DOI:10.1093/jnci/djs464
Advance Access publication November 12, 2012
© The Author 2012. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: [email protected].
Article
Roles Played by Chemolipiodolization and Embolization in
Chemoembolization for Hepatocellular Carcinoma: Single-Blind,
Randomized Trial
Ming Shi, Li-Gong Lu, Wan-Qiang Fang, Rong-Ping Guo, Min-Shan Chen, Yong Li, Jun Luo, Li Xu, Ru-Hai Zou, Xiao-Jun Lin,
Ya-Qi Zhang
Manuscript received June 25, 2012; revised September 17, 2012; accepted September 17, 2012.
Correspondence to: Ming Shi, MD, Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, P.R. China (e-mail:
[email protected]).
Background
The aim of our study was to compare the efficacy and safety of: 1) transarterial chemolipiodolization with gelatin sponge embolization vs chemolipiodolization without embolization, and 2) chemolipiodolization with triple
chemotherapeutic agents vs epirubicin alone.
Methods
A single-blind, three parallel arm, randomized trial was conducted at three clinical centers with patients with
biopsy-confirmed unresectable hepatocellular carcinoma. Arm 1 received triple-drug chemolipiodolization and
sponge embolization, whereas Arm 2 received triple-drug chemolipiodolization only. Patients in arm 3 were
treated with single-drug chemolipiodolization and sponge embolization. We compared overall survival and time
to progression. Event–time distributions were estimated by the Kaplan–Meier method. All statistical tests were
two-sided.
Results
From July 2007 to November 2009, 365 patients (Arm 1: n = 122; Arm 2: n = 121; Arm 3: n = 122) were recruited.
The median tumor size was 10.9 cm (range = 7–22 cm), and 34.5% had macrovascular invasion. The median survivals and time to progression in Arm 1, Arm 2, and Arm 3 were 10.5 and 3.6 months, 10.1 and 3.1 months, and
5.9 and 3.1 months, respectively. Survival was statistically significantly better in Arm 1 than in Arm 3 (P < .001),
whereas there was no statistically significant difference between Arm 1 and Arm 2 (P = .20). Objective response
rates were 45.9%, 29.7%, and 18.9% for Arm 1, Arm 2, and Arm 3, respectively.
C
onclusions
Chemolipiodolization played an important role in transarterial chemoembolization, and the choice of chemotherapy regimen may largely affect survival outcomes. However, the removal of embolization from chemoembolization might not statistically significantly decrease survival.
J Natl Cancer Inst 2013;105:59–68
Transarterial chemoembolization (TACE) is the most widely
used palliative treatment for hepatocellular carcinoma (HCC)
patients (1). The advantage of TACE over supportive care has been
reported in two randomized controlled trials (2,3). Classic TACE
is composed of chemolipiodolization (local delivery of chemotherapy agents emulsified with lipiodol) and embolization. In theory,
chemolipiodolization and embolization have synergistic antitumor effects: the former causes high intratumoral concentrations of
cytotoxic drugs, and the latter cuts off blood supply to the tumor.
However, this theory has been challenged by many
clinicians because there is no convincing evidence to clarify the
mechanism by which TACE improves patient survival. Some
think chemolipiodolization plays a major role and embolization
might do more harm than good. Therefore, embolization should
not be used to maintain long-term arterial patency, and the
treatment sessions should be repeated at 3 week intervals (4–10).
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Conversely, others believe that embolization plays a key role
and chemolipiodolization has no effect but leads to side effects.
Therefore complete embolization should be administered in the
initial treatment, and chemotherapy should be limited to reduce
toxic effects (11–15). As a result, TACE protocols, including
regimens, delivery methods, and treatment intervals, vary among
global medical centers, and there is no doubt that some of these
protocols are not as effective as others (16). Therefore, we
performed a trial to compare the safety and efficacy of 1) TACE
with gelatin sponge embolization vs chemolipiodolization without
embolization and 2) TACE with multiple chemotherapeutic agents
vs a single agent alone. Three transarterial regimens were studied:
triple-drug chemolipiodolization with embolization, triple-drug
chemolipiodolization without embolization, and single-drug
chemolipiodolization with embolization. The first regimen was
selected as the reference arm.
JNCI | Articles 59
We used epirubicin as the single-agent chemotherapy regimen.
The most common chemotherapeutic drug used for TACE is doxorubicin/epirubicin, followed by cisplatin and mitomycin. However,
a number of chemotherapeutic agents have been used, and controversy exists about the selection of the most appropriate drug
(16). We used epirubicin, lobaplatin (a third-generation platinum
analogue), and mitomycin as a triple-agent chemotherapy regimen.
Cisplatin was replaced by lobaplatin because the latter has been
reported to have reduced toxicity, a better therapeutic index, and
much higher solubility (17–19). In this study, we used fixed-dose
chemotherapy, and the dose was based on previous studies (16,20).
Methods
Patients and Study Design
We undertook a multicenter, single-blind, randomized, parallel
group clinical trial between July 2007 and November 2010 in three
medical centers in southern China. The study was approved by the
institutional review board at each center and complied with the provisions of the Declaration of Helsinki. All patients provided written
informed consent before enrollment in the study. The study has
been registered at http://ClinicalTrials.gov (No. NCT00493402).
Patients with histologically confirmed HCC with unresectable
disease without extrahepatic metastases were assessed for eligibility
(Figure 1). The Barcelona Clinic Liver Cancer (BCLC) system and
Cancer of the Liver Italian Program classifications were used for
staging (1,21). Eligibility criteria also included: 1) age between 18
and 75 years; 2) main tumor size greater than 7 cm; 3) HCC with
no previous treatment; 4) adequate hematologic function (platelet
count: >60 × 109 platelets/L; hemoglobin: >8.5 g/L; and prothrombin time: <3 seconds above control); 5) normal liver or Child-Pugh
A liver cirrhosis with adequate hepatic function (albumin: ≥3.5 g/L;
total bilirubin: ≤1.5 mg/L; and alanine aminotransferase and aspartate aminotransferase: ≤5 × upper limit of normal); 6) adequate
renal function (serum creatinine: ≤1.5 × upper limit of normal);
and 7) Eastern Co-operative Group performance status of zero or
one (22). Patients were excluded from the study if they had one or
more of the following: 1) a hypovascular tumor (defined as a tumor
with all its parts less contrast-enhanced than the nontumorous liver
parenchyma on arterial phase computed tomography scans); 2) diffuse-type HCC; 3) evidence of hepatic decompensation including
esophageal or gastric variceal bleeding or hepatic encephalopathy;
4) severe underlying cardiac or renal diseases; 5) color Doppler
ultrasonography showing portal vein tumor thrombosis with complete main portal vein obstruction without cavernous transformation; or 6) obstructive jaundice. The patients remained blinded
to the TACE regimen received. During the TACE procedure, a
radiation shield encased in a sterile towel was placed between the
patient’s eyes and the operator. The attending staff was instructed
not to reveal the identity of the TACE regimen to the patient.
Randomization and TACE Procedure
The interval from pretreatment evaluation to random assignment
was limited to no more than 2 weeks. TACE was performed using
the techniques we have described previously (23). In brief, depending on size, location, and arterial supply to the tumor, the tip of
the catheter was advanced into the segmental artery or specific
60 Articles | JNCI
tumor-feeding artery. After that, patients were randomly allocated
to a treatment group by opening a sealed envelope containing their
randomly assigned treatment group. The computer-generated randomization sequence was created by an independent organization
with a 1:1:1 allocation, and was stratified by three centers, BCLC
stage (stage B vs stage C), and tumor size (≤10 cm vs >10 cm). For
two centers, the random block size for each stratum was 9 and
18. For the third center, where the subject recruitment rate was
expected to be lower, the random block size for each stratum was 6
and 12. The three treatment groups were as follows:
1. Arm 1 received triple-drug chemolipiodolization with embolization. Lobaplatin (50 mg), epirubicin (50 mg), and mitomycin C (6 mg) were mixed in 9 mL of water-soluble contrast
medium and 1 mL of sterile water for injection. The mixture
was thoroughly mixed with 10 mL of lipiodol. After injection of the emulsion, 20 mL of pure lipiodol were injected.
The injection was stopped either at the point of near stasis
within the main artery feeding the tumor or after the entire
amount of the above agent was administered. The actual volume administered was recorded. After that, embolization was
performed with injection of gelatin-sponge particles 500 to
1000 μm in diameter through the catheter to reach stasis in
the tumor-feeding artery.
2.Arm 2 received triple-drug chemolipiodolization without
embolization. Chemolipiodolization was performed with the
same combined regimen without gelatin-sponge embolization.
3. Arm 3 received single-drug chemolipiodolization with embolization. Treatment was the same as for Arm 1, except that
only a single-drug, epirubicin (50 mg), was used.
Study Endpoint
The primary endpoint was the comparison of overall survival
among the different treatment arms. After inclusion of the last
patient in the study, a follow-up period of 12 months was scheduled.
Follow-up ended on December 1, 2010. The secondary outcome
was the time to radiological progression (TTP), which was defined
as the time from random assignment to disease progression.
Statistical Analysis
For comparisons of baseline variables, the Student’s t test for
continuous variables and the χ2 test for categorical variables were
used. Treatment response and survival time were determined on an
intent-to-treat basis. The survival curves and univariable analysis
were calculated by the Kaplan–Meier method and compared using
a log-rank test. Any factors that were statistically significant at P
less than .10 in the univariate analysis were candidates for entry
into a multivariable Cox proportional hazards model, the results
of which are presented for the last step of the reverse selection
of random variables. The proportional hazard assumption was
checked by graphical inspection of the linearity of the hazards over
time and log−log plots and by plotting Schoenfeld residuals over
time. P values less than .05 were considered statistically significant.
All statistical tests were two-sided. We analyzed the data for
differences by sex but did not analyze ethnicity data. All statistical
processing was performed by the Statistical Package for Social
Science version 13.0 (SPSS Inc., Chicago, IL).
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Figure 1. CONSORT flow diagram. TACE = transarterial chemoembolization.
Results
Patient Characteristics
From July 2007 to November 2009, 381 patients were registered
for the study; 16 (4.2%) patients were excluded because the TACE
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procedure could not be accomplished (Figure 1). In total, 122, 121,
and 122 patients were allocated to Arm 1, Arm 2, and Arm 3, respectively. The data from these patients were included in all subsequent
analyses. The median tumor size was 10.9 cm (range = 7–22 cm).
JNCI | Articles 61
Table 1. Baseline characteristics and univariable analysis for all recruited patients*
Baseline characteristics analysis
Characteristic
Sex
Men
Women
Age, y
≤50
>50
Neutrophil:lymphocyte ratio
≤3
>3
Platelet count, 109/L
≤100
>100
Prothrombin time, s
≤14
>14
Hepatitis B surface antigen
Positive
Negative
HBV DNA, copy
≤1000
>1000
Alanine aminotransferase, U/L
≤40
>40
Aspartate aminotransferase, U/L
≤45
>45
Alkaline phosphatase, U/L
≤110
>110
Glutamyl transpeptidase, U/L
≤100
>100
Serum albumin, g/L
≤37
>37
Total bilirubin, mol/L
≤20
>20
Alpha-fetoprotein, ng/mL
≤200
>200
Indocyanine green retention rate in 15 min, %
≤10
>10
Liver cirrhosis
No cirrhosis
Child A
Tumor size, cm
≤10
>10
Tumor number
Single
Multiple
Portal vein tumor thrombus
Absence
Presence
Other vascular invasion
Absence
Presence
Arm 1,
n = 122
Arm 2,
n = 121
Arm 3,
n = 122
Univariable analysis
P†
No.
Median survival
time, months
.31
115
7
113
8
109
13
77
45
68
53
72
50
72
50
72
49
70
52
8
114
7
114
16
106
109
12
106
15
100
21
114
8
102
19
114
8
45
77
46
75
43
79
40
82
49
72
41
81
24
98
34
87
23
99
49
73
57
64
43
79
35
87
30
91
35
97
27
95
23
98
35
87
97
25
93
28
93
29
43
79
45
76
41
81
108
14
104
17
100
22
52
70
58
63
53
69
46
76
58
63
53
69
49
73
51
70
53
69
82
40
80
41
77
45
113
9
113
8
113
9
P‡
.07
337
28
8.3
12.4
217
148
7.2
11.9
214
151
10.9
5.9
31
334
9.1
8.3
315
48
8.9
7.2
330
35
8.1
12.2
134
231
9.3
8.1
130
235
8.4
8.3
81
284
12.4
7.6
149
216
10.4
7.6
90
275
14.2
7.3
85
280
7.0
9.5
283
82
9.7
5.6
129
236
12.8
6.8
312
53
8.4
7.2
163
202
8.4
8.3
157
208
10.9
7.4
153
212
8.7
8.3
239
126
11.9
5.4
339
26
8.7
7.2
.54
.001
.94
.001
.08
.83
.50
.04
.02
.06
.90
.15
.39
.54
.16
.007
.17
.05
.33
<.001
.19
.001
.81
.001
.84
<.001
.57
.73
.90
.58
.27
.007
.27
.78
.76
<.001
.90
.83
(Table continues)
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Vol. 105, Issue 1 | January 2, 2012
Table 1. (Continued)
Baseline characteristics analysis
Characteristic
Ascites
Absence
Presence
CLIP stage
≤2
>2
BCLC stage
Stage B (intermediate)
Stage C (advanced)
Arm 1,
n = 122
Arm 2,
n = 121
Arm 3,
n = 122
Univariable analysis
P†
Median survival
time, months
No.
.54
115
7
110
11
111
11
61
61
70
50
72
50
82
40
80
41
77
45
P‡
.19
336
29
8.6
7.0
203
161
9.3
8.2
239
126
11.9
5.4
.29
.42
.79
<.001
* Arm 1 = three-drug chemolipiodolization with embolization; Arm 2 = three-drug chemolipiodolization without embolization; Arm 3 = single-drug chemolipiodolization
with embolization. BCLC = Barcelona Clinic Liver Cancer; CLIP = Cancer of the Liver Italian Program; HBV = hepatitis B virus.
† P value was calculated by a two-sided χ2 test.
‡ P value was calculated with two-sided log-rank test.
One patient in Arm 1, two patients in Arm 2, and one patient in
Arm 3 were lost to follow-up. One patient in Arm 2 died in a traffic
accident. Their data were censored at the time of their last followup visit (12.7, 5.2, 22.6, 17.1, and 22.5 months after randomization, respectively). Table 1 shows the baseline characteristics of all
recruited HCC patients. The only difference between arms was
that Arm 2 had fewer patients with positive hepatitis B surface antigen (P = .02).
Treatment Administration
Among all 365 patients, a mean of 1.61 study TACE sessions
(range = 1–6 sessions; total = 592 sessions) was performed. There
was no statistically significant difference in lipiodol administered in
each TACE session among the three arms (21.6 ± 8.2 ml in Arm 1,
20.3 ± 7.0 ml in Arm 2, 19.4 ± 6.6 ml in Arm 3; P = .06). The study
TACE sessions and subsequent treatments administered in each arm
are listed in Table 2. There was no statistically significant difference
in the number of study treatment sessions among the three arms
(Arm 1 vs Arm 2: P = .88; Arm 1 vs Arm 3: P = .11), and there was
also no statistically significant difference in the number of subsequent treatment sessions between Arm 1 and Arm 2 (P = .11). There
was, however, a statistically significant difference in the number of
subsequent treatment sessions between Arm 1 and Arm 3 (P = .009).
Mortality and Morbidity
One patient in Arm 3 died of bleeding caused by tumor rupture
on day 2 after first TACE. Another patient in Arm 1 died of irreversible liver failure on day 14 after second TACE. The in-hospital
mortality rate was 0.3%, and the 1-month mortality rate was 0.3%.
The average length of stay in hospitals after every study TACE session in Arm 1, Arm 2, and Arm 3 was 6.1 (range = 3–30) days, 5.6
(range = 2–21) days, and 5.7 (range = 2–21) days, and there was no
statistically significant different between Arm 1 and Arm 2 (P = .11)
or Arm 1 and Arm 3 (P = .30). Twenty-two (18.0%), 16 (13.2%),
and 12 (9.8%) patients experienced adverse events of at least grade
3 in Arm 1, Arm 2, and Arm 3, respectively. There was no statistically significant difference in the severe adverse event rate between
Arm 1 and Arm 2 (P = .22) or between Arm1 and Arm 3(P = .10).
Table 3 shows the incidence of complications.
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Table 2. Treatment numbers administered for each arm*
Types of Treatment
Study TACE sessions
Subsequent treatments
Hepatic resection
Radiofrequency ablation
TACE
Sorafenib
Antiviral therapy
Arm 1,
n = 122
Arm 2,
n = 121
Arm 3,
n = 122
211
201
180
15
32
33
7
12
10
21
10
6
15
9
6
15
9
10
* Arm 1 = three-drug chemolipiodolization with embolization; Arm
2 = three-drug chemolipiodolization without embolization; Arm 3 = singledrug chemolipiodolization with embolization; TACE = transarterial
chemoembolization..
Tumor Response
The tumor response among patients in the study is shown in
Table 4. Objective response rates were 45.9%, 29.7%, and 18.9%
for Arm 1, Arm 2, and Arm 3, respectively.
Time to Progression
Eighty-two patients (n = 33 patients in Arm 1, n = 24 patients in
Arm 2, and n = 25 patients in Arm 3, respectively) who could not
be evaluated for TTP because their tumor was removed by resection or ablation or becaseu of death, poor performance, or patients’
refusal of further computed tomography scans. These patients
were excluded from the analysis of TTP. The median TTP was
3.6 months (95% confidence interval [CI] = 2.4 to 4.8), 3.1 months
(95% CI = 1.6 to 4.5), and 3.1 months (95% CI = 2.0 to 4.2) in
Arm 1, Arm 2, and Arm 3, respectively. In univariable analysis, there
was no statistically significant difference in TTP between Arm 1
and Arm 2 (P = .43), whereas the TTP was statistically significantly
longer in Arm 1 than in Arm 3 (P = .03). However, in Cox multivariable analysis model, there was no statistically significantly difference in TTP among these three arms (Table 4).
Survival Outcomes (Intention-to-Treat Analysis)
At the time of analysis, the median survival time was 8.4 months
(range = 1–40 months), and 295 patients had died, including 97
JNCI | Articles 63
Table 3. Number of complications that occurred in studied transarterial chemoembolization sessions*
Arm 1, n = 211
Incidence of
complications
Any grade
Postembolization syndrome‡
Fever
Pain
Vomiting
Blood‡
Platelets
Hemoglobin
Leukocytes
Liver function change‡
Ascites/pleura effusion
Edema: limb
Liver dysfunction
Renal failure
Bleeding
Arm 2, n = 201
Arm 3, n = 180
P†
Arm 1 vs Arm
2 (any grade)
Arm 1 vs Arm
3 (any grade)
0
0
3
.28
.41
.35
.10
.59
.46
18
3
1
11
2
0
.90
.40
.75
.16
.30
.24
11
6
34
0
1
0
0
0
0
1
.92
.69
.16
.17
.59
.29
.21
.33
.19
.66
Grade 3–5
Any grade
Grade 3–5
Any grade
151
102
50
3
0
12
134
89
40
1
0
11
142
92
37
13
7
4
10
7
2
13
4
3
3
3
0
8
3
32
2
2
0
0
1
2
1
8
2
41
0
1
0
0
0
0
0
Grade 3–5
* Arm 1 = three-drug chemolipiodolization with embolization; Arm 2 = three-drug chemolipiodolization without embolization; Arm 3 = single-drug chemolipiodolization
with embolization.
† P value was calculated by a two-sided χ2 test.
‡ Postembolization syndrome or blood change or liver function change might include more than one complication item.
Table 4. Summary of patients outcomes*
P
Outcome
Overall survival, months
Median
95% CI
Time to radiological progression, months
Median
95% CI
Tumor response evaluation, %
Objective response
Complete response
Partial response
Stable disease
Progressive disease
Not evaluated§
Arm 1, n = 122
Arm 2, n = 121
Arm 3, n = 122
10.5
8.3 to 12.8
10.1
6.0 to 14.0
5.9
4.2 to 7.6
3.6
2.4 to 4.8
3.1
1.6 to 4.5
3.1
2.0 to 4.2
45.9
0
45.9
25.4
23.8
4.9
29.7
0.8
28.9
34.7
29.7
5.9
18.9
Arm1 vs Arm 2
Arm1 vs Arm 3
.20†
<.001†
.89†
.071†
.009‡
<.001‡
18.9
30.3
43.4
7.4
* Arm 1 = three-drug chemolipiodolization with embolization; Arm 2 = three-drug chemolipiodolization without embolization; Arm 3 = single-drug chemolipiodolization
with embolization; CI = confidence interval
† Two sided P-value was calculated after covariable adjustment by multivariable Cox proportional-hazards analysis.
‡ P value was calculated by a two-sided χ2 test.
§ There were 22 patients who could not be evaluated for treatment response because of death, poor performance status, or patients’ refusal of computed
tomography scan at 6 weeks.
patients in Arm 1, 94 patients in Arm 2, and 104 patients in Arm
3. For all 365 recruited patients, their overall survival at 6 months,
1 year, and 2 years was 63.2%, 38.6%, and 22.7 %, respectively.
The median survivals in Arm 1, Arm 2, and Arm 3 were 10.5, 10.1,
and 3.1 months, respectively. Survival was statistically significantly
better in Arm 1 than in Arm 3 (P < .001), whereas there was no statistically significant difference between the two arms treated with
triple-drug chemolipiodolization with or without embolization
(Arm 1 vs Arm 2: P = .20) (Table 4; Figure 2).
The analysis stratified according to the BCLC stage (stage B vs
stage C) is shown in Figure 3. In both stage B and stage C HCC
patients, Arm 1 had statistically significantly improved survival outcomes when compared with Arm 3 (P = .02, P = .003, respectively),
64 Articles | JNCI
and there was no statistically significant difference between Arm 1
and Arm 2 (P = .93, P = .13, respectively) (Figure 3).
Univariable and Multivariable Analysis of Predictors of
Survival
The results of univariable survival analysis are listed in Table 1. In
multivariable analysis, independent risk factors of survival were
treatment allocation Arm 1 vs Arm 3 (hazard ratio [HR] =1.80, 95%
CI = 1.35 to 2.39; P < .001), treatment allocation Arm 1 vs Arm 2
(HR = 1.21, 95% CI = 0.91 to 1.61; P = .20), age (HR = 0.98, 95%
CI = 0.97 to 1.00; P = .003), neutrophil:lymphocyte ratio (HR = 1.12,
95% CI = 1.06 to 1.19; P < .001), serum albumin (HR = 0.95, 95%
CI = 0.93 to 0.98; P < 0.001), total bilirubin (HR = 1.02, 95%
Vol. 105, Issue 1 | January 2, 2012
Figure 2. Kaplan–Meier estimated curves of patients with unresectable hepatocellular carcinoma, stratified based on transarterial chemoembolization allocation, including triple-drug chemolipiodolization with embolization (Arm 1), triple-drug chemolipiodolization without embolization (Arm
2), and single-drug chemolipiodolization with embolization (Arm 3). CI = confidence interval.
CI = 1.01 to 1.03; P < .001), alpha-fetoprotein (HR = 1.46, 95%
CI = 1.13 to 1.90; P = .004), and BCLC stage (HR = 2.07, 95%
CI = 1.62 to 2.64; P < .001).
Discussion
In this study, patients in Arm 1 and Arm 3 had median survivals
of 10.5 and 5.9 months, respectively. Triple-drug chemolipiodolization with embolization statistically significantly improved
tumor response and survival when compared with a single-drug
chemolipiodolization with embolization in patients either with
intermediate or advanced HCC. Treatment allocation was identified as an independent prognostic predictor, further confirming
the benefits of triple-drug chemolipiodolization. These results
show that the chemotherapeutic agents played an important role
in the survival advantage of TACE and might also be valuable for
other transarterial therapies. It is well known that drug-eluting
beads have a great advantage by offering simultaneous embolization and sustained release of chemotherapeutic agents in a controlled manner (24,25). However, beads were commonly loaded
with single-agent doxorubicin in previous studies. It might be
valuable to study the efficacy and safety of beads loaded with
multiple chemotherapeutic agents. Furthermore, radioembolization is another kind of transarterial therapy, which can deliver
high doses of radiation inside the tumor. Because many studies
have shown that radioembolization is effective and safe (26,27),
it might be valuable to evaluate the feasibility of radioembolization combined with chemolipiodolization or beads loaded with
chemotherapeutic agents.
It should be noted that Sahara et al. recently reported a randomized trial that failed to show survival differences between 24
patients who received TACE with multiple drugs and 27 patients
who received single-agent epirubicin (28). However, the sample
size might not have been large enough.
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The impact on survival of adding embolization to the treatment
of patients given transarterial chemotherapy also remains largely
controversial. One randomized trial published in 1995 showed a
statistically significant survival advantage of gelatin-sponge embolization (29). However, all three recent randomized trials failed
to show survival differences between transarterial chemotherapy
with or without embolization (8–10). In our study, the difference
in overall survival between Arm 1 and Arm 2 was also small and
not statistically significant (median survival = 10.5 vs 10.1 months),
although patients in Arm 1 achieved more objective responses than
those in Arm 2 (P = .009). These results suggest that removal of
embolization from chemoembolization might not statistically significantly decrease survival and triple-drug chemolipiodolization
without embolization might be a good therapeutic option for treating HCC patients with poor hepatic reserve or major portal vein
occlusion by tumor thrombosis.
In this trial, the incidence of major complications was not statistically significantly different among all three arms, and all TACErelated complications were adequately managed using nonoperative
treatment, except for one death associated with the TACE procedure. These results suggest that the three TACE regimens are safe.
The overall median survival among participants in our study
appeared to be less satisfactory compared with results from previous studies (16) because this trial enrolled patients with more
advanced tumors than most previous studies: only patients with
HCC larger than 7 cm were included, most well-encapsulated
HCCs were excluded from this study because surgeons thought
they were still resectable, and 34.5% of included patients had portal vein tumor thrombosis. It is reasonable that we set such inclusion criteria, although sorafenib was recommended as the standard
care for patients with HCC and portal vein tumor thrombosis.
To date, developing countries account for 85% of all HCCs that
occur globally (30). There is a need to develop effective treatments
for HCC with portal vein tumor thrombosis in settings where
JNCI | Articles 65
Figure 3. Kaplan–Meier subgroup analysis stratified according to
Barcelona Clinic Liver Cancer stage B or stage C hepatocellular carcinoma (HCC). A) Stage B HCC patients. Survival in Arm 1 (triple-drug
chemolipiodolization with embolization) was statistically significantly
higher than that in Arm 3 (single-drug chemolipiodolization with
embolization) (P = .02), whereas there was no difference between Arm
1 and Arm 2 (triple-drug chemolipiodolization without embolization) (P
= .93). B) Stage C HCC patients. Survival in Arm 1 was statistically significantly higher than that in Arm 3 (P = .003), whereas there was no
difference between Arm 1 and Arm 2 (P = .13).
sorafenib is not feasible at the population level. Furthermore, in
previous studies, our group and a Korean group demonstrated that
these patients were still good candidates for TACE (17,31). Also, if
the trial had included patients with less-advanced HCC, a considerable number of patients might have been downstaged to undergo
curative treatment (32). The survival of these patients would be
largely influenced by the choice of subsequent resection or ablation, options of resection margin, and so on (33).
One limitation of this study is its single-blind nature. The treating oncologist needed to be informed about the actual regiment
to report and treat toxicity. However, this was unlikely to influence the patient’s overall survival, which is the objective primary
endpoint of the trial, and the sample size of this study was large
enough to make an important contribution to the available literature. The second limitation is that the subsequent treatments
for patients who had stopped study TACE might be influenced by
investigator and patient decisions. Also, the subsequent treatment
in Arm 1 was more active than in Arm 3. However, this can be
explained by the better treatment response in the former because
the subsequent treatments depended mostly on tumor burden and
liver function. The third limitation was that the gelatin sponge particles used in this study might be too large and cause only temporary thrombosis. The small particle size of polyvinyl alcohol may
be a more permanent and effective choice (12).
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In summary, this study showed that chemolipiodolization played
an important role in the survival advantage of TACE. However, the
removal of embolization from chemoembolization might not statistically significantly decrease survival.
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Funding
This work was supported by the Eleventh Five-Year Key Plan of the China
National Science and Technique Foundation (2006BAI02A04); National
Natural Science Foundation of China (81272639); Science and Technology
Planning Project of Guangdong Province (2010B031600221); the Fundamental
Research Funds for the Central Universities of China (09ykpy53); and the
5010 Foundation of Sun Yat-sen University (2007043).
Notes
The paper was based on a project established and supervised by Jin-Qing Li, but
unfortunately he passed away before the manuscript was prepared.
The principal investigator (M Shi) had full access to all of the data in the study
and takes responsibility for the integrity of the data and the accuracy of the data
analysis. All authors reviewed the manuscript draft and approved the final version for
JNCI | Articles 67
submission. No authors reported financial disclosures. The conduct of this study was
supervised and monitored by GCP center of Cancer Center, Sun Yat-sen University.
The sponsors had no role in the design, conduct, or interpretation of the study.
The participating centers were Cancer Center, Sun Yat-sen University,
Guangzhou, People’s Republic of China; Cancer Center, Guangdong General
Hospital, Guangzhou, People’s Republic of China; and Kaiping Central
Hospital, Jiangmen, People’s Republic of China.
The authors acknowledge Ying Guo and Qing Liu for help with statistical
analysis.
68 Articles | JNCI
Affiliations of authors: The State Key Laboratory of Oncology in
Southern China (MS, R-PG, M-SC, JL, LX, R-HZ, X-JL, Y-QZ), Department
of Hepatobiliary Oncology (MS, R-PG, M-SC, JL, LX, X-JL, Y-QZ), and
Department of Ultrasound (R-HZ), Cancer Center, Sun Yat-sen University,
Guangzhou, People’s Republic of China; Cancer Center, Guangdong General
Hospital, Guangzhou, People’s Republic of China (L-GL, YL); Department of
Oncology, Kaiping Central Hospital, Guangdong, People’s Republic of China
(W-QF).
Vol. 105, Issue 1 | January 2, 2012