Original Article

Yonago Acta medica 2016;59:270–278

The Negative Effect of Preoperative Transcatheter Arterial Chemoembolization
on Long-Term Outcomes for Resectable Hepatocellular Carcinoma: A Propensity
Score Matching Analysis
Masataka Amisaki,* Soichiro Honjo,* Masaki Morimito,* Takehiko Hanaki,* Yosuke Arai,* Naruo Tokuyasu,*
Teruhisa Sakamoto,* Yasufumi Ohuchi† and Hiroaki Saito**Division of Surgical Oncology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504,
Japan and †Division of Radiology, Department of Pathophysiological and Therapeutic Science, School of Medicine, Tottori University
Faculty of Medicine, Yonago 683-8503, Japan

ABSTRACT

neoadjuvant

in the liver remnant complicates 70% of cases at 5 years
after resection, reflecting either intrahepatic metastasis
from the primary tumor or the development of de novo
tumors.3–8 As a result, the 5-year overall survival rate
after curative resection is reported to be 40%–50%.9 To
counter this, several therapies have been administeredprior to surgical resection, in an attempt to improveoverall survival.10–12 Because the efficacy of preoperative therapy before curative resection remains unclear,
there is no preoperative therapy that is currently recommended.
Transcatheter arterial chemoembolization (TACE)
has been used since the beginning of the 1980s as a neoadjuvant therapy to improve long-term survival by preventing cancer cell dissemination and intrahepatic recurrence.13–15 Several reports, including four randomized
controlled trials, failed to demonstrate an improvementin survival rate with the administration of preoperative
TACE.13, 16–18 Other studies, however, presented conflicting results.19–21 Key reasons for the continuing debate are the considerable variation in background factors
and radiological techniques involving HCC in previous
studies and the various improvements in the TACE technique over the period of study. Because TACE has beenshown to offer a survival advantage for patients withunresectable HCC,22, 23 in theory, preoperative TACE
is considered to have positive effects on postoperative
clinical course. Thus, the aim of the present study wasto evaluate the survival benefit of preoperative TACE inpatients who underwent resection of HCC.

Hepatocellular carcinoma (HCC) is the third leading
cause of cancer death worldwide.1 Hepatic resection isconsidered a curative treatment for HCC, and the current
the Japan Society of Hepatology, European Associationfor Study of the Liver and the American Association for
the Study of Liver Diseases guidelines recommend resection as one of the first-line treatments for early stage
HCC.2, 3 However, survival of HCC patients after hepatic resection remains unsatisfactory. Tumor recurrence

Corresponding author: Masataka Amisaki, MD
amisakim@med.tottori-u.ac.jp
Received 2016 September 15
Accepted 2016 October 24
Abbreviations: AFP, alpha-fetoprotein; ALT, alanine transaminase;
AST, aspartate transaminase; CT, computed tomography; HCC,
hepatocellular carcinoma; ICG-R15, rate of indocyanine green disappearance 15 min after injection; IRB, institutional review board;
MRI, magnetic resonance imaging; TACE, transcatheter arterial
chemoembolization

Background

Preoperative transcatheter arterial
chemoembolization (TACE) is administered to improve
long-term outcome after surgical resection of hepatocellular carcinoma (HCC). However, the survival benefitof preoperative TACE is controversial. We conducted aretrospective case-control study to evaluate the effect of
preoperative TACE on prognosis.
Methods A total of 121 patients who underwent curative resection of HCC were divided into two groups
according to whether they received preoperative TACE.
We determined the control group (n = 34) and TACE
group (n = 34) through propensity score matching. The
primary endpoint of this study was overall survival, andthe secondary endpoints were recurrence-free survival.
Results The overall survival rate and the recurrence
free survival rate were significantly lower in the TACE
group than in the control group (P = 0.014 and P = 0.043,
respectively). Furthermore, recurrence free survival
within less than 2 years after resection was significantly
worse in the TACE group than in the control group (P =0.035).
Conclusion Preoperative TACE seemed to worsen
the long-term outcomes of the patients who underwent
surgical resection for the treatment of resectable HCC.
Therefore, preoperative TACE should not be considered
as a standard therapy in patients with resectable HCC.
Key words

surgical resection; survival; hepatectomy;270

Negative effects of preoperative TACE

MATERIALS AND METHODS

classification of chronic hepatitis), tumor recurrence andpatient survival were collected from our database. Tumor recurrence was diagnosed based on the findings ofeither CT or MRI.
Propensity score matching was performed using R
version 3.1.3 software; the grouping variable was preoperative TACE and the matching variables were age,presence or absence of prior treatment, cause of hepatitis, Child–Pugh score, comorbidity (cardio-vasculardisease and diabetes mellitus), serum albumin, bilirubin,
AFP level, platelet count, prothrombin time, ICG-R15,
number of tumors, tumor size, and stage of fibrosis of
nontumor-bearing liver. The stage of fibrosis was the
only histological finding included in this list of variables
because this stage was rarely affected by preoperative
TACE,24 and played an important role in the development of de novo tumors in the remnant liver.25 Because
histological findings concerning the primary tumor in
the TACE group were believed to be affected by preoperative TACE, histological findings were not included in
the list of variables to be matched.

Patients

We used a propensity-based matching case-control design in this study. A series of 189 consecutive patients
who underwent a curative hepatic resection of primary
hepatic cancer at our hospital between January 2004
and December 2012 were included in the current study.
All patients were diagnosed based on contrast-enhanced
computed tomography (CT) or Gd ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (MRI). Intrahepatic cholangiocarcinoma
and combined HCC-cholangiocarcinoma tumors were
excluded based on histological findings in the resected
specimens. Patients with extrahepatic lesions, preoperatively diagnosed as vascular invasion, positive surgicalmargins or macroscopic residuals were also excluded.
Patients who had undergone liver transplantation or
surgical resection combined with ablation therapy werealso excluded. On the basis of this exclusion criteria,
121 patients were eligible in this study. Then, patientswere divided into two groups according to whether they
underwent preoperative TACE or not (the TACE groupand control group). Thirty-four patients who had highly
vascularized HCCs so that were considered to have sensitivity for preoperative TACE by hepatologists assigned
to the TACE group were administered preoperative
TACE for two reasons: to improve long-term outcome (29cases), to be completely cured (5 cases).
Written informed consent was obtained from all patients prior to TACE and surgery. Medical records werereviewed retrospectively after approval by the Institutional Review Board (IRB) of our institution in accordance with the ethical standards laid down in the 1964
Declaration of Helsinki and its later amendments (IRB
approval number: 1606A029).

Statistical analysis

We used R version 3.1.3 software for comparative statistical analysis. All continuous values are presented as
the mean ± standard deviation and the median with interquartile range. Statistical analysis was conducted using
the chi-square test for categorical variables and Welch’s
two-sample t test for continuous variables, with the exception of categorical variables containing factors lessthan 5, which were analyzed using Fisher’s exact test.
Overall survival and recurrence free survival rates were
calculated according to the Kaplan–Meier method andcompared using the Gehan-Breslow-Wilcoxon test. All
P values < 0.05 were considered significant. The primary endpoint of this study was overall survival, and thesecondary endpoints were recurrence-free survival andpostoperative complications.

Variables

Data including patient characteristics [age, sex, bodymass index (BMI), past medical history, presence orabsence of prior local treatment for HCC, cause of hepatitis, Child–Pugh score, serum creatinine, albumin,
total bilirubin, aspartate transaminase (AST), alaninetransaminase (ALT), cholinesterase, platelet count, prothrombin time, rate of indocyanine green disappearance
15 min after injection (ICG-R15)], tumor characteristics[number of tumors, maximum diameter of tumor, alpha-fetoprotein (AFP) level], intra-operative data (extent
of resection, surgical procedure, duration of surgery, intraoperative hemorrhage volume, length of hospital stayafter surgical resection, postoperative complications), tumor pathological findings (histotype and stage of fibrosis
of nontumor-bearing liver according to the new Inuyama

RESULTS
Patient characteristics

Table 1 shows the characteristics of the 121 eligible
patients before matching. Propensity score matching
was carried out using 16 selected patient characteristics,
tumor-related factors and surgical factors. Thirty-four
patients were selected as the control group and included
for further analysis. Tables 2 and 3 detail the clinicopathological characteristics and perioperative clinicaloutcomes, respectively, of the patients included in thecurrent study. There were no significant differencesin patient characteristics and perioperative outcomes
between the control and TACE groups. To determine271

M. Amisaki et al.
Table 1. Patient background before propensity score matching
Control group (87)
Mean, SDMedian [IQR]TACE (34)
Mean, SDMedian [IQR]

P

Age (y)67, s = 10.8
69 [62–74]
71.0, s = 8.5
72.5 [66.8–77.0]
0.036
Prior treatment (%)
17 (20)8 (24)
0.812
Gender (male; %)73 (84)30 (88)0.777
BMI (kg/m²)
22.9, s = 3.0
22.8 [21.1–24.5]
23.1, s = 2.8
24.2 [20.6–25.4]
0.737
Cause of hepatitis (%) NBNC
15 (17)
4 (11)
0.098
HBV
39 (45)10 (29)HCV
24 (28)14 (41)
Alcohol
9 (10)
5 (15)
Other
1 (1)
3 (9)
Child-Pugh score (%) 5
70 (80)26 (76)0.538
613 (15)8 (24)
7
2 (2)
0
8
2 (2)
0
Cardio-vascular
Comorbidity (%)
9 (10)
5 (15)
0.534
diseaseDiabetes
27 (31)
11 (32)
1.000
Creatinine (mg/dL)
17.6, s = 9.1
0.75 [0.66–0.88]
0.78, s = 0.13
0.8 [0.70–0.87]
0.321Albumin (g/dL)
3.9, s = 0.5
4 [3.6–4.3]
3.9, s = 0.42
3.9 [3.7–4.2]
0.504
Bilirubin (mg/dL)
0.73, s = 0.27
0.7 [0.5–0.9]
0.68, s = 0.22
0.7 [0.5–0.8]
0.292
AST (IU/L)
38.5, s = 21.9
31 [23.5–48]
37.8, s = 21.9
33 [26.8–39.0]
0.881
ALT(IU/L)
41.2, s = 46.2
26 [19–46]
36.3, s = 24.7
30 [23.3–39.8]
0.451
Cholinesterase (IU/L)
195.1, s = 74.3
196.5 [135.2–241.5] 205.6, s = 80.0
191.5 [152.8–249.5] 0.510
AFP (ng/mL)
7645.4, s = 39707
9.8 [3.7–80.5]
1251.4, s = 4445.4
10.1 [4.3–110]
0.144
Platelet (/10³μL)
167, s = 63.2
161 [119.5–200.5]
179.5, s = 80.7
172.5 [120.5–213]
0.420
Prothrombin time (%)
86.3, s = 18.0
87.7 [78.1–96.6]
88.8, s = 9.8
90 [81–97.6]
0.340
ICG-R15 (%)
13.5, s = 6.9
13 [9–16]
17.8, s = 13.9
15 [13–20]
0.101
38
(44)
17
(50)
0.851
Non-anatomic
Extent of hepatic
resection (%)
Segmentectomy
14 (16)
4 (12)
Sectorectomy
20 (23)7 (21)
Lobe hepat
14 (16)8 (24)-ectomyHemi-hepat
11 (13)3 (9)-ectomyNumber of tumor (%) 1
69 (79)25 (74)0.758
2
14 (16)8 (24)
3
2 (2)
1 (3)
≥4
2 (2)
0
Maximum diameter
48.7, s = 41.5
30.5 [22–57.3]
40.8, s = 30.0
30 [21.3–48.8]
0.333
(mm)
Histotype (%)
Well
5 (6)
3 (9)
0.106
Moderate
77 (89)26 (76)Poor
3 (3)4 (12)
NA
2 (2)
1 (3)
Fibrosis stagee* (%)
0
19 (22)
1 (3)
0.047
1
23 (26)7 (21)
2
10 (11)8 (24)38 (9)5 (15)
4
24 (28)8 (24)*New Inuyama classification of chronic hepatitis. AFP, alpha-fetoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; ICG-R15, 15-minute retention rates of indocyanine green; IQR, interquartile range; NA, not available;
NBNC, non-HBV non-HCV hepatitis; TACE, transcatheter arterial chemoembolization; y, year(s).

272Negative effects of preoperative TACE
Table 2. Patient background after propensity score matching
Control group (34)
Mean, SDMedian [IQR]TACE group (34)
Mean, SDMedian [IQR]

P

Age (y)71.8, s = 6.7
72.5 [68–75]
71.0, s = 8.5
72.5 [66.8–77.0]
0.647
11 (32)8 (24)
0.588
Prior treatment (%)
25 (74)30 (88)0.217
Gender (male; %)23.6, s = 2.4
23.8 [22.2–25.2]
23.1, s = 2.8
24.2 [20.6–25.4]
0.457
BMI (kg/m²)
8 (24)
4 (11)
0.171
Cause of hepatitis (%) NBNC
15 (38)10 (29)HBV
HCV
10 (29)14 (41)
Alcohol
1 (3)5 (15)
Other
1 (3)
3 (9)
Child-Pugh score (%) 5
27 (79)26 (76)0.765
6 (18)
8 (24)
68
1 (3)0Cardio-vascular
Comorbidity (%)
5 (15)
5 (15)
1.000
diseaseDiabetes
9 (26)
11 (32)0.796
0.80, s = 0.23
0.76 [0.68–0.92]
0.78, s = 0.13
0.8 [0.70–0.87]
0.626
Creatinine (mg/dL)
3.9, s = 0.4
4.0 [3.7–4.2]
3.9, s = 0.42
3.9 [3.7–4.2]
0.815
Albumin (g/dL)
0.70, s = 0.28
0.60 [0.53–0.88]
0.68, s = 0.22
0.7 [0.5–0.8]
0.663
Bilirubin (mg/dL)
40.1, s = 25.2
32 [26–48.3]
37.8, s = 21.9
33 [26.8–39.0]
0.602
AST (IU/L)
34.4, s = 26.0
24 [20–40.1]
36.3, s = 24.7
30 [23.3–39.8]
0.753
ALT(IU/L)
205.1, s = 68.5
203.5[146–250.5]
205.6, s = 80.0
191.5 [152.8–249.5] 0.979
Cholinesterase (IU/L)
3342, s = 19120
5.8 [2.9–21.5]
1251.4, s = 4445.4
10.1 [4.3–110]
0.540
AFP (ng/mL)
181.1, s = 51.8
180.5 [143–217.8]
179.5, s = 80.7
172.5 [120.5–213]
0.923
Platelet (/10³μL)
91.5, s = 14.6
91.4 [80.6–102]
88.8, s = 9.8
90 [81–97.6]
0.396
Prothrombin time (%)
16.4, s = 6.6
14 [12–19.5]
17.8, s = 13.9
15 [13–20]
0.596
ICG-R15 (%)
Extent of hepatic
Non-anatomic
15 (44)17 (50)0.724
resection (%)
7 (21)
4 (12)
Segmentectomy
Sectorectomy
6 (18)
7 (21)
Lobe hepat
5 (15)
8 (24)-ectomyHemi-hepat
5 (15)
3 (9)-ectomyNumber of tumor (%) 1
26 (76)25 (74)0.803
6 (18)
8 (24)
2
3
2 (6)
1 (3)
Maximum diameter
42.3,
s
=
35.7
27
[22–50]40.8,
s = 30.030 [21.3–48.8]
0.851
(mm)
Histotype (%)
Well
1 (3)
3 (9)
0.138
32 (94)26 (76)ModeratePoor0
4 (12)
NA
1 (3)
1 (3)
Necrosis rate (%)≥ 90%
12 (35)89–50%
4 (12)< 50%
18 (53)
Fibrosis stage* (%)
0
4 (12)
1 (3)0.515
8 (24)
7 (21)
1
2
5 (15)
8 (24)
33 (9)
5 (15)
4
11 (32)8 (24)*New Inuyama classification of chronic hepatitis. AFP, alpha-fetoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; ICG-R15, 15-minute retention rates of indocyanine green; IQR, interquartile range; NA, not available;
NBNC, non-HBV non-HCV hepatitis; TACE, transcatheter arterial chemoembolization; y, year(s).

273

M. Amisaki et al.
Table 3. Outcomes of clinical course
Control group (34)
Mean, SDMedian [IQR]TACE group (34)
Mean, SDP

Median [IQR]Time from diagnosis to66.2, s = 7.3
61.2 [33.8–75.5]
83.9, s = 35.0
87.5 [62.5–94.5]
0.134
surgical resection (d)Intraoperative hemor946.7, s = 1135.5
502.5 [197.5–976.2] 935.9, s = 1340.4
392.5 [258.8–995] 0.975
rhage volume (mL)
Operative duration
437, s = 134.8
435 [324–515]
391, s = 150.9
378 [316–457]
0.197
(min)
16
13
0.624
Postoperative compli- Any grade
cation*58
0.537
Grade ≥ 3
Hospital stay (d)24.2, s = 19.7
19.5 [16–22]
20.5, s = 11.3
18 [14.3–22.3]
0.350*According to Clavien-Dindo classification. d, day(s); IQR, interquartile range; TACE, transcatheter arterial chemoembolization.

Table 4. Detail of methodology for preoperative TACE
Prior term (17)Selectivity of hepatic artery (%)

Lobe
Segment
Subsegment or more
Other (1st-branch of right inferior phrenic artery)
Chemotherapeutic agent (%)
Epirubicin
Epirubicin plus mitomycin C
Cisplatin
Miliplatin
NA
Embolic agent (%)
Gelatin sponge
NANA, not available; TACE, transcatheter arterial chemoembolization.

methodological homogeneity of preoperative TACE,
survey period was divided into two terms. Details of
preoperative TACE were shown separately depends on
periods of study in table 4. We also confirmed no significant difference of surgical outcomes between first- andsecond- half period of this study.

2 (12)
4 (24)
10 (59)1 (6)2 (12)
5 (29)
6 (35)
04
12 (71)
5

Latter term (17)
3 (18)
5 (29)
9 (53)0
3 (18)
10 (64)
2 (6)
1 (6)
1
14 (82)
3

P
0.617

0.153

NA

recurrence free survival within less than 2 years was significantly worse in the TACE group than in the control
group (Fig. 3; P = 0.035). With regard to type of surgicalprocedures, there were no significant difference between
anatomical or non-anatomical resection among eachgroups (Fig. 4).
DISCUSSION
Preoperative TACE has been used in the following ways:
as neoadjuvant chemotherapy for resectable HCCs,13
as a conversion therapy for unresectable HCC throughdown-staging,21 to prepare for portal venous embolization to reduce the risk of rapid growth of HCC,26 andwith curative intent prior to salvaging surgical resection.
In the current study, we evaluated the efficacy of TACE
as a neoadjuvant therapy by comparing the prognosis ofpatients who underwent preoperative TACE and those
who did not. The overall 5-year survival rate and therecurrence-free survival rate were significantly lower in
the TACE group than in the control group. These findings clearly indicate that preoperative TACE negatively

Overall and recurrence free survival

Among the 68 patients evaluated by propensity scorematching, tumor recurrence occurred in 37 (54.4%) anddeath from all causes occurred in 26 (38.2%). Figure 1
shows the overall survival rates in the two groups. The
1-, 3-, and 5-year overall survival rates were 97.0%,
93.9%, and 80.5%, respectively, in the control group and87.5%, 62.3%, and 62.3%, respectively, in the TACE
group; the difference was statistically significant (P =0.014). The 1-, 3-, and 5-year recurrence-free survival
rates were 90.8%, 62.6%, and 49.4%, respectively, in thecontrol group and 68.7%, 44.9%, and 44.9%, respectively, in the TACE group (Fig. 2; P = 0.043). Furthermore,
274

Negative effects of preoperative TACE

Recurrence-free survival rates

Overall survival rates
Fig. 1. Overall survival rates of the TACE and control groups.
TACE, transcatheter arterial chemoembolization.

without completely killing poorly differentiated cells
that are related to poor prognosis.28 In the present study,
however, such factors were unlikely to have influenced
the poor prognosis observed in the TACE group because
we performed statistical matching to reduce heterogeneity in patient profiles.
As previously mentioned, there are two types of
intrahepatic recurrence after resection, namely metastasis of the primary tumor and secondary de novo tumor
formation. Recurrence rates also peak twice after resection—recurrence in the early phase (˂ 2 years) is mainly
the result of metastases, whereas recurrence in the latephase (≥ 2 years) is attributable to new lesions.2, 32 Several
studies have demonstrated a higher recurrence rate andlower overall survival in patients who underwent preoperative TACE.18, 29–31 In the present study, recurrence
free survival within less than 2 years was significantly
worse in the TACE group than in the control group,
indicating the possibility that intrahepatic metastasis
occurred more frequently in the TACE group than in
the control group. Therefore, it is possible that increased
early recurrence is related to the poor overall survival
observed in the TACE group in the current study.
Recent studies have revealed that preoperative
TACE may enhance the expression of vascular endothelial growth factor protein, which encourages angiogenesis and results in metastasis.33 TACE may also increase
the expression of a hypoxia-inducible factor that is related to hepatic damage, resulting in carcinogenesis.34–36
These molecular alterations might also be responsible
for the low overall survival and high early-phase recur-

Recurrence-free survival rates

affects the prognosis of patients with potentially resectable HCC. Similar findings have been reported in previous studies.18, 20, 27–31
Several disadvantages of preoperative TACE havebeen postulated. First, it is likely that treatment withTACE delays surgical resection and that preoperative
TACE renders surgical resection more difficult and delays the operation time, resulting in intraoperative tumor
feeding through collateral vessels.20, 27 Another possibility is that TACE mainly affects well-differentiated cells,

MonthsMonthsMonthsFig. 2. Recurrence-free survival rates of the TACE and control
groups. TACE, transcatheter arterial chemoembolization.

Fig. 3. Recurrence-free survival rates within less than 2 years after resection. TACE, transcatheter arterial chemoembolization.

275

Overall survival rates

Recurrence-free survival rates

M. Amisaki et al.

MonthsMonthsFig. 4. Long-term outcomes in both TACE and control group according to operative procedure. A: Overall survival rates. B: Recurrence-free survival rates. AR, anatomical resection; NAR, non-anatomical resection; TACE, transcatheter arterial chemoembolization.

rence rate observed in the TACE group in the current
study.
This study had several limitations. First, histopathological analysis could not be conducted prior to
the interventions; therefore, the two groups could not bematched for histopathological characteristics, which may
have been a confounding factor. Second, the study was
retrospective in design, meaning that there were missing
values for several variables. Finally, the sample size may
have limited the statistical robustness of the results tosome extent. However, consistent results were obtainedin previous studies that support our current findings.
With regard to survival rates in previous reports, 5-year
overall and recurrence-free survival rates in patientswith preoperative TACE were similar to our results.29
Moreover, Roayaie et al reported outcomes of treatments
other than resection among patients who were candidate
for resection.37 Comparing our result to their results,
resection with preoperative TACE may be superior to radiofrequency ablation or TACE but inferior to resection,
so that our result seem plausible.
In conclusion, our results indicated that preoperative
TACE seems to adversely affect the long-term outcomesof patients who underwent surgical resection to treat resectable HCC. Ischemic stimulation of resectable HCC
induced by preoperative TACE might worsen the postoperative clinical course, especially in the early phase.
Therefore, preoperative TACE should not be considered

as a standard therapy for patients with potentially resectable HCC.
The authors declare no conflict of interest.

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