Results of treatment for patients with hepatocellular carcinoma by conventional transarterial chemoembolization and drug eluting bead transarterial chemoembolization

Journal of military pharmaco-medicine no5-2019

RESULTS OF TREATMENT FOR PATIENTS WITH
HEPATOCELLULAR CARCINOMA BY CONVENTIONAL
TRANSARTERIAL CHEMOEMBOLIZATION AND DRUG-ELUTING
BEAD TRANSARTERIAL CHEMOEMBOLIZATION
Pham Trung Dung1; Nguyen Quang Duat2; Vu Van Khien3
SUMMARY
Objectives: Hepatocellular carcinoma is high in prevalence and mortality rate. Palliative
treatments of hepatocellular carcinoma include conventional transarterial chemoembolization
and drug-eluting bead transarterial chemoembolization. This study aims to compare results of
treatments by conventional transarterial chemoembolization and drug-eluting bead transarterial
chemoembolization and to assess factors related to treatment outcomes between the 2 groups.
Results: Tumor size reduction after 1 - 3 months in conventional transarterial chemoembolization
group was 26.4% and drug-eluting bead transarterial chemoembolization group was 40.2%,
significantly different (p = 0.048). Decreasing serum AFP level of conventional transarterial
chemoembolization group was 36.7%, drug-eluting bead transarterial chemoembolization group
was 50.2%, significantly different (p = 0.002). Average survival time of conventional transarterial
chemoembolization group was 17.1 ± 1.3 months, drug-eluting bead transarterial chemoembolization
2
group was 21.6 ± 1.3 months, significantly different (χ = 7.1, p = 0.008). Side effects: Pain in
the liver, fever, fatigue and nausea, vomitting for the conventional transarterial chemoembolization
group were 73.7%, 30.9%, 42.5%, 2.0%, respectively, for the drug-eluting bead transarterial
chemoembolization group 81.6%, 18.7%, 28.2%, 3.0%, respectively. The risk of death of the
drug-eluting bead transarterial chemoembolization group was higher than that of drug-eluting
bead transarterial chemoembolization group (p < 0.05) in relation to AFP levels (> 20 ng/mL)
(1.56 times); poorly cell differentiation (1.37 times), Okuda I (2.34 times), no tumor response
after treatment (according to mRECIST) (1.54 times). Conclusion: Drug-eluting bead transarterial
chemoembolization has a better therapeutic effect than conventional transarterial
chemoembolization. However, the side effects of the 2 groups were still contradictory .
Morphological characteristics of poorly differentiated tumor, serum AFP increased (> 20 ng/mL)

before treatment, disease stage Okuda I, not respond soon hepatoma (according to mRECIST)
are predictive factors which positively associated long-term survival results after treatment.
* Keywords: Hepatocellular carcinoma; Conventional transarterial chemoembolization;
Drug-eluting bead transarterial chemoembolization.
1. Construction Hospital
2. 103 Military Hospital
3. 108 Military Central Hospital
Corresponding author: Pham Trung Dung ()
Date received: 10/04/2019
Date accepted: 20/05/2019

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Journal of military pharmaco-medicine no5-2019
INTRODUCTION
Hepatocellular carcinoma (HCC) is one
of the most common cancer that accounts
for 95% of liver malignancy. HCC is the
sixth in prevalence of cancer worldwide
(fifth in Vietnam) and third in cancer-related
deaths [1, 5]. HCC has poor prognosis
with 5 years survival rate at 5% [6].
In 2002, transarterial chemoembolization
(TACE) was approved as an alternative
treatment for HCC patients who were
not suitable for curative treatments.
Conventional transarterial chemoembolization
(cTACE) was defined as injection of anticancer drug with or without lipiodol to
embolize nourishing arteries of tumors.

Drug-eluting
bead
transarterial
chemoembolization (DEB-TACE) was
developed based on cTACE. The method
used drug-loaded beads to control,
maintain high chemical concentration
inside tumors and to reduce chemical
concentration in the cardiovascular
system. In Vietnam, cTACE was widely
performed in cardiovascular intervention
centers, DEB-TACE was mainly performed
in large centers. Data on comparison of
treatment results and side effects between
these two methods was limited. Therefore,
we conducted this study with aims to:

103 Military Hospital and Deparment of
Gastroenter5

Average tumor size (cm)

9.04 ± 4.49

9.28 ± 4.20

0.25

A

115

95.0

154

96.9

B

6

5.0

5

3.1

I

70

57.9

99

62.3

II

51

42.1

60

37.7

Child-Pugh

0.44

Okuda

0.46

The characteristics of patients in the cTACE group and the DEB-TACE group were
mostly identical.
2. Post-treatment tumor response and serum AFP.
Table 2: Tumor response 1 - 3 months after the first treatment.
Tumor response evaluated
by RECIST

cTACE

DEB-TACE

n = 121

%

n = 159

%

Complete response (1)

16

13.2

32

20.1

Partial response (2)

16

13.2

32

20.1

Stable disease (3)

52

43.0

59

37.2

Progressive disease (4)

37

30.6

36

22.6

p

p1,2 - 3,4

0.11

0.048

DEB-TACE had higher rates of complete response and partial response than cTACE
(p = 0.048).
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Journal of military pharmaco-medicine no5-2019

Decrease

No change

Increase

Figure 1. Serum AFP between two groups.
DEB-TACE had a significantly better rate of serum AFP reduction compared to
cTACE, the difference was statistically significant (p = 0.002).
3. Side effects.
Table 3: Side effects after treatment between two groups.
cTACE

DEB-TACE

Symptoms after intervention

p
n = 346

%

n = 305

%

Liver pain

255

73.7

249

81.6

0.016

Fever

107

30.9

57

18.7

0.001

Fatigue

147

42.5

86

28.2

0.001

7

2.0

9

3.0

0.45

Nausea, vomitting

Patients treated by cTACE had lower proportion of liver pain and higher proportion
of fever and fatigue after treatment compared with DEB-TACE group.
4. Survival time after treatments.
At the end of our research, there were 176 deaths and 104 patients were followed.
Average follow-up time was 14.3 months.
Table 4: Overall survival time (OS) and progressive-free survival time (PFS).
Mean survival time
(95% CI)
cTACE

Cummulative survival rates (%)
p

17.1 ± 1.3

OS

1 year

2 year

3 year

52.1

25.0

13.9

65.3

42.6

24.1

30.2

18.6

18.6

53.0

33.7

10.2

0.008
DEB-TACE

21.6 ± 1.3

cTACE

12.7 ± 1.3

PFS

0.001
DEB-TACE

17.7 ± 1.4

Mean survival time in the DEB-TACE group was statistically longer than that in
cTACE group (χ2 = 7.1, p = 0.008).
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Journal of military pharmaco-medicine no5-2019
5. Factors related to survival time of HCC patients.
We analyzed several factors that could be related to mortality of HCC patients treated
by cTACE or DEB-TACE. The results was shown in figure 2.

Figure 2: Hazard ratio of factors related to survival rate.
Histopathology of poor differentiation, serum AFP > 20 ng/mL, Okuda class I,
unresponsive liver tumors (based on mRECIST) were positive predictive factors of

mortality in patients treated by cTACE and DEB-TACE.
DISCUSION
1. Tumor response after treatment.
Tumor response is an important
prognostic factor in the treatment of HCC.
Tumor shinkage is related to patient's
prognosis and survival time. Currently, the
European Association for the Study of the
Liver (EASL) recommends using mRECIST
to assess post-treatment response. The
classification includes: Complete response,
partial response, stable disease and
progressive disease.
182

Our results showed that cTACE group
had better tumor response in 1 - 3 months
after treatment: complete response was
13.2%, partial response was 13.2%, stable
disease was 43%, progressive disease
was 30.6%; DEB-TACE group rates of
response was 20.1%, 20.1%, 37.2% và
22.6%, respectively. Our results showed
that DEB-TACE was better than cTACE,
especially in post-treatment tumor response.
However, patients selection, the time
of treatment intervention and the experience
of the physician... are related to the efficacy

Journal of military pharmaco-medicine no5-2019
of treatments. Thai Doan Ky performed
DEB-TACE in the patients with HCC and
reported that the tumor response were
quite high: Complete response was 32.4%,
partial response was 40.0%, stable
disease was 17.1%, progressive disease
was 10.5% [2].
Assessing tumor response after treatments
by DEB-TACE required long-term followup. A study by Varela M et al stated that
the rate of tumor response at 1 - 6 months
after treatment was 75% [8]. A multicenter
randomized clinical trials by PRECISION
V in Europe reported: response rate,
complete response and tumor control rate
in the DEB-TACE group were all higher
than cTACE group [9].
2. Serum AFP after treatment.
Serum AFP was a common tumor
marker and was widely used for diagnosis,
follow-up and prognosis after treatment.
Decreased level of serum AFP showed
good prognosis and was usually associated
with tumor shrinkage. Changes of serum
AFP depended on treatment methods
of HCC.
In our research (figure 1), 3 months
after treatments, the proportions of patients
with decreased, no change and increased
level of serum AFP were: 36.7%, 25.1%

and 38.2%, respectively; these rates in
the DEB-TACE group were 50.2%, 17.4%
and 32.5%, the differences were statistically
significant (p < 0.05). A study by Song
M.J et al (2012), the proportion of patients
with decreased AFP in the DEB-TACE
group was statistically higher than cTACE
group (77.4% compared to 45.4%, p = 0.011)
[10].

Le Van Truong performed cTACE for
108 HCC patients with an average tumor
size of 9.4 cm, the results showed that
only 30% had decreased serum AFP,
50% remained unchanged and 15% had
increased serum AFP after treatment [1].
The Thai Doan Ky’s study on 105 patients
treated by DEB-TACE reported 50% of
patients had decreased serum AFP, 39%
remained unchanged and 13.3% had
increased serum AFP after treatment.
3. Side effects after treatment.
Side effects after treatment were seen
in both groups. In our research (table 3),
the rates of patients with fever and fatigue
were lower in the DEB-TACE group.
However, liver pain was more prominant
in the DEB-TACE group. The side effects
found in our research were similar to
other research in Vietnam [1, 2].

4. Survival time after treatments.
Survival time is an important indicator
to evaluate the efficacy of treatment for
patients with HCC. The overall survival
and average life time depend on many
objective
and
subjective
factors.
Characteristics of tumors, cirrhosis status,
patient's condition and treatment methods
are related to the patient's lifetime.
In our study, 1-year, 2-year and 3-year
cummulative survival rates of cTACE was
52.1%, 25.0%, 13.9% and DEB-TACE
was 65.3%, 42.6%, 24.1%. Mean survival
time of the cTACE group was 17.1 ±
1.3 months and DEB-TACE group was
21.6 ± 1.3 months, the difference was
statistically significant (χ2 = 7.1, p = 0.008).
The mean PFS time of cTACE group was
12.7 ± 1.3 months and DEB-TACE group
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Journal of military pharmaco-medicine no5-2019
was 17.7 ± 1.4 months, the difference
was statistically significant (χ 2 = 11.11,
p = 0.001).
Le Van Truong performed cTACE on

108 HCC patients and reported that the
mean survival time was 13 months,
1-year, 2-year and 3-year survival rates
were 55.6%, 21.3% and 11.2%, respectively
[1]. Most patients in this research had
large liver tumors accompanied by cirrhosis.
Thai Doan Ky's study on 105 patients
with HCC treated by DEB-TACE showed
mean survival time at 27.9 ± 1.6 months,
1-year, 2-year and 3-year cummulative
survival rates were 72.9%, 54.4% and 41.3%,
respectively [2].
A meta-analysis done by Huang K
(2014) from 7 studies on 700 patients
reported that DEB-TACE had significantly
higher 1-year, 2-year and 3-year survival
rates compared with the group cTACE
(p = 0.007, p = 0.0003 and p = 0.01,
respectively) [11].
5. Factors related to survival time of
two groups: cTACE and DEB-TACE.
Multivariate analysis by Cox regression
model showed that mortality risk of
cTACE group was higher than DEB-TACE
group. Comparing with DEB-TACE, cTACE
was significantly associated to mortality
in patients having elevated serum AFP
(1.56 times); poor differentiation (1.37 times),
Okuda class I (2.34 times), nonresponsive
tumors after first treatment based on

mRECIST (1.54 times).
Facciousso (2016) evaluated prognostic
factors of treament outcomes in 104 patients
treated by cTACE and 145 patients
treated by DEB-TACE (all patients had
184

BCLC class A or B tumors). The study
showed that cTACE had significant
association with survival rate in patients
with high level of AFP, malignancy in both
liver lobes and portal hypertension. The
hazard ratios were 2.29, 2.5 and 1.75,
respectively [12]. A study conducted by
Song et al showed that AFP < 200 ng/mL
was an independent factor of survival rate
[10].
CONCLUSIONS
- Patients treated by DEB-TACE had
better tumor response, serum AFP
response and survival time than cTACE.
Side effects were seen in both groups.
- Poor differentiation, high pre-treatment
serum AFP (> 20 ng/mL), Okuda class I,
non-responsive tumors (based on mRECIST)
were positive predictive factors of HCC
patients’ long-time survival.
REFERENCES
1. Le Van Truong. Treatment of hepatocellular
carcinoma size > 5 cm by selective transarterial

chemoembolization. Docteral Dissertation.
Vietnam Military Medical University. 2006.
2. Thai Doan Ky. Treatment of hepatocallular
carcinoma by transarterial chemoembolization
using drug-loaded microspheres DC beads.
Doctoral Dissertation. Scientific Research
Institute for Clinical Medicine and Pharmacy
108. 2015.
3. Oncology Department - Hanoi Medical
University. Primary liver cancer. Oncology.
Medical Publishing House. 1997, p.205.
4. Vietnam Ministry of Health. Guidelines
for diagnosis and treatment of primary liver
cell cancer. 2012.
5. Union for International Cancer Control.
Clinical Oncology. Medical Publishing House.
1991, pp.382-386.


Journal of military pharmaco-medicine no5-2019
6. Ulmer S.C. Hepatocellular carcinoma: A
concise guide to its status and mamagement.
Postgrad Med. 2000, 107 (5), pp.117-124.
7. Llovet J.M et al. Prognosis of
hepatocellular carcinoma: The BCLC staging
classification. Semin Liver Dis. 1999, 19 (3),
pp.329-338.

10. Song M.J, Chun H.J, Song D.S et al.
Comparative study between doxorubicin-eluting

beads and conventional transarterial
chemoembolization for treatment of hepatocellular
carcinoma. Journal of Hepatology. 2012, 57 (6),
pp.1244-1250.

8. Varela M, Isabel R.M, Burrel M et al.
Chemoembolization
of
hepatocellular
carcinoma with drug eluting beads: Efficacy
and doxorubicin pharmacokinetics. Journal of
Hepatology. 2007, 46 (3), pp.474-481.

11. Huang K, Zhou Q, Wang R et al.
Doxorubicin-eluting beads versus conventional
transarterial chemoembolization for the
treatment of hepatocellular carcinoma.
Journal of Gastroenterology and Hepatology.
2014, 29, pp.920-925.

9. Lammer J, Malagari K, et al. Prospective
randomized study of doxorubicin-eluting-bead
embolization in the treatment of hepatocellular
carcinoma: Results of the PRECISION V
study. Cardiovascular Intervention Radiology.
2010, 33, pp.41-52.

12. Facciorusso A, Mariani L, Sposito C
et al. Drug-eluting beads versus conventional
chemoembolization for the treatment of

unresectable hepatocellular carcinoma. Journal
of Gastroenterology and Hepatology. 2016, 31 (3),
pp.645-653.

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