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1694
Percutaneous Microwave Coagulation Therapy for
Patients with Small Hepatocellular Carcinoma
Comparison with Percutaneous Ethanol Injection Therapy
Toshihito Seki, M.D.1
Masayuki Wakabayashi,
Taiichi Nakagawa, M.D.1
Masato Imamura, M.D.1
Toru Tamai, M.D.1
Akira Nishimura, M.D.1
Noriyo Yamashiki, M.D.1
Akiharu Okamura, M.D.2
Kyoichi Inoue, M.D.1
BACKGROUND. The authors compared the efficacy of percutaneous microwave
1
M.D.
1
Third Department of Internal Medicine, Kansai
Medical University, Moriguchi, Osaka, Japan.
2
Department of Clinical Pathology, Kansai Medical
University, Moriguchi, Osaka, Japan.
coagulation therapy (PMCT) and percutaneous ethanol injection therapy (PEIT) in
the treatment of patients with cirrhosis and a solitary nodular hepatocellular
carcinoma (HCC) # 2 cm in greatest dimension.
METHODS. Of 43 patients with well-differentiated HCC, 23 were treated with PMCT
and 20 with PEIT. Of the 47 patients with moderately or poorly differentiated HCC,
25 were treated with PMCT and 22 with PEIT. In a retrospective, nonrandomized
study, the prognoses of 90 patients during the 12–72 months preceding the study
were analyzed according to histologic tumor grade.
RESULTS. The overall 5-year survival rates for patients with well-differentiated HCC
treated with PMCT (70%) and PEIT (78%) were not significantly different. No
difference between the patterns of recurrence was observed. Among the patients
with moderately or poorly differentiated HCC, overall survival with PMCT (5-year
survival rate: 78%) was significantly better than with PEIT (5-year survival rate:
35%) (P 5 0.03). Nine of 22 patients with moderately or poorly differentiated HCC
treated with PEIT experienced recurrence in the original target subsegment. Only
2 of 25 patients treated with PMCT had a recurrence in the same subsegment as the
initial tumor.
CONCLUSIONS. PMCT may be superior to PEIT for the local control of moderately
or poorly differentiated small HCC. Cancer 1999;85:1694 –702.
© 1999 American Cancer Society.
KEYWORDS: microwave coagulation, hepatocellular carcinoma, tumor cell differentiation, ethanol injection, percutaneous local treatment.
S
Address for reprints: Toshihito Seki, M.D., Third
Department of Internal Medicine, Kansai Medical
University, 10-15 Fumizonocho, Moriguchi, Osaka
570-8507, Japan.
Received June 25, 1998; revision received November 23, 1998; accepted December 7, 1998.
© 1999 American Cancer Society
urgical resection, transcatheter arterial embolization (TAE), and
ultrasound (US)-guided percutaneous ethanol injection therapy
(PEIT) are used alone or in combination as the initial treatment for
small hepatocellular carcinoma (HCC). However, surgical resection is
not a viable option for all patients due to poor liver function induced
by chronic liver disease (cirrhosis). Furthermore, TAE is ineffective
sometimes because of inadequate angioneogenesis in small HCCs.1
For these reasons, PEIT is widely performed as a local treatment
because of its simplicity and minimal invasiveness. It has been reported by many that PEIT is a satisfactory therapeutic modality.2– 8
However, PEIT occasionally has been found to be ineffective when
there is intra- or extracapsular invasion, because the injected ethanol
is blocked by the fibrous capsule and fails to reach the tumor cells.2,9
In some cases, the injected ethanol may flow into the vessels surrounding the tumor instead of causing tissue necrosis.
Microwave Coagulation for Small HCC/Seki et al.
To overcome the disadvantages of PEIT, percutaneous microwave coagulation therapy (PMCT) was
developed to induce more complete tumor necrosis
for the local treatment of HCC. In a previous study, we
suggested that PMCT may be an effective percutaneous local treatment for small HCCs.10 However, we
had no available data to compare the long term therapeutic efficacy of PMCT and PEIT.
In this study, we retrospectively compared PMCT
with PEIT in patients with solitary small HCCs measuring 2.0 cm or less in greatest dimension according
to the histologic grade of the tumor, because it has
been reported that tumor cell differentiation is associated closely with recurrence and prognosis.11–15
1695
lumped together in a single group because of the small
numbers of patients with poorly differentiated HCC.
In this study, there were no patients with severe
bleeding tendency or ascites. Furthermore, tumors located at sites near the liver surface showing extrahepatic extension were excluded because of the difficulty
in maintaining the puncture line.
Each patient and one family member chose the
initial treatment after they were informed of the advantages and disadvantages of both PMCT and PEIT.
The purpose of the study and all procedures were
explained thoroughly to the patients, and informed
consent was obtained from each patient and one family member.
PATIENTS AND METHODS
Patients
Ninety patients with cirrhosis and a solitary nodular
HCC measuring # 2.0 cm in greatest dimension who
were admitted to Kansai Medical University and its
affiliated hospital between September 1990 and March
1997 were qualified to undergo US-guided percutaneous local treatment. They either were not candidates
for surgical resection due to impaired liver function or
had requested US-guided percutaneous treatment as
the initial therapy despite having operable small
HCCs.
The tumors were all classified as Stage I according
to the International Union Against Cancer.16 Cancer
staging was performed using ultrasonography, dynamic computed tomography (CT), dynamic magnetic resonance imaging, and digital subtraction angiography. The histologic diagnosis was confirmed by
US-guided fine-needle biopsy. The lesions were biopsied twice, and two specimens were obtained from
each tumor. These specimens were assessed blindly
by two authors independently. The histologic grade of
differentiation was defined as follows: well differentiated, corresponding to Edmondson’s Grade I or I–II;
moderately differentiated, corresponding to Edmondson’s Grade II or II–III; or poorly differentiated, corresponding to Edmondson’s Grade III or IV.17 In cases in
which there was a discrepancy in the differentiation of
the two biopsied specimens, indicating heterogeneity
in the differentiation of the tumor, the tumor was
assigned to the lower degree of differentiation.
Of the 43 patients with well differentiated HCC, 23
were treated with PMCT, and 20 were treated with
PEIT. Of the 47 patients with moderately or poorly
differentiated HCC, 25 (24 moderately differentiated
HCCs, 1 poorly differentiated HCC) were treated with
PMCT, and 22 (21 moderately differentiated HCCs, 1
poorly differentiated HCC) were treated with PEIT.
The moderately and poorly differentiated HCCs were
Methods
Microwave coagulation system
The frequency of the microwave used for our system is
2450 mHz 6 50 mHz, which is internationally recognized as an Industrial, Scientific, and Medical (ISM)
band. The microwave is generated by a magnetron in
a microwave generator (Microtaze OT-110M; Nippon
Syouji Kaisya, Osaka, Japan). The electric energy of the
microwave is supplied to a high frequency coaxial
cable with an impedance of 50 Ohm through an isolated sympathizer cavity in the generator and then
conducted to an electrode attached to another end of
the cable for irradiation from the tip to the tissue. For
easy manipulation, we used a coaxial cable 2.5 meters
long with a diameter of 5.7 mm. The structure of the
electrode (MD-20CDL-10/25; Nippon Syouji Kaisya)
from the tip to the other end consists of an antenna 10
mm long made of stainless steel, an insulator 2 mm
long made of polytetrafluorethlyene, and a coaxial
construction 238 mm long, the inner conductive rod
of which is made of silver-plated tool steel and is
electrically connected to the antenna. The outer conductor of the coaxial construction is made of nickelplated brass and is an outer electrode. The electrode
measures 2.0 mm in diameter and 25 cm in length.
It is known from the specific absorption rate (SAR)
distribution of this kind of heating system that heating
is limited to the area adjacent to the antenna. Our
electrode generates an electromagnetic field surrounding the insulator, and the heated area of the
tissue is limited to and focused on the area adjacent to
the tip of the electrode.18,19 To avoid unintended and
unexpected irradiation, the generator is equipped with
a fail-safe system so that the microwave cannot be
irradiated unless both the inner and outer electrodes
completely contact the tissue.
1696
CANCER April 15, 1999 / Volume 85 / Number 8
PMCT
The procedure of PMCT was carried out as described
previously.10 After local anesthesia under US guidance, a guide needle was inserted in the vicinity of the
tumor. After the inner needle of the guide was removed, the microwave electrode was inserted through
the outer needle of the guide to place the electrode in
the tumor area. The electrode was connected to the
microwave generator by a flexible coaxial cable. The
tumor area was irradiated with microwaves. The electrode and the outer needle of the guide were removed.
The puncture track was irradiated with microwaves to
prevent bleeding from the hepatic surface when the
electrode was removed.
In a previous study, we used of a thin microwave
electrode measuring 1.6 mm in diameter and 30 cm in
length for PMCT. However, this electrode could not
produce an extensive necrotic area with one-time microwave irradiation, because the electrode could not
withstand high power microwaves, e.g., 80 W, with
microwaves at 60 W for 120 seconds using a thin type
electrode, the coagulated area elliptic, with maximal
and minimal dimensions of 2.4 cm 6 0.4 cm and 1.6
cm 6 0.3 cm, respectively, in normal rabbit liver tissue
in vivo.10 Therefore, repeated electrode insertions are
required to obtain a sufficiently large treated margin.
In this study, to overcome the disadvantages of the
thin type electrode, we used a microwave electrode
measuring 2.0 mm in diameter and 25 cm in length
that could withstand high power microwave irradiation and a 13-gauge guide needle. The coagulated area
induced by high power microwave irradiation is larger
than that induced by low power irradiation. With microwaves at 80 W for 60 seconds using a thick electrode, the coagulated area was elliptical, measuring
3.1 cm 6 0.5 cm in maximal dimension and 2.2 cm 6
0.4 cm in minimal dimension on normal rabbit liver
tissue in an in vivo test.
With regard to the irradiation time, 60 seconds
was optimal for obtaining the maximal coagulated
area. Even if microwave irradiation was continued for
more than 60 seconds, the coagulated area would be
much the same as that obtained with 60 seconds of
irradiation in an in vivo test using normal rabbit liver
tissue.
At each session, the multiple electrode insertions
were performed on the tumor, including different sites
in its proximity, and one microwave irradiation at 80
W for 60 seconds was performed for each electrode
insertion until the hyperechogenic change covered the
entire tumor to produce extensive necrosis, depending on the size of the tumor and the change seen on
echo images. Two to four microwave irradiations
(equal to two to four electrode insertions for different
sites) could change the echo image of the tumor area
to a high echo area that included not only the tumor
but also the neighboring noncancerous tissue. When
this change in the echo images was achieved, we finished the initial session.
PEIT
PEIT was performed as described previously.2 After
local anesthesia, a 21-gauge, 25-cm needle was introduced into the tumor under US guidance. Approximately 2– 4 mL of ethanol were mixed with 1% lidocaine at a ratio of 9 to 1 (99.5% in 1% lidocaine) and
injected into the tumor and into two or three different
sites in its proximity (one session). For the purpose of
acquiring reliable local control of the tumor, we tried
to induce a 5-mm or greater margin of necrosis in the
noncancerous tissue surrounding the tumor (the
treated margin; Fig. 1).
To assess the necrotic area, dynamic CT was performed 2–3 days after each treatment. When the initial
session (PMCT or PEIT) failed to obtain the treated
margin, the next session was performed under US
guidance with reference to postdynamic CT images
taken after the initial session. Therefore, the total
number of sessions was determined by dynamic CT
image findings. We performed both PMCT and PEIT
twice a week. To evaluate the efficacy of PMCT and
PEIT independently, TAE was not performed as part of
the therapy.
Follow-up
Following discharge from the hospital, all patients
were followed closely. Follow-up ultrasonography was
performed every 2 months. Dynamic CT and dynamic
magnetic resonance imaging were performed every
3–5 months. Serum alpha-fetoprotein concentrations
were measured monthly. The clinical observation periods following treatment ranged from 12 months to
72 months.
Classification of the pattern of recurrence
Intrahepatic recurrences were classified into five
types, as follows: Type A, a single recurrent nodule at
the margin of treatment or enlargement of the treated
tumor; Type B, a single recurrent nodule in the same
subsegment as the initial tumor; Type C, recurrent
nodules in the same subsegment as the initial tumor
or in multiple subsegments, including the same subsegment as the initial tumor; Type D, a single recurrent nodule in a different subsegment than that in
which the initial nodule was seen; and Type E, recurrent nodules in multiple subsegments without involvement of the subsegment in which the initial nod-
Microwave Coagulation for Small HCC/Seki et al.
1697
FIGURE 1. Dynamic computed tomographies obtained before and 1 week after percutaneous microwave coagulation therapy
(PMCT). (a) Before treatment. The tumor site
(white arrow; tumor size 5 1.8 cm in greatest dimension) was demonstrated as a enhanced area. (b) One week after treatment
(five microwave irradiations). PMCT induced
a sufficient treated margin. The tumor and
the surrounding area were not enhanced.
ule was seen. Subsegments were defined according to
Couinaud’s segmental model of the liver.20 When an
intrahepatic recurrence was suspected on imagings
studies, we performed digital subtraction angiography
and US-guided liver biopsy to confirm the diagnosis.
Treatment of recurrences
In patients with a single recurrent nodule measuring
2.0 cm or less in greatest dimension, we performed
PMCT or PEIT. For a recurrence after treatment with
PMCT, PMCT was performed again. For patients previously treated with PEIT, PEIT was performed again.
In patients with a single recurrent nodule measuring
more than 2.0 cm in greatest dimension or with multiple recurrent nodules, we performed TAE in combination with PMCT or PEIT.
Statistical analysis
Patient age and tumor size are expressed as the
mean 6 standard deviation. We used the chi-square
test to compare values between groups, applying Yates
correction when needed. Continuous variables were
compared by means of the Mann–Whitney U test.
Cumulative survival rates and cumulative cancer free
survival rates were calculated by using the Kaplan–
Meier method.21 Differences in survival and cancer
free survival were analyzed with the generalized Wilcoxon test.22 A P value of ,0.05 was considered statistically significant.
RESULTS
There were no differences with regard to age, gender,
status of the underlying liver disease, tumor size, or
serum alpha-fetoprotein concentration between the
two treatment groups (Table 1). At the time of analysis,
no difference was evident with regard to the median
follow-up times of patients subjected to PMCT (well
differentiated HCC: 30 months; range, 12– 63 months;
moderately or poorly differentiated HCC: 34 months;
range, 14 – 68 months) or PEIT (well differentiated
HCC: 32 months; range, 13–71 months; moderately or
poorly differentiated HCC: 33 months; range, 12–72
months). None of the patients dropped out during the
follow-up period in this study.
Treatment Efficacy
The PMCT of the tumors was finished within one week
in all patients. The number of sessions was one or two
(mean, 1.6 sessions).
After three to four microwave irradiations (60 seconds comprised one microwave irradiation) were performed on a tumor %1.5 cm, including different sites
in its proximity, and four to six irradiations were performed on a tumor .1.5 cm in greatest dimension,
including different sites in its proximity, 45 of 48 patients showed complete necrosis of the tumor lesion
with a treated margin $ 5 mm on dynamic CT. To
obtain a treated margin $ 5 mm, large numbers of
microwave irradiations (six electrode insertions) were
necessary for some patients. This may have been due
to the cooling effect of circulated blood.
In the other 3 patients (2 patients with well differentiated HCC and 1 patient with moderately differentiated HCC), despite showing complete necrosis of the
tumor lesion, the parenchyma surrounding the tumor
1698
CANCER April 15, 1999 / Volume 85 / Number 8
TABLE 1
Clinical Characteristics of Patients with a Single Hepatocellular Carcinoma
Histologic grade
Well
M or P
Characteristic
PEIT (n 5 20)
PMCT (n 5 23)
P valuea
PEIT (n 5 22)
PMCT (n 5 25)
P valuea
Gender (M:F)
Age (yrs)b
Child-Pugh class (A/B/C)
HCV/HBV/unknown
Maximal tumor size (mm)b
AFP (ng/mL)
#10
11–100
.100
17:3
61.5 6 8.6
13/5/2
19/1/0
16.3 6 3.0
20:3
60.9 6 7.9
15/8/0
18/4/1
16.0 6 3.4
NS
NS
NS
NS
NS
20:2
61.0 6 8.4
11/10/1
21/1/0
18.8 6 2.4
22:3
65.2 6 8.0
12/12/1
23/1/1
18.3 6 2.3
NS
NS
NS
NS
NS
11
8
1
8
13
2
NS
NS
NS
4
15
3
3
20
2
NS
NS
NS
Well: well-differentiated; M or P: moderately or poorly differentiated; PEIT: percutaneous ethanol injection therapy; PMCT: percutaneous microwave coagulation therapy; NS: not significant; HCV: hepatitis C virus;
HBV: hepatitis B virus; AFP: alpha-fetoprotein.
a
Mann–Whitney U test or chi-square test with Yates correction.
b
Data are expressed as the mean 6 standard deviation.
still was viable. This was because PMCT could not be
performed extensively due to the presence of the gall
bladder or to large vessels near the tumor.
There were no clinically serious side effects or
complications associated with PMCT in this study.
Most patients reported a heat sensation in the upper
abdominal region. Half of them experienced some
pain during treatment, but it was not severe enough to
warrant cessation of treatment. None of the patients
in this study refused to continue PMCT.
PEIT was performed for three to five sessions per
tumor. The total amount of injected ethanol was 12–20
mL for each tumor. Twenty-six of 42 patients had
complete necrosis of the tumor lesion with a treated
margin $ 5 mm on dynamic CT. In the other 16
patients (7 patients with well differentiated HCC and 9
patients with moderately or poorly differentiated
HCC), the dynamic CT showed complete necrosis of
the tumor lesion, but the treated margin was not acquired completely, because the injected ethanol
flowed into the branch of the portal vein or the hepatic
vein around the tumor instead of remaining homogeneously in the marginal area despite multiple injections (maximum, 10 injections).
There were no clinically serious side effects or
complications associated with PEIT. Almost all patients suffered transient pain during ethanol injection.
Survival
The 5-year overall survival rate for patients with well
differentiated HCC treated with PMCT was 70%,
whereas that for patients treated with PEIT was 78%.
FIGURE 2. Overall survival of patients with moderately or poorly differentiated hepatocellular carcinoma (HCC) treated with percutaneous microwave
coagulation therapy (PMCT) or percutaneous ethanol injection therapy (PEIT).
The survival of patients treated with PMCT (n 5 25) was significantly higher
than that of patients treated with PEIT (n 5 22) at 5 years (P 5 0.03). Heavy
line: PMCT; light line: PEIT; section sign: death by HCC progression (initial
therapy, PEIT); cross with dots: death by HCC progression (initial therapy,
PMCT).
The difference between the two treatment groups was
not statistically significant (P 5 0.85).
The 5-year overall survival rate for patients with
moderately or poorly differentiated HCC treated with
PMCT was 78%, whereas that for patients treated with
PEIT was 35%. The difference in overall survival between the two treatment groups was statistically significant (P 5 0.03; Fig. 2).
Among the patients treated with PEIT, the 5-year
overall survival rate associated with well differentiated
HCC was considered significantly better than that for
Microwave Coagulation for Small HCC/Seki et al.
1699
TABLE 2
Pattern of Recurrence after Initial Therapy
Histologic gradea
Well
FIGURE 3. Cancer free survival of patients with moderately or poorly
differentiated hepatocellular carcinoma (HCC) treated with percutaneous microwave coagulation therapy (PMCT) or percutaneous ethanol injection therapy
(PEIT). There was no significant difference in cancer free survival between the
two groups (P 5 0.17). Heavy line: PMCT: light line: PEIT.
patients with moderately or poorly differentiated HCC
(P 5 0.04). Conversely, among the patients treated
with PMCT, the 5-year overall survival rate was slightly
higher for those with moderately or poorly differentiated HCC than for those with well differentiated HCC.
However, this difference was not statistically significant (P 5 0.45).
Cancer Free Survival Rate
The 4-year cancer free survival rate for patients with
well differentiated HCC treated with PMCT was 37%,
whereas that for patients treated with PEIT was 39%.
This difference was not statistically significant (P 5
0.37).
The 4-year cancer free survival rate for patients
with moderately or poorly differentiated HCC treated
with PMCT was 30%, whereas that for patients treated
with PEIT was 18%. This difference was not statistically significant (P 5 0.17; Fig. 3). However, 9 of 13
patients who had a recurrence after treatment with
PEIT recurred within 2 years. This is in contrast to
recurrences that occurred throughout the follow-up
period in the patients treated with PMCT. At present,
we cannot obtain the 5-year cancer free survival rates
for the two treatment groups in this study.
Pattern of Recurrence
In patients with well differentiated HCC, there were no
differences in the pattern of recurrence between the
two therapeutic groups. Furthermore, there was no
correlation between the recurrence pattern and the
response to therapy. Of 7 patients who were without
complete necrosis of the surrounding parenchyma after PEIT, 2 patients experienced a recurrence: Type B
(1 patient) or Type D (1 patient). Two patients who
M or P
Recur. p.\initial therapy
PEIT
PMCT
PEIT
PMCT
Type A
Type B
Type C
Type D
Type E
0
3
0
7
1
0
2
0
5
1
2
2
5
2
2
0
2
0
7
1
Well: well differentiated; M or P: moderately or poorly differentiated; Recur. p.: recurrence pattern (the
types of recurrences are described in Methods); PEIT: percutaneous ethanol injection therapy; PMCT:
percutaneous microwave coagulation therapy.
a
Statistical significance: M or P, PEIT versus PMCT (Type A 1 Type B 1 Type C) versus (Type D 1 Type
E): P 5 0.03; chi-square test.
were without complete necrosis of the surrounding
parenchyma after PMCT had not experienced a recurrence.
Among the patients with moderately or poorly
differentiated HCC, there were 2 with Type A recurrence in patients treated with PEIT. Furthermore,
Type C recurrence was more frequent with PEIT than
with PMCT. Type A and Type C recurrence was not
observed in patients treated with PMCT.
Of nine patients who were without complete necrosis of the surrounding parenchyma after PEIT, 8
developed recurrence in the original target subsegment: Type A (2 patients), Type B (1 patients), and
Type C (5 patients). One patient who was without
complete necrosis of the surrounding parenchyma after PMCT experienced a Type B recurrence.
Type D recurrence was more frequent in patients
treated with PMCT than in patients treated with PEIT.
Recurrence after PMCT was observed mainly in a different subsegment than the original tumor (P 5 0.03;
Table 2). No extrahepatic recurrence was seen in any
patients.
Histologic Grade of Recurrent Nodules
Recurrent nodules in patients with an initial well differentiated HCC nodule usually were well differentiated, regardless of the therapy. Nine of 11 recurrences
(Type B, 2 patients; Type D, 6 patients; Type E, 1
patient) after initial PEIT and 6 of 8 recurrences (Type
B, one patient; Type D, 5 patients) after initial PMCT
were well-differentiated HCC.
In patients with an initial moderately or poorly
differentiated HCC treated with PEIT, 9 of 13 recurrences (Type A, 2 patients; Type B, 2 patients; Type C,
5 patients) were moderately or poorly differentiated.
1700
CANCER April 15, 1999 / Volume 85 / Number 8
There were 4 well-differentiated recurrences (Type D,
2 patients; Type E, 2 patients). Conversely in the patients treated with PMCT, 7 of 10 recurrences (Type B,
1 patient; Type D, 6 patients) were well differentiated.
The other three patients showed moderately or poorly
differentiated recurrence.
TABLE 3
Causes of Death in Patients with Hepatocellular Carcinoma Treated
with Percutaneous Ethanol Injection Therapy or Percutaneous
Microwave Coagulation Therapy
Histologic grade
Well
Treatment of Recurrence
In patients with an initial well differentiated HCC,
PEIT was performed for 10 recurrences, and PMCT
was carried out for 7. TAE was performed for only 2
patients.
After treatment for moderately or poorly differentiated HCC, PEIT was performed for 5 recurrences,
and PMCT was performed for 9. TAE (in combination
with PEIT/PMCT) was performed for 9 recurrences. Of
the 9 recurrences treated with TAE, 8 had undergone
PEIT as the initial treatment. Of 16 recurrences treated
with PMCT, 15 demonstrated complete necrosis of the
recurrent lesion with a treated margin $ 5 mm. Of 15
recurrences treated with PEIT, 11 showed complete
necrosis of the recurrent lesion with a treated margin $ 5 mm. Definite local recurrences of treated
recurrent nodules were observed in 1 patient after
retreatment by PEIT. Moreover, in some patients (10
patients retreated with PMCT, 9 patients retreated
with PEIT), other types of recurrence were detected
during the follow-up period. Of 11 patients treated
with TAE, 10 developed the tumor regrowth or multiple recurrent nodules. Of 42 recurrent patients in this
study, 28 remain alive at present.
Causes of Death
No differences in causes of death were found between
the two therapeutic groups among the patients with
well-differentiated HCC. Among the patients with
moderately or poorly differentiated HCC, deaths due
to HCC progression were common after PEIT (Fig. 1,
Table 3). Seven patients with Type A recurrence (1
patient), Type B recurrence (1 patient), or Type C
recurrence (5 patients) after initial PEIT and 1 patient
with a Type E recurrence after initial PMCT died of
HCC progression despite several retreatments. No patients died of liver failure without HCC progression in
either group.
DISCUSSION
In this study, among the patients with well-differentiated HCC, there were no significant differences in
5-year overall survival, 4-year cancer free survival, or
pattern between the patients treated with PMCT and
those treated with PEIT. Generally speaking, well-differentiated, small HCC is a good indication for PEIT
because of the low incidence of intra- or extracapsular
M or P
Cause of death\initial therapy
PEIT
PMCT
PEIT
PMCT
HCC progression
Liver failure without HCC progression
Variceal bleeding
Others
2
0
1
1a
1
0
0
1b
7
0
1
1c
1
0
0
2d
Well: well differentiated; M or P: moderately or poorly differentiated; HCC: hepatocellular carcinoma;
PEIT: percutaneous ethanol injection therapy; PMCT: percutaneous microwave coagulation therapy.
a
Myocardial infarction.
b
Lung carcinoma.
c
Subarachnoidal haemorrhage.
d
Lung carcinoma and cerebral haemorrhage.
invasion, vascular invasion, and intrahepatic metastases, including microscopic metastatic lesions around
the main tumor.11 The therapeutic results with PEIT in
this study are in agreement with previous reports.23,24
Therefore, PEIT is indicated in cases of well differentiated, small HCC because of its simplicity and low
cost compared with PMCT.
Among the patients with moderately or poorly
differentiated HCC, the 5-year overall survival for patients treated with PMCT was higher than that for
patients treated with PEIT. The better overall survival
after PMCT may be related to the fibrous capsules or
intratumor septae that often are produced by moderately or poorly differentiated HCC.15,25 The ethanol
used in PEIT may not penetrate the capsule or the
septa, sparing cancer cells that have invaded beyond
the capsule. These few remaining viable cells in the
capsule or extracapsular area cannot be detected by
modern imaging techniques.9 In fact, although various
images indicated that PEIT had induced complete tumor necrosis, we often have observed viable cancer
cells persisting in the intracapsular or extracapsular
area in surgically resected specimens.2,8
Cancer cells remaining in the tumor capsule or
extracapsular area may produce local recurrences as
well as intrahepatic metastases and can worsen the
patient’s prognosis. It has been reported that the local
recurrence rate after PEIT is higher for small HCCs
with fibrous septae than for small HCCs without fibrous septae.26 We confirmed recurrences at the margin of treated nodules and a few patients with recurrent nodules in the same subsegment as the initial
tumor or in multiple subsegments, including the same
Microwave Coagulation for Small HCC/Seki et al.
subsegment as the initial tumor, after PEIT in this
study.
Moderately or poorly differentiated HCC has a
high incidence of microscopic metastases adjacent to
the primary tumor.11 We therefore try to produce extensive necrosis not only of the tumor lesion but also
of the surrounding normal parenchyma. The possibility that occult metastasic lesions persist in the surrounding parenchyma after treatment with PEIT may
be high.7 This may be because the ethanol, which is
injected into the parenchyma surrounding the tumor,
sometimes is distributed inhomogeneously or flows
into the vessels around the tumor instead of remaining in the tissue. In this study, some patients treated
with PEIT did not obtain adequate margins despite
inducing necrosis of the tumor lesion. Moreover, the
number of recurrences in the original target subsegment was higher after PEIT than after PMCT. These
results indicate that PEIT is less efficacious than PMCT
for the local control of moderately or poorly differentiated small HCCs, leading to a poorer prognosis. In
fact, in this study, among the patients with moderately
or poorly differentiated HCC, deaths due to HCC progression were common after PEIT. However, it is possible that the poorer survival in patients treated with
PEIT is related to liver damage due to the nonuniform
application of TAE in recurrent cases.
The cancer free survival rates for patients treated
with PMCT were similar to those for patients treated
with PEIT, but the types of recurrences and the histologic grade of recurrences differed. The recurrences
after PMCT were observed mainly in a different subsegment than the segment that contained the original
tumor. With regard to the histologic grade of recurrent
nodules after PMCT, 7 of 10 recurrent nodules were
well differentiated. On the other hand, after PEIT, 4 of
13 recurrent nodules were well differentiated. According to the previously reported criteria, well-differentiated, recurrent nodules may be metachronous multicentric developments without a correlation to initial
nodules.27–29
Regardless of the presence of a fibrous capsule,
intratumor septae, or vessels around the tumor, microwave irradiation can induce tissue coagulation
across a designated area if the tip of the microwave
electrode is located in the target area.10 The reliable
local control capability of PMCT may reduce intrahepatic metastases from a initial tumor or microscopic
metastases adjacent to the primary tumor and improve the patients prognosis. However, PMCT cannot
inhibit occurrences of metachronous multicentric tumors.
Therefore, the improved local control and the
ability to treat recurrences more successfully, includ-
1701
ing metachronous multicentric developments, may
explain why the overall survival for patients with moderately or poorly differentiated HCC treated with
PMCT is better than that for patients treated with PEIT
despite the similar cancer free survival rates for the
two groups. In fact, it has been reported that the
prognoses for patients showing metachronous multicentric development as recurrent nodules were superior to those for patients showing intrahepatic metastasis because percutaneous local treatments are
effective for well-differentiated, recurrent nodules.29
Unexpectedly, among the patients treated with
PMCT, the 5-year overall survival rate was slightly
higher for those with moderately or poorly differentiated HCC than for those with well-differentiated HCC.
The number of patients treated with PMCT may have
been too small to obtain accurate results. However,
this difference was not statistically significant. These
data indicate that PMCT demonstrated a good therapeutic effect for small HCCs measuring 2.0 cm or less
in greatest dimension despite different grades of tumors.
This study was not a prospective, randomized trial
and has the potential for selection biases of treatment
groups. Therefore, in assessing the therapeutic efficacy of PMCT, there is a great need for a multicenter,
randomized, controlled trial compared with PEIT or
other treatments with longer follow-up and a larger
series. Based on our experience, however, we think
that PMCT should have priority over PEIT for moderately or poorly differentiated small HCC because of its
better rate of local control. Although we did not perform PMCT for multiple small lesions in this study, we
consider that PMCT may be effective for multiple
small HCCs and small metastatic liver tumors due to
its reliable coagulation capability and mild invasiveness.
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