Alimentary Pharmacology & Therapeutics
Clinical trial: percutaneous acetic acid injection vs.
percutaneous ethanol injection for small hepatocellular
carcinoma a long-term follow-up study
W.-L. TSAI*,, J.-S. CHENG*,,, K.-H. LAI*,, C.-P. LIN, G.-H. LO*,, P.-I. HSU*,, H.-C. YU*,,
C.-K. LIN*,, H.-H. CHAN*,, W.-C. CHEN*,, T.-A. CHEN*,, W.-L. LI* & H.-L. LIANG
*Division of Gastroenterology,
Department of Internal Medicine,
Kaohsiung Veterans General Hospital,
Kaohsiung, Taiwan; School of
Medicine, National Yang-Ming
University, Taipei, Taiwan;
Department of Internal Medicine,
Yongkang Veterans Hospital, Tainan,
Taiwan; Division of Gastroenterol-
ogy, Department of Internal Medicine,
Gods help Hospital, Chia-yi, Taiwan;
Department of Radiology, Kaohsiung
Veterans General Hospital, Kaohsiung,
Taiwan
Correspondence to:
Dr J.-S. Cheng, Division of
Gastroenterology, Department of
Internal Medicine, Kaohsiung
Veterans General Hospital, 386
Ta-Chung 1st Road, Kaohsiung 813,
Taiwan.
E-mail: rcheng@ms2.hinet.net
Publication data
Submitted 6 December 2007
First decision 27 December 2007
Resubmitted 12 February 2008
Accepted 1 April 2008
Epub OnlineAccepted 4 April 2008
304
SUMMARY
Background
The long-term outcome of percutaneous acetic acid injection (PAI) and
percutaneous ethanol injection (PEI) for treating small hepatocellular
carcinoma (HCC) remains unclear.
Aim
To compare the long-term outcome of PAI vs. PEI for treating small
HCC.
Methods
From July 1998 to July 2004, 125 patients with small HCC were
enrolled. Seventy patients receiving PAI and 55 patients receiving PEI
were enrolled. There were no significant differences in the clinical char-
acteristics between the two groups. Tumour recurrence and survival
rates were assessed.
Results
Mean follow-up time was 43 months. The local recurrence rate and new
tumour recurrence rate were similar between the PAI and PEI groups.
The PAI group had significantly better survival than the PEI group
(P = 0.027). Multivariate analysis revealed that PAI was the significant
factor associated with overall survival [PAI vs. PEI, RR: 0.639, 95% CI:
(0.4191.975), P = 0.038]. The treatment sessions required to achieve
complete tumour necrosis were significantly fewer in the PAI group
than in the PEI group (2.4  1.0 vs. 2.9  1.3, P = 0.018).
Conclusion
Percutaneous acetic acid injection required fewer treatment sessions
than PEI and provided better survival after long-term follow-up.
Aliment Pharmacol Ther 28, 304311
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
doi:10.1111/j.1365-2036.2008.03702.x
 C L I N I C A L T R I A L : A C E T I C A C I D V S . E T H A N O L F O R H C C 305
INTRODUCTION
Hepatocellular carcinoma (HCC) is the fifth most com-
mon cancer in the world and ranked as the second
cause of cancer death in Taiwan.1 Surgical resection is
considered to be the standard treatment for curative
therapy for HCC in patients with good liver reserve.2, 3
In the past two decades, several percutaneous ablation
therapies including percutaneous ethanol injection
(PEI), percutaneous acetic acid injection (PAI) and
radiofrequency ablation (RFA) have been developed46
and found to have a result similar to surgical resection
for treating small HCC.7, 8 Recent studies showed that
RFA seemed to achieve a lower rate of tumour recur-
rence and higher survival rates than PEI for treating
small HCC.911 However, the survival of RFA for treat-
ing HCC less than 3 cm in size was similar to PEI.10
However, the complication and mortality rates of RFA
are substantially higher than PEI.1215 In two recent
studies, the authors stated that 925% of cases could
not be treated by RFA safely because of unfavorable
locations.16, 17 The applicability of RFA might be even
lower in institutions with limited skills in intervention-
al radiology procedures and hence PEI or PAI would
continue to play an important role in treating small
HCC.18 Acetic acid seemed to have a higher necrotiz-
ing power than ethanol4 and PAI was found to have a
better local control and improved survival rate than
PEI in a randomized trial.19 However, two recent stud-
ies found similar outcome of PEI vs. PAI for treating
small HCC.20, 21 The mean follow-up times of previous
studies were short (2429 months).1921 Long-term fol-
low-up studies comparing the therapeutic effects of
PAI and PEI have not been shown.
In view of the above, we conducted this research
with a long-term follow-up to compare the effects of
PAI and PEI for treating small HCC.
MATERIALS AND METHODS
From July 1998 to July 2004, 125 consecutive eligible
patients with small unresectable hepatocellular carci-
noma (HCC) were allocated to either treatment with
PAI or PEI. The choice of either PAI or PEI was deter-
mined in a somewhat random manner by the operator
and was not influenced by the clinical condition of the
patient. HCC was diagnosed by pathology or elevation
of alpha-fetoprotein (AFP) level above 400 ng mL with
at least two different imaging techniques.3 The imag-
ing criterion for the diagnosis of HCC is the typical
2008 The Authors, Aliment Pharmacol Ther 28, 304311
Journal compilation 2008 Blackwell Publishing Ltd
hypervascular tumour with washout in the portal ve-
nous phase in dynamic computed tomography (CT)
scan or magnetic resonance imaging (MRI). All
patients met the following criteria: (i) tumour of 4 cm
or less in diameter, and tumour numbers were less
than or equal to 3, (ii) tumours were unresectable or
patients refused operation, (iii) platelet counts
>50 000 cumm, (iv) prothrombin time INR < 1.5, (v)
no evident ascites and (vi) tumour could be found by
sonogram. Patients with a previous history of treat-
ment for HCC, thrombosis of portal vein, or distant
metastasis were excluded. Patients who were willing to
receive surgical resection received indocyanine green
(ICG) clearance test and were evaluated by a surgeon
expert in surgery for hepatocellular carcinoma (HCC).
Patients were not considered to receive surgical resec-
tion if poor ICG clearance test and clinical condition
were noted. Liver transplantation was not routinely
performed in our hospital and hence was not the treat-
ment option in this study. Seventy patients with 81
tumours received PAI and 55 patients with 65 tumours
received PEI.
Conventional liver function tests, prothrombin time,
HBsAg, HCV-Ab, AFP and complete blood cell counts
were measured before enrolment. Three-phase CT
imaging was used to evaluate treatment response.
Percutaneous ethanol injection percutaneous
acetic acid injection
The first session of treatment was performed during
admission and additional sessions of treatment were
performed at the outpatient clinic. Around 30 min
before treatment, oral diclofenac potassium 25 mg and
morphine 10 mg were given. After local anesthesia with
2% lidocaine, a 20-cm-long 2122 gauge multiple-side-
hole needle (36 side holes, Cliny, Yokohama, Japan)
was inserted percutaneously into the proper part under
the guidance of real-time ultrasound (US) and pure eth-
anol or 50% acetic acid was injected. Ethanol was
injected at a volume of 210 mL per session and total
volume was estimated using the modified equation: V
(mL) = 4 3 3.14 (r + 0.5),3 where r represents the
radius of the tumour in centimeters. 50% acetic acid
was injected at a volume of 13 mL per session and
total volume was estimated using the modified equa-
tion: V (mL) = 4 3 3.14 (r + 0.5)3 1 3, where r
represents the radius of the tumour in centimeters. The
procedure was repeated twice weekly until the estimated
volume of ethanol or acetic acid was injected.10, 11
306 W . - L . T S A I et al.

platelet count (60 000 vs. >60 000 mm3), and treat-
Assessment of therapeutic response and
ment (PAI vs. PEI) were performed using Coxs regres-
follow-up
sion model with proportional hazards. A P-value of
Three-phase dynamic CT scan was performed 1 month less than 0.05 was considered statistically significant.
after treatment. If residual tumour was found by CT
scan as suggested by foci of nodular enhancement,
RESULTS
another course of PEI or PAI was performed. Complete
tumour necrosis was defined as persistent low attenua- The average follow-up period was 43  29 months
tion of the ablated tumour on CT scan one month after (range: 2110 months). The PAI and PEI groups did
the most recent ablation therapy. If residual tumour not show a significant difference in age, gender, Child
was still noted, failure of complete necrosis was con- class, underlying liver disease (HBV or non-HBV),
sidered and patients would be referred for further Model for End-Stage Liver Disease (MELD) score,
treatment modalities including further local ablation tumour size, tumour number, level of AST, ALT, total
therapy, transcatheter arterial embolization (TAE) with bilirubin, albumin, platelet count, AFP and prothrom-
or without local ablation therapy or transhepatic arte- bin time (Table 1). Among 125 patients, seven tumours
rial chemotherapy (HAIC). in seven patients in the PAI group and seven tumours
Follow-up studies included liver function tests, AFP in seven patients in the PEI group did not achieve
and dynamic CT scan of the liver every three months. complete tumour necrosis following two courses of
Long-term outcome was examined for local recur- therapy. Additional and alternative therapies were
rence, new tumour recurrence, overall survival and given as needed. The rate of complete tumour necrosis
cancer free survival. Local recurrence was defined as was 91% (74 81 tumours) in the PAI group and 87%
the presence of an enhanced tumour on CT, corre- (56 65 tumours) in the PEI group; no significant dif-
sponding to the initial tumour and new recurrence of ference was noted (P = 0.631). The treatment courses
HCC was defined as developing an enhanced tumour needed to achieve complete tumour necrosis did not
in a different segment from the original tumour.
The periods of follow-up were defined as follows: (i)
for the local tumour progression rate, the time from the Table 1. Clinical characteristics in the PAI and PEI
beginning of local injection treatment to local tumour groups
progression or death was used; (ii) for the overall sur- PAI PEI
vival rate, the time to last follow up or death was used; n = 70 n = 55 P
and (iii) for the recurrence-free survival rate, the time
to local tumour progression, extrahepatic metastasis, Age (years) 65  10 66  10 0.735
tumour recurrence or death were used. Male female 47 23 41 14 0.368
Underlying liver disease: 26 44 20 35 0.929
HBV non-HBV
Statistical analysis Child-Pugh Class (A BC) 56 14 39 16 0.237
MELD score 9.0  5 9.4  5 0.633
Data were presented as mean  s.d. for quantitative No. of tumour: 1 23 59 11 47 9 0.993
variables and as absolute frequencies for qualitative Size of main tumour (cm) 2.2  0.7 2.2  0.7 0.918
variables. Differences between the two groups were Laboratory data
AST (U L) 90  118 82  44 0.672
analyzed by unpaired t-test for continuous variables
ALT (U L) 85  76 84  63 0.942
and Fisher exact test for categorical variables. Bilirubin (mg dL) 1.4  1.2 1.7  2.3 0.472
Local tumour progression, new recurrence of tumour, Albumin (g dL) 3.7  0.6 3.5  0.6 0.222
overall survival and recurrence free survival were esti- Prothrombin time (INR) 1.2  0.2 1.1  0.1 0.175
mated using the KaplanMeier method and the differ- Platelet count 112  48 109  59 0.699
ence was determined by the log-rank test. Univariate (1000 mm3)
AFP (ng mL) 307  675 137  456 0.184
and multivariate analysis with age (60 vs. <60 years), Complete necrosis (%) 91 87 0.631
gender, Child grade (A vs. BC), hepatitis B virus
(HBV) related vs. non-HBV-related liver disease, two or Values are expressed as mean  s.d.
three tumours vs. single tumour, size of main tumour MELD score, model for end-stage liver disease score.
(2 cm vs. <2 cm), AFP level (200 vs. <200 ng mL),

2008 The Authors, Aliment Pharmacol Ther 28, 304311

Journal compilation 2008 Blackwell Publishing Ltd
 C L I N I C A L T R I A L : A C E T I C A C I D V S . E T H A N O L F O R H C C 307

50
Table 2. Factors in relation to achieve complete tumour
necrosis after PAI and PEI

Local recurrence (%)

40
PAI PEI P
30
No. of patients 63 48
No. of tumours 74 56 20 PEI
Treatment course (1 2) 47 16 40 8 0.268 PAI
Treatment sessions per tumour 2.4  1.0 2.9  1.2 0.018 10
Total volume injected per 74 19  10 <0.001
tumour (mL) 0
0 6 12 18 24 30 36
Months
Values are expressed as mean  standard deviation (s.d.). PAI 70 55 43 39 33 28 22

PEI 55 41 32 27 21 20 14

differ in the PAI and PEI group. The treatment sessions

required to achieve complete tumour necrosis were Figure 1. Comparison of the local recurrence rate for the
main tumour between the PAI and PEI group. No
significantly fewer in the PAI group than in the PEI
significant difference of local recurrence was noted
group (2.4  1.0 vs. 2.9  1.3, P = 0.018) and the between the PAI and PEI group (P = 0.892).
total volume of ethanol or acetic acid injected per
tumour required to achieve complete tumour necrosis
were significantly smaller in the PAI group than the 100
PEI group (7  4 vs. 19  10 mL, P < 0.001) (Table 2).
New tumor recurrence (%)

80

60
Recurrence
40 PEI
Among the patients who achieved complete tumour
PAI
necrosis, after a mean follow-up of 43 months, 23 20
patients (36%) in the PAI group and 16 patients (34%)
in the PEI group developed local recurrence. The 0
0 6 12 18 24 30 36 42 48 54 60
cumulative local recurrence rates for the main tumour
Months
at the end of 1, 2, 3, 4 and 5 years were 25%, 28%,
36%, 36% and 36% in the PAI group and 25%, 31%, PAI 70 43 26 18 7 6

33%, 33% and 33% in the PEI group, respectively PEI 55 25 13 6 4 3

(Figure 1). No significant difference of local recurrence
was noted between the PAI and PEI group (P = 0.892).
Fifty-one patients (73%) in the PAI group and 40
patients (73%) in the PEI group developed new tumour
recurrence. The cumulative new tumour recurrence
rates at the end of 1, 2, 3, 4 and 5 years were 32%,
51%, 56%, 70% and 71% in the PAI group and 40%,
56%, 64%, 65% and 69% in the PEI group, respec-
tively (Figure 2). No significant difference in new
tumour recurrence was noted between the PAI and PEI
group (P = 0.261).
Survival
During follow-up, 44 patients (63%) in the PAI group
and 44 patients (80%) in the PEI group died. Causes of
Figure 2. Comparison of the new tumour recurrence rate
between the PAI and PEI group. No significant difference
in new tumour recurrence was noted between the PAI
and PEI group (P = 0.261).
death were tumour progression (24 patients), liver fail-
ure (14 patients), oesophageal variceal bleeding (3
patients), and miscellaneous (3 patients), in the PAI
group and tumour progression (22 patients), liver failure
(13 patients), oesophageal variceal bleeding (2 patients),
and miscellanelous (2 patients), in the PEI group.
The overall survival rates at 1, 2, 3, 4 and 5 years
were 89%, 73%, 56%, 46% and 43% in the PAI group
and 84%, 62%, 42%, 37% and 26% in the PEI
group, respectively (Figure 3). The PAI group had

2008 The Authors, Aliment Pharmacol Ther 28, 304311

Journal compilation 2008 Blackwell Publishing Ltd
308 W . - L . T S A I et al.
100
80
Overall survival (%)
60
40
PEI
PAI
20
0
0 6 12 18 24 30 36 42
Months
PAI 70 63 51 39
PEI 55 46 34 23
Figure 3. Comparison of the overall survival rate between
the PAI and PEI group. The PAI group had significantly
better survival than the PEI group (P = 0.038).
significantly better survival than the PEI group
(P = 0.027). Multivariate analysis revealed the signifi-
cant factors associated with overall survival were
treatment method [PAI vs. PEI, relative risk (RR):
0.639, 95% confidence interval (CI): 0.4191.975,
P = 0.038] and Child Class (A vs. B and C, RR: 0.377,
95% CI: 0.2340.608, P < 0.001).
When only patients with Child A liver reserve were
included in the analysis, the overall survival rates at 1,
3 and 5 years were 93%, 70% and 54% in the PAI
group and 85%, 44% and 23% in the PEI group,
respectively. The PAI group had better survival than
the PEI group, but the significance was marginal
(P = 0.091). Multivariate analysis found that treatment
method [PAI vs. PEI, relative risk (RR): 0.600, 95%
confidence interval (CI): 0.4190.999, P = 0.05] was
the significant factor associated with overall survival.
Adverse effects
No procedure related mortality developed in both the
PAI and PEI group. Major complication was defined as
a complication that might threaten the patients life, if
left untreated leading to substantial morbidity and dis-
ability or result in a lengthened hospital stay and all
other complications were considered minor.12 One
patient (1.4%) in the PAI group developed a major
complication presented with gross haematuria and
recovered after supportive treatment during admis-
sion. No patient in the PEI group developed a major
complication. Seven patients developed transient fever,
eight developed nausea and vomiting and five devel-
oped severe abdominal pain in the PAI group and all
were resolved after supportive treatment. Ten patients
developed transient fever, four developed nausea and
vomiting and two developed severe abdominal pain in
the PEI group and all were resolved after supportive
treatment.
48 54 60 DISCUSSION
Local injection treatment with PAI or PEI remains an
31 22
important treatment modality for the ablation of small
13 9 HCC in many institutions and hospitals throughout the
world.5, 16, 23, 24 RFA has emerged as another impor-
tant therapeutic option for small HCC. However, many
published researches on RFA lacked sufficient method-
ological strength to be reliable enough to establish the
beneficial effects of the procedure.18, 25 The European
Association for the Study of the Liver (EASL) recom-
mended comparing all newer methods for tumour
ablation with the well-established PEI through ran-
domized controlled trials.3 Three randomized studies
compared the outcome of RFA vs. PEI for early stage
HCC.911 The first trial from Europe failed to prove an
overall survival benefit of RFA over PEI.9 Another
study from Japan showed survival benefits of RFA
over PEI, but they were not confirmed in the subgroup
analysis of patients with single solitary tumour.11
Another study from Taiwan found no significant dif-
ference in overall and cancer free survival between
RFA and PEI in patients with HCC less than 3 cm in
size.10 Therefore, survival data are not robust enough
to establish RFA over PEI for treating small HCC.18
Besides, previous studies found the procedure related
mortality rates of RFA were 0.30.5% and the major
complication rates of RFA were 2.28.9%,12, 13, 15
which were higher than the reported mortality rate of
0.09% and major complication rate of 3.2% after PEI
in another multicenter study.14 The local injection
treatment procedure could be safely performed even
for lesions bulging from the surface of the liver,
adjoining the gastrointestinal tract, diaphragm, gall
bladder or the heart, which were considered locations
difficult or high risk for safely performing percutane-
ous radiofrequency ablation.16, 26, 27 In two recent
studies, the authors stated that 925% of cases could
not be safely treated by RFA because of unfavorable
locations.16, 17 Therefore, PEI or PAI remained an
important therapeutic option for treating small HCC.
2008 The Authors, Aliment Pharmacol Ther 28, 304311
Journal compilation 2008 Blackwell Publishing Ltd
 C L I N I C A L T R I A L : A C E T I C A C I D V S . E T H A N O L F O R H C C 309
In this study, we found that PAI had significantly
better overall survival over PEI after a mean follow-up
of 43 months. Multivariate analysis also revealed that
PAI was the significant factor associated with overall
survival. Acetic acid seemed to have higher necrotiz-
ing power than ethanol because of the ability of acetic
acid to dissolve lipid and extract collagen fiber from
intratumoural septa and capsules that often contain
viable cancer cells.4, 22, 28 Major limitations of PEI
were the presence of fibrous septa inside the tumour,
limiting the spread of ethanol and the irregular diffu-
sion outside the limits of the tumour, making the crea-
tion of a safety margin difficult.4, 25 Complete tumour
necrosis rate which was considered to predict survival
in patients with HCC undergoing local ablation ther-
apy was higher in the PAI group than in the PEI group
(91% vs. 87%), but a statistical significance was not
reached (P = 0.637). Although the difference was not
significant, it may have some contributions to the
higher survival of PAI over PEI. The treatment sessions
required to achieve complete tumour necrosis were
significantly fewer in the PAI group than in the PEI
group (2.4  1.0 vs. 2.9  1.3, P = 0.018). The total
volume of ethanol or acetic acid injected per tumour
required to achieve complete tumour necrosis was sig-
nificantly smaller in the PAI group than in the PEI
group (7  4 vs. 19  10 mL, P < 0.001). More ses-
sions of percutaneous injection and more volume of
injected materials in the liver may cause increased risk
of vascular shunting and more injury of the liver after
the treatment. The residual liver reserve after local
ablation therapy also may influence the treatment out-
come. PAI required fewer treatment sessions and smal-
ler volume needed to be injected into the liver and so
the liver injury after the treatment may be less severe.
Besides, the spreading of ethanol may be influenced
by the fibrous septa in the tumour and so irregular
diffusion outside the limits of the tumour may hap-
pen.4, 25 Hence, some of the injected ethanol may dif-
fuse into liver parenchyma unexpectedly and cause
injury to the liver. This effect may not happen easily
after PAI. The cumulative new tumour recurrence rates
at the end of 1, 2, and 3 years were 32%, 51% and
56% in the PAI group and 40%, 56% and 64% in the
PEI group, respectively. The PAI group had lower new
tumour recurrence rates than the PEI group; although
not statistically significant, the difference may have
some contributions to the higher survival rate of PAI
over PEI. Although the exact causes of the survival
benefit of PAI may not be completely explained from
2008 The Authors, Aliment Pharmacol Ther 28, 304311
Journal compilation 2008 Blackwell Publishing Ltd
this study, further studies that compare the effect of
different sessions and volumes of PAI vs. PEI on the
tumour and liver parenchyma may help us understand
the difference in the pathophysiological events after
the treatment.
A randomized trial from Japan found a better sur-
vival of PAI than PEI after a mean follow-up period
of 29 months.19 Another randomized study from
Taiwan found no significant difference in survival
between PAI and PEI after a mean follow-up period of
27 months.21 Another nonrandomized study from Tai-
wan did not find significant difference in outcome
between PAI and PEI after a mean follow-up period of
24 months.20 But the follow-up period was not long
in these studies. Our study is the longest follow-up
study to date to have compared the outcome of PAI
and PEI, and a survival benefit of PAI over PEI was
found.
Previous studies found the 5-year survival rate after
PEI was 2454%.25 The 5-year survival rate of the PEI
group in this study was 26%. In this study, patients
who were good candidates for surgical resection were
not considered to be enrolled, and 29% of the patients
had Child BC liver reserve. Besides, the patients
enrolled had a mean age of 66 years. In a recent study
from Spain, local ablation therapy for small HCC had
a 5-year survival rate of 27% and this result is similar
to this study.29
The 3-year local tumour recurrence rates were 33%
in the PEI group and did not increase after a follow-
up beyond 3 years. Previous studies revealed that the
3-year local tumour recurrence rates after PEI were
around 2945%10, 30 and that these results were simi-
lar to our findings. The 3-year local tumour recurrence
rates were 36% in the PAI group. In the previous ran-
domized study from Japan, the author found that the
2-year local recurrence rate after PAI was 10%, but
this study enrolled only HCC with tumour sizes less
than 3 cm.19 In another randomized study, which
enrolled HCC with tumour sizes less than 3 cm, the 3-
year local recurrence rate after PAI was 31%.21 In this
study, we enrolled HCC with tumour size less than or
equal to 4 cm and so the local recurrence rate in our
study might be higher.
In this study, we found PAI required fewer sessions
of treatments and smaller volume of injection materi-
als to achieve complete tumour necrosis. More treat-
ment sessions may cause more discomfort of the
patient, an increased risk of complications and
increased medical costs.
310 W . - L . T S A I et al.

No procedure related mortality developed in this
study. One patient (1.4%) in the PAI group developed
major complications and no patient in the PEI group
developed major complications. Minor complications
after PAI or PEI were also similar and all could be
treated conservatively. So PAI could be performed as
easily and safely as PEI with similar adverse events.
One randomized study, two cohort studies and one
retrospective casecontrol study comparing surgical
resection and PEI did not find significant differences in
survival between surgical resection and PEI.7, 8, 31, 32
Although PAI was shown to provide survival benefits
over PEI in this study, there has been no study to eval-
uate the clinical outcome of surgical resection and PAI.
Further randomized studies are required to compare the
outcome of PAI and surgical resection.
The clinical outcome of RFA vs. PAI remained
unclear. There is only one randomized controlled study
that compared the outcome of RFA and PAI until
now.21 The study found that RFA and PAI had similar
new tumour recurrence rate, but RFA yielded better
overall survival than PAI in HCC with tumour sizes of
23 cm, but not in tumour sizes less than 2 cm, but a
higher major complication rate was found in the RFA
group. Further randomized studies are required to
compare the clinical outcome and complication rates
of RFA vs. PAI.
In our previous study, we found that a single session
of high-dose PAI (mean injected volume: 6.4 mL) is
safe and effective for treatment of small HCC.33 Fur-
ther studies to compare the outcome of a single ses-
sion of high dose PAI with PEI or RFA might be
required to confirm the efficacy of this treatment
method.
Although this is not a randomized study, the base-
line characteristics between patients who received PAI
or PEI were not different and the patients enrolled
received follow-up prospectively. Further randomized
controlled study with long-term follow-up to compare
the outcome of PAI vs. PEI may be required.
In conclusion, PAI required fewer treatment sessions
than PEI and provided better survival after long-term
follow-up. Adverse events were similar.
ACKNOWLEDGEMENTS
Declaration of personal interests: None. Declaration
of funding interests: This study was funded by
Kaohsiung Veterans General Hospital, funding
VGHKS88-57.

REFERENCES
1 Kao JH, Chen DS. Changing disease bur-
den of hepatocellular carcinoma in the
FarEast and Southeast Asia. Liver Int
2005; 25: 696703.
2 Llovet JM, Schwartz M. Resection and
liver transplantation for hepatocellular
carcinoma. Semin Liver Dis 2005; 25:
181200.
3 Bruix J, Sherman M, Llovet M, et al.
EASL panel of experts on HCC: clini-
cal management of hepatocellualr
carcinoma. Conclusions of the
Barcelona-2000 EASL conference.
European Association for the Study of
the Liver. J Hepatol 2001; 35: 421
30.
4 Beaugrand M, NKontchou G, Seror O,
Ganne N, Trinchet JC. Local Regional
and systemic treatments of hepatocellu-
lar carcinoma. Semin Liver Dis 2005;
25: 20111.
5 Hou TI, Huang YS, Wu JC. Percutaneous
ablation therapy for hepatocellular car-
cinoma: current practice and future per-
spectives. J Chin Med Assoc 2005; 68:
1559.
6 Omata M, Tateishi R, Yoshida H, Shiina
S. Treatment of hepatocellular carci-
noma by percutaneous tumor ablation
methods: ethanol injection therapy and
radiofrequency ablation. Gastroenterol-
ogy 2004; 127 (Suppl 1): S15967.
7 Huang GT, Lee PH, Tsang YM, et al.
Percutaneous ethanol injection versus
surgical resection for the treatment of
small hepatocellular carcinoma: a pro-
spective study. Ann Surg 2005; 242:
3642.
8 Yamamoto J, Okada S, Shimada K, et al.
Treatment strategy for small hepatocel-
lular carcinoma: comparison of long-
term results after percutaneous ethanol
injection therapy and surgical resection.
Hepatology 2001; 34: 70713.
9 Lencioni RA, Allgaier HP, Olschwski M,
et al. Small hepatocellular carcinoma in
cirrhosis: randomized comparison of
radio-frequency thermal ablation versus
percutaneous ethanol injection. Radiol-
ogy 2003; 228: 23540.
10 Lin SM, Lin CJ, Lin CC, Hsu CW, Chen
YC. Radiofrequency ablation improves
prognosis compared with ethanol injec-
tion for hepatocellular carcinoma
4 cm. Gastroenterology 2004; 127:
171423.
11 Shiina S, Teratani T, Obi S, et al. A ran-
domized controlled trial of radiofre-
quency ablation with ethanol injection
for small hepatocellular carcinoma.
Gastrotenterology 2005; 129: 12230.
12 Livraghi T, Solbiati L, Melonji MF,
Gazelle GS, Halpern EF, Goldberg SN.
Treatment of focal liver tumors with
percutaneous radiofrequency ablation:
complications encountered in a multi-
center study. Radiology 2003; 226: 441
51.
13 Mulier S, Mulier P, Ni Y, et al. Compli-
cations of radiofrequency coagulation
of liver tumors. Br J Surg 2002; 89:
120622.
14 Stasi MD, Buscarini L, Livraghi T, et al.
Percutaneous ethanol injection in the
treatment of hepatocellular carcinoma:
a multicenter survey of evaluation

2008 The Authors, Aliment Pharmacol Ther 28, 304311

Journal compilation 2008 Blackwell Publishing Ltd

practices and complication rates. Scand
J Gastroenterol 1997; 32: 116873.
15 Hou TI, Lee SD, Wu JC. Ethanol injec-
tion versus radiofrequency ablation for
hepatocellular carcinoma: which is bet-
ter. Gastroenterology 2005; 128: 8067.
16 Ebara M, Okabe S, Kita K, et al. Percuta-
neous ethanol injection for small hepa-
tocellular carcinoma. J Hepatol 2005;
43: 45864.
17 Lencioni R, Cioni D, Crocetti L, et al.
Early-stage hepatocellular carcinoma in
cirrhosis: long-term results of percuta-
neous image-guided radiofrequency
ablation. Radiology 2005; 234: 9617.
18 Lencioni R, Llovet JM. Percutaneous
ethanol injection for hepatocellular car-
cinoma: alive or dead? J Hepatol 2005;
43: 37780.
19 Ohnishi K, Yoshioka H, Ito S, Fujiwara
K. Prospective randomized controlled
trial comparing pecutaneous acetic acid
injection and percutaneous ethanol
injection for small hepatocellular carci-
noma. Hepatology 1998; 27: 6772.
20 Hou TI, Huang YH, Wu JC, Lee PC,
Chang FY, Lee SD. Comparison of pre-
cutaneous acetic acid injection and per-
cutaneous theanol injection for
hepatocellular carcinoma in cirrhotic
patients: a prospective study. Scand J
Gastroenterol 2003; 38: 7708.
21 Lin SM, Lin CJ, Lin CC, Hsu CW, Chen
YC. Randomized controlled trial com-
2008 The Authors, Aliment Pharmacol Ther 28, 304311
Journal compilation 2008 Blackwell Publishing Ltd
C L I N I C A L T R I A L : A C E T I C A C I D V S . E T H A N O L F O R H C C 311
paring percutaneous radiofrequency
thermal ablation, percutaneous thanol
injection, and percutaneous acetic acid
injection to treat hepatocellular carci-
noma of 3 cm or less. Gut 2005; 54:
11516.
22 Ohnishi K, Ohyama N, Ito S, Fujiwara K.
Ultrasound guided intratumor injection
of acetidc acid for the treatment of
small hepatocellular carcinoma. Radiol-
ogy 1994; 193: 74752.
23 Shiina S, Teratani T, Obi S, Hamamura
K, Koike Y, Omata M. Percutaneous
ethanol injection therapy for liver
tumors. Eur J Ultrasound 2001; 13:
95106.
24 Lin XD, Lin LW. Local injection therapy
for hepatocellular carcinoma. Hepatobil-
iary Pancreat Dis Int 2006; 5: 1621.
25 Lencioni R, Crocetti L. A critical apprai-
sal of the literature on local ablative
therapies for hepatocellular carcinoma.
Clin Liver Dis 2005; 9: 30114.
26 Llovet JM, Vilana R, Bru C, et al.
Increased risk of tumor seeding after
percutaneous radiofrequency for single
hepatocellular carcinoma. Hepatology
2001; 33: 11249.
27 Kurkohchi K, Watanabe S, Masaki T,
et al. Combination therapy of percuta-
neous ethanol injection and radiofre-
quency ablation against hepatocellular
carcinoma difficult to treat. Int J Oncol
2002; 21: 6115.
28 Timpl R, Wiedemann H, Delden VV,
Furthmayr H, Kuhn K. A network model
for the organization of type IV collagen
molecules in basement membranes. Eur
J Biochem 1981; 120: 20311.
29 Sala M, Llovet JM, Vilana R, et al. Ini-
tial response to percutaneous ablation
predicts survival in patients with hepa-
tocellular carcinoma. Hepatology 2004;
40: 135260.
30 Koda M, Murawaki Y, Mitsuda A, et al.
Predictive factors for intrahepatic recur-
rence after percutaneous ethanol injec-
tion therapy for small hepatocellular
carcinoma. Cancer 2000; 88: 52937.
31 Castells A, Bruix J, Bru C, et al. Treat-
ment of small hepatocellular carcinoma
in cirrhotic patients: a cohort study
comparing surgical resection and percu-
taneous ethanol injection. Hepatology
1993; 18: 11216.
32 Daniele B, De Sio I, Izzo F, et al. CLIP
Investigators. Hepatic resection and per-
cutaneous ethanol injection as treat-
ments of small hepatocellular
carcinoma: Cancer of the Liver Italian
Program (CLIP 08) retrospective case
control study. J Clin Gastroenterol
2003; 36: 637.
33 Liang WL, Yang CF, Pan HB, et al.
Small hepatocellular carcinoma: safety
and efficacy of single high-dose percu-
taneous acetic acid injection treatment.
Radiology 2000; 214: 76974.