENCES 1. Brown DB, Fundakowski CE, Lisker-Melman M, et al. Comparison of MELD and Child-Pugh scores to predict survival after chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2004; 15:1209–1218. 2. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60:646–649. 3. Bruix J, Sherman M, American Association for the Study of Liver Disease. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53:1020–1022. 4. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach—the ALBI grade. J Clin Oncol 2015; 33:550–558. 5. Toyoda H, Lai PB, O’Beirne J, et al. Long-term impact of liver function on curative therapy for hepatocellular carcinoma: application of the ALBI grade. Br J Cancer 2016; 114:744–750.
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6. Hickey R, Mouli S, Kulik L, et al. Independent analysis of albuminbilirubin grade in a 765-patient cohort treated with transarterial locoregional therapy for hepatocellular carcinoma. J Vasc Interv Radiol 2016; 27:795–802. 7. Hansmann J, Evers MJ, Bui JT, et al. Albumin-bilirubin and plateletalbumin-bilirubin grades accurately predict overall survival in high-risk patients undergoing conventional transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2017; 28: 1224–1231.e2. 8. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001; 33:1394–1403. 9. de Baere T, Arai Y, Lencioni R, et al. Treatment of liver tumors with Lipiodol TACE: technical recommendations from experts opinion. Cardiovasc Intervent Radiol 2016; 39:334–343. 10. Kim TY, Kim DJ. Acute-on-chronic liver failure. Clin Mol Hepatol 2013; 19: 349–359. 11. National Cancer Institute. Common Terminology Criteria for Adverse Events v4.03. Available at: https://ctep.cancer.gov/protocolDevelopment/ electronic_applications/docs/CTCAE_4.03.xlsx. Accessed August 20, 2018. 12. Kiely JM, Rilling WS, Touzios JG, et al. Chemoembolization in patients at high risk: results and complications. J Vasc Interv Radiol 2006; 17: 47–53. 13. Kothary N, Weintraub JL, Susman J, Rundback JH. Transarterial chemoembolization for primary hepatocellular carcinoma in patients at high risk. J Vasc Interv Radiol 2007; 18:1517–1526; quiz 1527. 14. Chan AO, Yuen MF, Hui CK, Tso WK, Lai CL. A prospective study regarding the complications of transcatheter intraarterial lipiodol chemoembolization in patients with hepatocellular carcinoma. Cancer 2002; 94: 1747–1752. 15. Katsushima S, Inokuma T, Oi H, et al. Acute hepatic failure following transcatheter arterial embolization for the treatment of hepatocellular carcinoma. Digestion 1997; 58:189–195. 16. Yi Z, Mayorga ME, Orman ES, Wheeler SB, Hayashi PH, Barritt AST. Trends in characteristics of patients listed for liver transplantation will lead to higher rates of waitlist removal due to clinical deterioration. Transplantation 2017; 101:2368–2374. 17. Graziadei IW, Sandmueller H, Waldenberger P, et al. Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome. Liver Transpl 2003; 9:557–563.
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APPENDIX A. ALBUMIN-BILIRUBIN (ALBI) SCORE EQUATION The equation to calculate ALBI score is as follows (4): ALBI score ¼ (log10 bilirubin 0.66) þ (albumin 0.085), where bilirubin is in μmol/L and albumin in g/L.
APPENDIX B. CHRONIC LIVER FAILURE– SEQUENTIAL ORGAN FAILURE ASSESSMENT Liver failure was defined by a serum bilirubin level 12.0 mg/dL. Kidney failure was defined by a serum creatinine level 2.0 mg/dL or the use of renal replacement therapy. Cerebral failure was defined by grade III or IV HE, according to the West Haven classification. Coagulation failure was defined by an international normalized ratio > 2.5 and/or a platelet count of 20 109/L. Circulatory failure was defined by the use of dopamine, dobut-
8.e1
amine, or terlipressin. Respiratory failure was defined by a ratio of arterial oxygen partial pressure to fractional inspired oxygen 200 or a ratio of oxygen saturation to fraction of inspired oxygen 200. Based on these criteria, ACLF grades were defined as follows (10): No ACLF—includes the following 3 subgroups: (a) patients with no organ failure; (b) patients with a single nonkidney organ failure (ie, single failure of liver, coagulation, circulation, or respiration) who had a serum creatinine level < 1.5 mg/dL and no HE; and (c) patients with single cerebral failure who had a serum creatinine level < 1.5 mg/dL. ACLF grade 1—includes the following 3 subgroups: (a) single kidney failure; (b) single liver, coagulation, circulatory, or lung failure associated with serum creatinine between 1.5 and 2 mg/dL and/or HE grades 1 or 2; or (c) single cerebral failure with serum creatinine between 1.5 and 2 mg/dL. ACLF grade 2—2 organ failures. ACLF grade 3—3 organ failures.