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CLINICAL INVESTIGATION INTERVENTIONAL ONCOLOGY
Long-Term Outcome of Transcatheter Subsegmentaland Segmental Arterial Chemoemobolization Using Lipiodolfor Hepatocellular Carcinoma
Satoshi Takaki • Hiroshi Sakaguchi • Hiroshi Anai • Toshihiro Tanaka •
Kiyosei Yamamoto • Kengo Morimoto • Hideyuki Nishiofuku • Masayoshi Inoue •
Satoru Sueyoshi • Takeshi Nagata • Teruyuki Hidaka • Hideo Uchida •
Kimihiko Kichikawa
Received: 23 February 2011 / Accepted: 16 June 2011 / Published online: 8 July 2011
� Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2011
Abstract
Purpose To clarify the efficacy of transcatheter hepatic
sub-subsegmental, subsegmental, and segmental arterial
chemoembolization using lipiodol (subseg/seg lip-TACE)
for hepatocellular carcinoma (HCC), long-term outcomes
of patients who had been treated using subseg/seg lip-
TACE alone were retrospectively examined.
Materials and Methods Subjects comprised 199 patients
with HCC (T1/2/C3 = 30/108/61; Child–Pugh A/B/
C = 115/52/32; Japan Integrated Staging [JIS] score B1/2/
C3 = 88/64/47) who underwent subseg/seg lip-TACE
using lipiodol mixed with an anticancer drug followed by
injection of gelatin sponge particles. Each patient was
followed-up every 3 months, and repeat subseg/seg lip-
TACE and/or conventional lip-TACE was performed in
cases showing recurrence. One-, 3-, 5-, 7-, and 10-year
cumulative survival rates were calculated. Subgroup anal-
yses were performed by stratifying the population accord-
ing to T-factor, Child–Pugh classification, and JIS score.
Results Median duration of follow-up was 3.8 years
(range 0.2 to 16.4). Median overall survival was 3.8 years.
One-, 3-, 5-, 7- and 10-year survival rates were 91.5, 66.1,
38.8, 20.3, and 9.4% for all patients, and 95.5, 76.9, 51.9,
27.9 and 20.4% for patients with JIS B1, respectively.
Significant survival differences were found across two
subgroups of staging systems (T2 vs. T3B [P = 0.0012]
and JIS score B1 vs. 2 [P = 0.0036]).
Conclusion This study demonstrated that subseg/seg lip-
TACE is a feasible treatment for obtaining prolonged
survival in patients with localized HCC showing rich
vasculature. Outcomes are influenced by both tumor stage
and liver function, as seen in the best prolonged survival in
patients with JIS score B1.
Keywords Hepatocellular carcinoma � Transcatheter
arterial chemoembolization � Subsegmental/segmental
embolization
Introduction
Although local ablation techniques, such as radiofrequency
ablation (RFA), have advanced and are becoming
increasingly prevalent, but trancatheter arterial chemoe-
mobolization (TACE) using iodized oil (lipiodol [lip];
Guerbet, France; distributed by Terumo in Japan) remains
an important therapeutic option for patients with hepato-
cellular carcinoma (HCC) in Japan [1–20, 24–30]. The
widespread use of sub-subsegmental, subsegmental, and/or
segmental lipiodol TACE (subseg/seg lip-TACE) is a
technique used to occlude arterial branches by the infusion
of a lipiodol emulsion containing anticancer drugs fol-
lowed by gelatin sponge (GS) particles into cancer-bearing
sub-subsegmental, subsegmental, and/or segmental seg-
ment arterial branches in the liver [5–20]. This approach
contributes to improved therapeutic outcomes and is
associated with low complication rates. Furthermore,
S. Takaki � H. Sakaguchi � H. Anai (&) � T. Tanaka �K. Yamamoto � K. Morimoto � H. Nishiofuku � M. Inoue �S. Sueyoshi � T. Hidaka � K. Kichikawa
Department of Radiology, Nara Medical University,
Nara 634-8522, Japan
e-mail: [email protected]
S. Takaki
Department of Radiology, Nagaoka Red Cross Hospital,
Niigata 940-2085, Japan
T. Nagata � H. Uchida
Interventional Radiology Center, Daiyukai General Hospital,
Aichi 491-8551, Japan
123
Cardiovasc Intervent Radiol (2012) 35:544–554
DOI 10.1007/s00270-011-0224-9
subseg/seg lip-TACE, in addition to conventional lip-
TACE, is effective in prolonging favorable prognosis in
patients with recurrent HCC encountered after cancer
resection or local ablation [21–23]. Lip-TACE, including
subseg/seg lip-TACE, before RFA is expected to extend
the application of RFA and further improve therapeutic
outcomes [22, 24]. Recently, subseg lip-TACE has been
modified and emphasized as the more effective and useful
therapeutic method for small or localized hypervascular
HCC and has been reported as angiographic subsegmen-
tectomy by Iwamoto et al. [18, 20] and ultraselective
TACE by Miyayama et al. [19], using more skillful
microcatheter techniques that improve on our original
methods [4–9, 11, 13] and those described by Matsui et al.
[10]. In addition, to improve exact catheterization for the
target tumor, various methods, e.g., superselective TACE
for collateral pathways to the recurrent lesion after repeat
TACE, utility of C-arm computed tomography (CT) for
identifying feeding arteries and studies related to variations
of tumor-feeding arteries have been described [25–27].
Lip-TACE, including subseg/seg lip-TACE, has been
generally accepted as an indispensable treatment modality
for HCC in Japan [1–32], but it is typically only evaluated
as a palliative therapy or second-line option for cases in
which surgical resection or ablation therapy, such as RFA,
is contraindicated [21–23, 28–32]. Few reports have
examined efficacy based on long-term outcomes during
5 years after TACE, including subseg/seg lip-TACE
[16, 20]. In Japan, sophisticated improved criteria and
surveys of therapeutic results for HCC have been periodi-
cally reported at intervals of several years. Recently, the
Japan Integrated Staging (JIS) score system, which com-
bines the Child–Turcotte–Pugh classification and tumor-
nodemetastasis (TNM) staging, has been proposed as a
more useful prognostic staging system for HCC by the
Liver Cancer Study Group of Japan (LCSGJ) [31, 32].
Furthermore, two Japanese data sets regarding the value of
TACE, based on studies with large cohorts showing the
present status of TACE for the treatment of unresectable
HCC, have been reported [28, 29]. A recent survey from
the TACE Group of Japan clarified that TACE using lipi-
odol and anticancer agents is the most popular option for
unresectable HCC treatment in Japan [30] based on the
common therapeutic algorithm using surgery or ablation
therapy as the first-choice therapies [21–23, 28–32]. In
contrast, for the purposes of providing better therapeutic
outcomes for TACE, a novel anticancer agent for use
mixed with lipiodol as a hepatic arterial-infusion drug for
HCC has been developed in Japan [33]. In addition, several
new embolic materials, such as drug-delivery beaded
embolic materials and superabsorbent polymer micro-
spheres [34], have been developed and used with favorable
results and are going to be introduced to Japan in the near
future. Under such circumstances, clarification of the long-
term therapeutic outcomes of subseg/seg lip-TACE will be
valuable as basic comparative data and will play an
important role in resolving current unstable situations and
achieving future advances. In this study, therapeutic out-
comes after long-term follow-up of patients who were
treated using only subseg/seg lip-TACE from initial to
repeated treatment during the entire course and who
underwent therapy before the official introduction of RFA
were retrospectively investigated.
Material and Methods
Patient Data Collection and Eligibility Criteria
Data from 199 patients (143 men and 56 women; mean age
65.9 years [range 37–87]) with HCC were retrospectively
analyzed. The diagnosis of HCC in this study was defined
as rich vascular HCC that demonstrated typical character-
istics on several imaging modalities, such as tumor
enhancement on arterial phase of contrast-enhanced CT,
enhanced Doppler ultrasound, and contrast-enhanced
magnetic resonance imaging (MRI), and also indicated
tumor stain on angiography. All patients had been treated
using only subseg/seg lip-TACE as initial treatment at our
hospitals from September 1986 to December 2004. For
recurrences after initial subseg/seg lip-TACE, subseg/seg
lip-TACE was selected as the most suitable therapy. If the
recurrence was multiple and subseg/seg lip-TACE was
inadequate, conventional lip-TACE to the lobar or entire
liver was selected. If the feeding arteries included extra-
hepatic collaterals, collateral lip-TACE was also selected
to repeat treatment during the entire treatment course
[18–20, 25–27]. A summary of clinical characteristics for
all patients is listed on Table 1. The degree of tumor
extension was assessed based on TNM stage by the LCSGJ
(stage I through IV = T1 to T4 factor), and the number of
patients in each stage (T-factor) was as follows: stage I
([T1] solitary lesion B2 cm in diameter) n = 30; stage II
([T2] solitary [2 cm or nonsolitary B2 cm) n = 108; and
stage III or greater ([CT3] more advanced than T2 or with
vascular invasion) n = 61. Grade of hepatic functional
reserve was judged using Child–Pugh classification, and
the number of patients in each classification was as fol-
lows: Child A n = 115; Child B n = 52; and Child C
n = 32. The number of patients with each JIS score, which
combines Child–Pugh classification and TNM staging [31,
32], was as follows: JIS B1 n = 88; JIS 2 n = 64; and JIS
C3 n = 47. All patients fulfilled the following criteria: (1)
definitive diagnosis of rich vascular HCC demonstrating
typical characteristics on several imaging modalities; (2)
no previous treatment for HCC (patients were excluded if
S. Takaki et al.: Subseg/Seg Lip-TACE for HCC 545
123
they had undergone any other treatments for HCC during
the entire course, e.g., hepatic resection, local ablation
therapy, or chemotherapy); and (3) follow-up until death or
at least for[2 years after initial subseg/seg lip-TACE. We
obtained written informed consent from each patient before
each TACE treatment. Institutional Review Board approval
was also obtained for this retrospective study for all par-
ticipating institutions.
Subseg/Seg Lip-TACE Procedures
Subseg/seg lip-TACE was performed by superselective
catheterization by inserting the tip of the microcatheter
(tip diameter 2.3–2.4F) as close as possible to each tumor
within the hepatic sub-subsegmental or subsegmental
arteries supplying the tumor. The basic techniques were the
same as has already been reported [5–11, 18–20]. Super-
selective infusion of lipiodol mixed with an anticancer
drug was slowly performed by hand into the hepatic sub-
subsegmental or subsegmental arteries supplying the
tumor-bearing subsegment using a 1-ml syringe until the
lipiodol had densely accumulated in the tumor, accompa-
nied by slight to moderate visualization of portal branches
around the tumor in almost all cases. Those feeding arteries
visualized were subsequently embolized to decrease arte-
rial flow without complete occlusion using GS particles.
When the tumor was supplied by several sub-subsegmental
or subsegmental arteries and/or those more peripheral
branches, particularly in cases of tumors[3 cm in diameter
and/or multiple tumors (T2 or T3), subseg lip-TACE for
each feeding arterial branch over the subsegmental area
was performed. Such cases were considered as seg lip-
TACE in this study. Furthermore, when tumors were
located in different distant subsegments, subseg lip-TACE
was usually performed for each tumor simultaneously. This
was defined as multisubseg lip-TACE and was also clas-
sified as seg lip-TACE for the purposes of this study.
Basically, subseg lip-TACE was defined as a procedure
only involving the sub-subsegmental artery, subsegmental
artery or that branch, and seg lip-TACE was defined as a
procedure involving two or three sub-subsegmental or
subsegmental arteries at the same time. That is, subseg and
seg lip-TACE were categorized on the basis of the extent of
lip-TACE performed according to the tumor size and
degree of tumor extension, including the number of tumors.
To promote the flow of lipiodol and prevent pain, a
small amount of 2% lidocaine hydrochloride (0.5–1 ml:
25–50 mg [usual total volume 5 ml]) and lipiodol or GS
particles was alternatively injected multiple times using the
‘‘sandwich’’ method into each feeding artery during
injection of lipiodol or GS particles [4, 6, 11, 13].
Preparing Emulsion of Lip and Anticancer Drug
Lipiodol (1–10 ml [usually 3–5 ml]) and epirubicin or
doxorubicin (20–60 mg) were used, with the dosage of
each agent determined based on tumor size and liver
function according to our basic criteria, as reported else-
where [4, 6, 11–13, 30]. Lipiodol emulsion was prepared
by pumping the mixture 20–30 times using a three-way
connector, mixing lipiodol inside one syringe with a small
amount of nonionic contrast medium and saline-dissolved
epirubicin or doxorubicin inside another syringe. The
average dosage (D ml) of lipiodol was basically equal to
the tumor diameter (d cm), with D and d being the same
numbers (D = d). For example, for a tumor 2 cm in
diameter, 3 ml emulsion was created by mixing 1 ml
nonionic contrast medium and saline with 2 ml lipiodol
and 20 mg doxorubicin or epirubicin. Likewise, for a
tumor 5 cm in diameter, 7.5 ml emulsion was created by
mixing 2.5 ml nonionic contrast medium and saline with
5 ml lipiodol and 30–50 mg epirubicin or doxorubicin.
Finally, dosages of anticancer agent and lipiodol were
Table 1 Summary of clinical characteristics for all patients
Characteristics No. of patients
Total no. of patients 199
Sex
Men 143
Women 56
Age (year)
Mean 65.9
Range 37–87
Clinical stage (T)
I 30
II 108
III 59
IV 2
Liver function: Child–Pugh grade
A 115
B 52
C 32
JIS score
0 20
1 68
2 64
3 37
4 10
Repeated TACE
0 69
1 57
2–3 48
4–6 23
[7 2
546 S. Takaki et al.: Subseg/Seg Lip-TACE for HCC
123
varied slightly according to certain factors, such as liver
function, embolized area, and patient age [12, 13].
Follow-up, Diagnosis of Recurrence, and Repeat
Treatment by Subseg/Seg Lip-TACE [4, 6–11]
All patients who were treated by subseg/seg lip-TACE
underwent regular follow-up (usually every 3 months) on
an outpatient basis. Follow-up included physical examina-
tion, tumor marker levels (alpha-fetoprotein [AFP], protein
induced by the absence of vitamin K or antagonist II
[PIVKA II]) and imaging (ultrasonography [US], CT, and/
or MRI). Local recurrence was diagnosed by low density
close to lipiodol accumulated in the tumor, a defect of
lipiodol accumulated in the tumor on plain CT, or tumor
stain consisting of low-density areas or defect regions on
contrast-enhanced CT, MRI and/or US. When recurrence
was observed on imaging diagnosis with occasional
increase of tumor markers (AFP and/or PIVKA II) and
subseg/seg lip-TACE was selected as the most suitable
therapy obtaining written informed consent from each
patient, enrolment of the patient in this study was continued.
Repeated subseg/seg lip-TACE using skillful superselective
or ultrasuperselective techniques and/or additional lip-
TACE was performed for the feeding arteries including
various kind collaterals in addition to the extrahepatic blood
supply feed the recurrent HCC [18–20, 25–27].
Investigated Items and Statistical Analysis
Seven outcomes were assessed as follows: (1) cumulative
survival rates and median survival time (MST) for all
patients after initial subseg/seg lip-TACE; (2) comparison
of cumulative survival rates and MST between subseg lip-
TACE and seg lip-TACE; (3) cumulative survival rates and
MST based on T-factor; (4) cumulative survival rates and
MST based on Child–Pugh classification; (5) cumulative
survival rates and MST based on JIS score; (6) rates of
local recurrence and number of performances of TACE;
and (7) complications.
Dr. SPSS II version 11.01J (SPSS Japan, Tokyo, Japan)
was used for statistical analysis, and survival was analyzed
using Kaplan-Meier survival curves. The log-rank test was
used for comparing groups. In all analyses, the level of
significance was set at P \ 0.05.
Results
The duration of follow-up for the subseg/seg lip-TACE
patient population ranged from 96 to 5975 days. By final
follow-up, 133 patients had died, 47 patients were alive,
and follow-up had been terminated because of a change in
institution for 19 patients. Causes of death were as follows:
liver failure n = 44; cancer n = 48; variceal rupture
n = 11; other diseases n = 15; accident n = 2; and
unknown n = 13. Cumulative survival rates and MSTs for
all patients and for patients grouped according to subseg or
seg lip-TACE, T factor, Child–Pugh classification, and JIS
score are listed in Table 2.
For the overall patient population, survival rates at 1, 3,
5, 7, and 10 years were 91.5, 66.1, 38.8, 20.3, and 9.4%,
respectively, and MST was 3.8 years (95% confidence
interval [CI] 3.4–4.2) (Table 2; Fig. 1). The subseg lip-
TACE group comprised 93 patients, including 25 patients
Table 2 Cumulative survival rates of all patients with subseg and seg lip-TACE, T-factor, Child–Pugh classification, and JIS score classification
No. of
patient
No. of
deaths
Median
(years)/
95% CI
(years)
1 year survival
rate (%)/no. of
survival
patient
3 year survival
rate (%)/no.
of survival
patient
5 year survival
rate (%)/no.
of survival
patient
7 year survival
rate (%)/no.
of survival
patient
10 year
survival rate
(%)/no. of
survival patient
P
All patients 199 133 3.8/3.4–4 2 91.5/182 66.1/111 38.8/43 20.3/17 9.4/6
Seg group 106 73 3.7/3.5–4.0 92.5/98 66.9/63 30.5/17 18.3/9 6.1/2 –
Sub group 93 59 4.4/2.8–6.1 90.3/84 62.9/48 48.4/26 22.5/8 12.9/4 0.4521 (NS)
T-l 30 16 5.3/4.5–6.1 93.3/28 83.2/20 61.5/11 35.1/3 17.6/1 –
T-2 108 68 4.4/3.8–5.0 93.5/101 68.7/61 43.5/26 21.9/11 12.2/5 0.2710 (NS)
T-3 59 46 3.1/2.5–3.7 88.1/52 53.3/29 21.1/6 12.7/3 0/0 0.0012 (\0.05)
T-4 2 2 0.8/– 50/1 50/1 0/0 0/0 0/0 0.5030 (NS)
Child-A 115 68 4.4/3.4–5.5 95.7/110 67.7/65 44.0/27 25.5/11 16.2/5 –
Child-B 52 38 3.7/3.5–3.9 94.2/49 72.6/32 35.3/10 11.9/3 4.0/1 0.1430 (NS)
Child-C 32 26 2.9/1.3–4.5 71.9/23 49.3/14 27.1/6 16.3/3 0/0 0.2545 (NS)
JISO and 1 88 47 5.3/4.2–6.4 95.5/84 76.9/55 51.9/25 27.9/9 20.4/5 –
JIS 2 64 46 3.5/2.9–4.0 96.9/62 62.3/34 33.6/11 15.3/5 5.1/1 0.0036 (\ 0.05)
3 over 47 39 3.3/2.0–4.6 76.6/36 50.7/22 22.8/7 14.3/3 0/0 0.1770 (NS)
S. Takaki et al.: Subseg/Seg Lip-TACE for HCC 547
123
who underwent sub-subseg lip-TACE and 68 patients who
underwent subseg lip-TACE. The seg lip-TACE group
comprised 106 patients, including 72 patients who under-
went seg lip-TACE and 34 patients who underwent mul-
tisubseg/seg lip-TACE. Survival rates at 1, 3, 5, 7, and
10 years for the subseg lip-TACE group were 90.3, 62.9,
48.4, 22.5, and 12.9%, respectively, and MST was
4.4 years (95% CI 2.8–6.1). Survival rates for seg lip-
TACE were 92.5, 66.9, 30.5, 18.3, and 6.1%, respectively,
and MST was 3.7 years (95% CI 3.5–4.0). There was no
significant difference between both groups (Fig. 2;
Table 2). Patients surviving for 10 years were only rec-
ognized in the subseg lip-TACE group. One-, 3-, 5-, 7-, and
10-year survival rates in the T1 group were 93.3, 83.2,
61.5, 35.1, and 17.6%, respectively, and MST was
5.3 years (95% CI 4.5–6.1). Survival rates in the T2 group
were 93.5, 68.7, 43.5, 21.9, and 12.2%, respectively, and
MST was 4.4 years (95% CI 3.8–5.0). The survival rates of
T3B group were 88.1, 53.3, 21.1, 12.7, and 0% respec-
tively and MST was 3.1 years (95% CI 2.5–3.7). A sig-
nificant difference was recognized between the T2 and
T3B groups (T2 vs. T3B, P = 0.0012) (Table 2; Fig. 3).
One-, 3-, 5-, 7-, and 10-year survival rates for the Child A
group were 95.7, 67.7, 44.0, 25.5, and 16.2%, respectively,
and MST was 4.4 years (95% CI 3.4–5.5). Survival rates
for the Child B group were 94.2, 72.6, 35.3, 11.9, and
4.0%, respectively, and MST was 3.7 years (95% CI
3.5–3.9). Survival rates for the Child C group were 71.9,
49.3, 27.1, 16.3, and 0%, respectively, and MST was
2.9 years (95% CI 1.3–4.5). Although survival rates
showed slightly better survival in Child A and B groups
than in the Child C group at 1, 3, and 5 years, no significant
differences were identified between groups (Table 2;
Fig. 4). One-, 3-, 5-, 7-, and 10-year survival rates for the
JIS B1 group were 95.5, 76.9, 51.9, 27.9, and 20.4%,
respectively, and MST was 5.3 years (95% CI 4.2–6.4).
Survival rates in the JIS = 2 group were 96.9, 62.3, 33.6,
15.3, and 5.1%, respectively, and MST was 3.5 years (95%
CI 2.9–4.0). Survival rates in the JIS C3 group were 76.6,
50.7, 22.8, 14.3, and 0%, respectively, and MST was
Fig. 1 Cumulative survival rates of all patients after initial subseg/
seg lip-TACE. The 1, 3, 5, 7, and 10-year survival rates were 91.5,
66.1, 38.8, 20.3, and 9.4%, respectively, and the MST was 3.8 years
(95% CI 3.4 initial cases 4.2)
Fig. 2 Comparison of the cumulative survival rates of after subseg
and seg lip-TACE. The 1, 3, 5, 7, and 10-year survival rates of the
subseg lip-TACE group were 90.3, 62.9, 48.4, 22.5, and 12.9%,
respectively, and the MST was 4.4 years (95% CI 2.8–6.1). Those of
the seg lip-TACE group were 92.5, 66.9, 30.5, 18.3, and 6.1%,
respectively, and the MST was 3.7 years (95% CI 3.5–4.0)
Fig. 3 Comparison of the cumulative survival rates based on T-factor
(T1, T2, T3B). One, 3, 5, 7, and 10-year survival rates of the T1 group
were 93.3, 83.2, 61.5, 35.1, and 17.6%, respectively, and the MST
was 5.3 years (95% CI 4.5–6.1). Those of the T2 group were 93.5,
68.7, 43.5, 21.9, and 12.2%, respectively, and the MST was 4.4 years
(95% CI 3.8–5.0). The survival rates of the T3 group were 88.1, 53.3,
21.1, 12.7, and 0%, respectively, and the MST was 3.1 years (95% CI
2.5–3.7). A significant difference was recognized between the T2 and
T3B groups (T2 vs. T3B, P = 0.0012)
548 S. Takaki et al.: Subseg/Seg Lip-TACE for HCC
123
3.3 years (95% CI 2.0–4.6). Significant differences in
survival rates were seen between the JIS B1 group and
JIS = 2 group (JIS B1 vs. JIS = 2, P = 0.0036) (Table 2;
Fig. 5).
Local recurrence rates for all 199 patients were 46, 58,
and 62% after 2, 3, and 5 years during follow-up. Repeat
TACE for patients with local or intrahepatic distant
recurrence was performed for 130 of 199 patients (65%),
among whom 57 patients (44%) underwent repeat TACE
once; 48 (37%) underwent repeat TACE 2 to 3 times; and
25 (19%) underwent repeat TACE C4 times (Table 1).
Fifty-five (42%) of the 130 patients who underwent repeat
TACE received subseg/seg lip-TACE. The other 75
patients (58%) underwent conventional lip-TACE, com-
bined subseg/seg and conventional lip-TACE, and/or col-
lateral lip-TACE (Table 1; Fig. 6).
Figure 7 illustrates a 50-year-old male patient with
chronic hepatitis (Child–Pugh class A) due to hepatitis C
virus infection who is still surviving 16 years after initial
subseg lip-TACE. His tumor stage was II (T2N0M0), and
his JIS score was 1. Contrast-enhanced CT showed a 3-cm
single hypervascular nodule tumor in subsegment III
(Fig. 7A). CT-arterioportgraphy showed a clearly defined
perfusion defect in the tumor (Fig. 7B). CT–hepatic arte-
riography showed hypervascular tumor (Fig. 7C). Subseg-
mental arteriography by way of A3 showed a hypervascular
tumor, and subseg lip-TACE was performed (Fig. 7D).
Homogeneous and dense accumulation of lipiodol was seen
on plain CT immediately after subseg lip-TACE (Fig. 7E).
Follow-up CT showed partial defect of lipiodol in the
tumor 2 years after initial subseg lip-TACE (Fig 7F). Left
inferior phrenic arteriography showed the tumor stain in
the recurrent portion of the tumor (Fig. 7G). Superselective
arteriography by way of the peripheral branch of left
inferior phrenic artery showed tumor stain (Fig. 7H). Good
lipiodol accumulation was seen on plain CT immediately
after the procedure (Fig. 7I). CT 10 years after initial
Fig. 4 Comparison of the cumulative survival rates of Child A, B,
and C based on Child–Pugh classification. The 1, 3, 5, 7 and 10-year
survival rates of the Child A group were 95.7, 67.7, 44.0, 25.5, and
16.2%, respectively, and the MST was 4.4 years (95% CI 3.4–5.5).
Survival rates of the Child B group were 94.2, 72.6, 35.3, 11.9, and
4.0%, respectively, and the MST was 3.7 years (95% CI 3.5–3.9).
Survival rates of the Child C group were 71.9, 49.3, 27.1, 16.3, and
0%, respectively, and the MST was 2.9 years (95% CI 1.3–4.5)
Fig. 5 Comparison of the cumulative survival rates based on JIS
score classification (JIS B1/2/C3). One-, 3-, 5-, 7-, and 10-year
survival rates for the JIS B1 group were 95.5, 76.9, 51.9, 27.9, and
20.4%, respectively, and the MST was 5.3 years (95% CI 4.2–6.4).
Survival rates in the JIS = 2 group were 96.9, 62.3, 33.6, 15.3, and
5.1%, respectively, and the MST was 3.5 years (95% CI 2.9–4.0).
Survival rates in the JIS C3 group were 76.6, 50.7, 22.8, 14.3, and
0%, respectively, and the MST was 3.3 years (95% CI 2.0–4.6).
Significant differences in survival rates were seen between the JIS B1
group and JIS = 2 group (JIS B1 vs. JIS = 2, P = 0.0036)
Fig. 6 Cumulative local recurrence rates of all patients after initial
subseg/seg lip-TACE. Local recurrence was recognized in 46, 58, and
63% of cases after 2, 3, and 5 years of follow-up, respectively
S. Takaki et al.: Subseg/Seg Lip-TACE for HCC 549
123
Fig. 7 A 50-year-old man with
chronic hepatitis (Child–Pugh
class A) due to hepatitis C virus
infection who is still surviving
16 years after initial subseg lip-
TACE. His tumor stage is II
(T2N0M0), and his JIS score
was 1. A Contrast-enhanced CT
shows a 3-cm single
hypervascular nodule tumor in
subsegment III. B CT-
arterioportgraphy shows a
clearly defined perfusion defect
in the tumor. C CT hepatic-
arteriography shows
hypervascular tumor stain.
D Subsegmental arteriography
by way of A3 shows
hypervascular tumor stain, and
subseg lip-TACE was
performed without any
complication. E Plain CT after
subseg lip-TACE shows dense
accumulation of lipiodol in the
tumor and the surrounding liver.
F Plain CT 2 years after initial
subseg lip-TACE shows a
partial defect of lipiodol in the
tumor, which suggests
recurrence. G Left inferior
phrenic arteriography shows
tumor stain in the recurrent
portion of the tumor.
H Superselective arteriography
by way of the peripheral branch
of left inferior phrenic artery
shows tumor stain. I Good
lipiodol accumulation is seen on
plain CT after lip-TACE. J CT
10 years after initial subseg lip-
TACE shows no signs of local
recurrence, and the tumor has
shrunk and shows little lipiodol
accumulation and a partial low-
density area
550 S. Takaki et al.: Subseg/Seg Lip-TACE for HCC
123
subseg lip-TACE showed no sign of local recurrence, and
the tumor had shrunk and showed decreased lipiodol
accumulation with a partial low-density area (Fig. 7J). The
patient has undergone repeat lip-TACE 10 times for distant
liver recurrence and is still alive 16 years after initial
subseg lip-TACE.
Regarding complications related to TACE, such as
nausea, vomiting, pain, and other complaints reported by
patients during and after subseg/seg lip-TACE, almost all
patients had no complaints. Although most patients usually
had mild fever (\38.0�C) for a few days, fever [38.0�C
was only recognized in a small number of patients with
advanced-stage HCC who underwent TACE of a relative
wide region, and the fevers were usually well controlled
without any severe complaints. With the exception of
unexpected accidents, such as esophageal variceal rupture,
no patients died due to hepatic failure directly related to
subseg/seg lip-TACE during the short-term period
of \ 1 year after the procedure. Almost all patients were
discharged within 7 approximately 10 days after the
procedure.
Discussion
TACE using lipiodol mixed with anticancer agents has
been routinely performed for the treatment of unresectable
HCC in Japan for 25 years [1–20, 24–30] and has been
widely used worldwide not only in Asian countries but also
in European countries, the United States, and other coun-
tries. In addition, we already reported the utility of seg lip-
TACE, including sub-subseg and subseg lip-TACE, to
further enhance the anticancer effects and decrease the
adverse effects on surrounding nontumorous tissues [4–9,
11–13]. These improvements have been adopted by many
physicians [10, 14–20, 42] and are routinely used for
patients with localized hypervascular HCC who are
excluded from hepatic resection or ablation therapy in
Japan. Although lip-TACE, including subseg/seg lip-
TACE, is the most popular option for unresectable HCC
treatment and contributes as an indispensable additional
therapeutic method for recurrence after surgery or RFA,
general evaluations of TACE, including subseg/seg lip-
TACE, have only examined the technique as a palliative
therapy or a second-line option for patients in whom sur-
gical resection or ablation therapy, such as RFA, are con-
traindicated due to advanced or multiple lesions or poor
liver function associated with liver cirrhosis according to
the therapeutic algorithm for HCC in Japan. The only
exception has been a report of TACE as potential first-line
therapy for the treatment of patients with stage I or II HCC
by Iwamoto et al. [18, 20]. However, because TACE,
including subseg/seg lip-TACE, is commonly recognized
as contributing to prolonged survival with favorable
prognosis and thus indispensable for the control of HCC, a
prospective randomized controlled study with reliable
quality was impossible from the perspective of medical
ethical concepts in Japan. In contrast, several randomized
controlled trials using TACE for unresectable HCC have
been conducted in other countries, and all found that TACE
possessed antitumor effects but did not improve prognosis
[35–39]. However, TACE in those trials was performed in
a nonselective manner and was applied periodically irre-
spective of tumor recurrence, a method that is completely
different from the super- or ultrasuperselective catheteri-
zation commonly used in Japan. We think that the most
noticeable causes of those relatively poor results were due
to not only the various backgrounds of HCC but also the
different TACE methods applied compared with our pro-
cedures, including catheter tip position, dose of injected
lipiodol, and interval until repeat TACE. Since those
reports, other randomized controlled studies have sup-
ported the efficacy of TACE for unresectable HCC,
showing superior results to conservative therapies [40, 41].
These discrepancies were explained by a report that
showed increased efficacy and tolerability of TACE when
used selectively and repeated only when necessary on the
basis of follow-up imaging [42].
Comparing survival rates between this study and pre-
vious reports using mainly conventional TACE, the 1-,
3- 5-, and 7-year survival rates for all patients who
underwent subseg/seg lip-TACE in this study were 91.5,
66.1, 38.8, and 20.3%, respectively, and these were better
than the results of not only the early reports [2, 3, 6, 8] but
also of two recent reports, which presumably included a
small number of patients underwent subseg/seg lip-TACE
and showed rates of 82, 47, 26, and 16% at 1, 3, 5, and
7 years, respectively [28], and 81, 46, and 25% at 1, 3, and
5 years, respectively [29]. In particular, our 1-, 3- 5-, and
7-year survival rates for the JIS B1 group were 95.5, 76.9,
51.9, and 27.9%, respectively, markedly better than the
previously cited results. In contrast, our outcomes were
generally almost equal to the survival rates reported for
subseg lip-TACE in several studies [10, 11, 15, 16, 20],
although the survival rates reported by Iwamoto et al. [20]
were greatly superior to those in the present study and other
reports. These differences in outcomes may be attributable
to differences in background factors, such as tumor size,
tumor number, and/or liver function in addition to the
procedures. The method of ‘‘angiographic subsegmentec-
tomy’’ emphasized by Iwamoto et al. [20] involves the
infusion of lipiodol from the sub-subsegmental artery into
the portal vein through drainage vessels of the HCC. Use of
natural arteriovenous shunts or sinusoids has already been
reported as ‘‘medical subsegmentectomy’’ by Matsui et al.
[10], basically representing the same theory and procedures
S. Takaki et al.: Subseg/Seg Lip-TACE for HCC 551
123
described by our group [4–9, 11], Nakamura et al. [5], and
Miyayama et al. [19]. We have already reported the rela-
tion between the histopathology of resected specimens and
the CT pattern of lipiodol accumulation after subseg/seg
lip-TACE, showing complete necrosis of the tumor,
including daughter nodules and capsular invasion, in[80%
patients showing homogenous lipiodol accumulation in and
around the tumor on CT (type 1a) [9]. In addition, as shown
by two reports [12, 13] reporting the optimal dose of lipi-
odol, this evidence helps to justify subsegmentectomy;
recurrence rates were low and survival rates were high for
HCC showing a CT pattern of type 1a after subseg/seg
lip-TACE.
Survival rates did not differ significantly between seg
lip-TACE and subseg lip-TACE groups in this study, even
although survival rates at 5 and 7 years tended to be
slightly better for subseg lip-TACE than for seg lip-TACE,
and MST tended to be slightly longer with subseg lip-
TACE than with seg lip-TACE (Fig. 2; Table 2). Con-
versely, survival rates at 1 and 3 years were greater for seg
lip-TACE than for subseg lip-TACE. These ambiguous
results were attributed to differences in patient back-
grounds between groups, including short-term deaths at
\2 years due to variceal rupture, liver failure, and other
causes in the subseg lip-TACE group. No significant dif-
ference in survival rates was seen among subgroups based
on T-factor and Child–Pugh classification as independent
morphological and functional factors. However, survival
rates based on JIS score, which combines both factors,
showed significant differences among subgroups as verified
by the best prolonged outcomes in the JIS B1 group
(Table 2; Figs. 1, 2, 3, 4, 5).
Although Child class C is usually considered a contra-
indication for TACE, considering that some strictly selec-
ted patients with relatively better physical condition due to
medication before subseg/seg lip-TACE will become an
indication for mild subseg/seg lip-TACE, we were able to
obtain relatively better results in such patients. Mild sub-
seg/seg lip-TACE is the method by which to decrease drug
dose (anticancer agent and lipiodol) as well as the embol-
ized area of TACE according to liver function, and we
must pay more attention and administer intensive medi-
cation in such cases even after mild subseg/seg lip-TACE.
Miyagawa and Kawasaki [21] reported 1-, 3-, and 5-year
survival rates after hepatic resection of 94, 75, and 52% in
patients, respectively. Tateishi reported that survival rates
at 1, 3, and 5 years after RFA were 95, 78 and 54% for
naive patients who received RFA as primary treatment
[22]. Our outcomes obtained from the JIS B1 group were
almost the same as those for hepatic resection and RFA.
Shortcomings and various side effects due to hepatic
resection and ablation therapy cannot be ignored [21–23].
Although hepatic resection is generally defined as the
first-line treatment for HCC, hospitals with high-quality
outcomes are limited, and recurrence rates after hepatic
resection are relatively high. In addition, disadvantages of
hepatic resection include loss of hepatic reserve caused by
decreased hepatic volume due to resection, chronic hepatic
failure, and subsequent increased intrahepatic distant
recurrence during follow-up. Smaller HCCs (\3 cm in
diameter), which represent a contraindication for resection
due to hepatic cirrhosis, are indicated for RFA; however,
RFA has some shortcomings in such cases. When tumors
are located close to important structures, such as the gall-
bladder, alimentary tract, diaphragm, portal vein, or infe-
rior vena cava, RFA is not usually feasible unless
performed by a limited number of doctors with sufficient
skill in advanced procedures. Reported complications for
RFA include massive bleeding due to arterial puncture and
seeding of HCC through the punctured tract [22, 23].
Compared with RFA and surgery, subseg/seg lip-TACE
offers several advantages, such as decreased invasiveness,
with side effects in almost no cases and high effectiveness
for tumors located in marginal regions, particularly those
abutting the diaphragm or gastrointestinal tract, which is a
difficult and dangerous position for RFA procedures. In
addition, even for exophytic hypervascular tumors beyond
the liver margin, which are usually contraindicated for
RFA, lip-TACE by way of collateral pathways from the
extrahepatic blood supply, such as the inferior phrenic
artery, is useful and effective [25–27] (Figs. 7G, H).
Although local recurrence rates after RFA may be slightly
lower than after subseg/seg lip-TACE, local recurrence
after RFA has been recognized, and the intrahepatic distant
recurrence rate is relatively high after RFA [22, 23] and is
usually treated using TACE, including subseg/seg lip-
TACE, in addition to RFA.
Regarding postembolization complications, although
TACE-related mortality rates and rates of complications
from conventional TACE, such as fever C38�C, abdominal
pain, and vomiting, were relatively greater in previous
reports [28, 37, 43], complications of subseg/seg lip-TACE
usually show a low incidence and are mild in our experi-
ence [4–11, 18–20, 43]. Subseg/seg lip-TACE was also
applicable even to patients with HCC who needed to be
treated with a combination of TACE and transjugular
intrahepatic portosystemic shunt for their esophagogastric
varices because of its minimum adverse effects to hepatic
functional reserves [44]. Because uncommon bile duct
stricture occurring after TACE has been reported [45], and
because we have also experienced a case associated with
partial bile duct dilatation without symptoms after subseg/
seg lip-TACE, relatively mild subseg/seg lip-TACE
suitable for each individual patient is recommended.
Postembolization fever (PEF), defined as a body tempera-
ture[38�C after chemoembolization in patients with HCC,
552 S. Takaki et al.: Subseg/Seg Lip-TACE for HCC
123
correlates strongly with large tumor size and develops in
only 4.8% of patients with tumor size \5 cm, which is
significantly lower than in patients with tumor size [5 cm
[41]. The incidence of PEF in the present investigation was
lower than that reported in the previously mentioned study
because tumors in our cohort were relatively smaller and
the embolized area was localized to the tumor-bearing
region. Abdominal pain during or after subseg/seg lip-
TACE is mild compared with that after RFA and is not
usually reported by patients.
Recently, combining therapies with TACE, including
subseg/seg lip-TACE, and RFA has gained attention as a
useful therapy for initial treatment. Yamakado et al. [24]
reported excellent survival rates after combined TACE and
RFA, similar to outcomes after hepatectomy. In terms of
the future of subseg/seg lip-TACE, the number of pure
subseg/seg lip-TACE procedures seems likely to decrease
with wider use of RFA and RFA combined with lip-TACE,
but subseg/seg lip-TACE will remain an important and
useful therapeutic option with the development of new
intra-arterial therapies using lipophilic platinum deriva-
tives, drug-eluting beads, and radioactive beads [33, 34].
In this study, although patients who underwent ablation
therapy for recurrent lesions during follow-up were
excluded to limit evaluations to pure subseg/seg lip-TACE,
improved outcomes might be expected by including
patients undergoing RFA for recurrent HCC after subseg/
seg lip-TACE.
Subseg/seg lip-TACE showed excellent outcomes for
patients with JIS B1, in which almost cases will be indi-
cated for surgery and/or RFA therapy. We believe that
subseg/seg lip-TACE may still be a useful and feasible
initial treatment for obtaining prolonged survival in
patients with localized HCC showing rich vasculature.
Conflict of interest None.
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