Original
IJ Tokyo Wom Med UnivI 84 (Extra 3)E342~E350 (2014)J
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Treatment o
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According t
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Recurrence a
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S
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Kunihiko AMANO
，
Shimpei OGAW
A and Shingo KAMEOKA Department of Surgery U， Tokyo Women's Medical University(Accepted October 17，2014)
Objective: Patients who underwent loca1 ablation for colorectalliver metastasis (CRLM) were analyzed to identify those who would benefit most from local ablation (LA). Materials and Methods: A total of 55 CRLM le -sions in 33 cases who underwent LA at our department from 1999 to 2004 were investigated. The local recurrence-free rate at出esite of ablation (true recurrence-free rate) and the distance between the lesion and the major intrahepatic vessels (MIVs) were analyzed. Results: True recurrence occurred in 29 lesions (52.7%)， and the 3・yeartrue recurrence-free rate was 44.3%. The threshold of maximal tumor diameter for recurrence was 1.8 cm. There was no true local recurrence for the small group (lesions less than1.8 cm)， and that group's 3-year true recurrence-free rate was signi自can
t
1
ybetter (small group vs large group (lesion三1.8
cm): 100% vs 27.7%， pく 0.0001). The 3ぅTeartrue recurrence-free rate for lesions far from MIV s (distance>
1 cm) was also significant
1
y bet -ter than that for lesionsc10se to MIV s (distance三1cm) (60.
1
% v
s 33%， p = 0.0152). Conclusion: In CRLM cases， le -sions less than1.8 cm and those further than 1 cm from MIV s are the most likely to benefit from LA.Key W ords: colorectalliver metastasis， local ablation， radiofrequency ablation， microwave coagulation
Introduction
According to the
J
apanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines for the Treatment of Colorectal Cancer 1)and guidelines prepared by the National Comprehensive Cancer Network2)， resection is recommended for colorectal liver metastasis (CRLM) in which curative resection can be carried ou
，
t
and hepatic infusion chemother-apy， systemic chemotherapy， and local ablation (such as radiofrequency ablation (RF A)， and micro -wave coagulation therapy (MCT)) are recom-mended for unresectable CRLM. U nlike chemother-apy， ablation is a local treatment modality， and it is less invasive in terms of larger remnant liver paren -chyma than with resection3).
I
t
is currently used as an adjunct with hepatic resection or used for the treatment of unresectable CRLMs4). Local ablation
is widely performed in the treatment of hepatocellu -lar carcinoma (HCC)5). However， there is no satisfac -tory evidence that supports its use in terms of local control and for the best indications for the treat
-ment of CRLMs 6). Therefore， the efficacy of and best indications for local ablation in terms of the 10 -cal recurrence“free rate at the site of local ablation
were retrospectively investigated by analyzing clinicopathological background characteristics and treatment outcomes of CLRM cases that under -went local ablation at our departmen
t
.
Materials and Methods
1
.
P
atientsA total of 33 cases in 26 patients who were fol -lowed up after treatment of the 35 cases that under -went ablation therapy at the Department of Sur -gery 2， Tokyo Women's Medical University， from 1999 to 2004 were studied retrospectively. Of the 33 cases，
8
had been previously treated with local abla -tion more than twice， and 55 CRLMs had been treated. The reasons for selecting local ablation were difficulty of curative resection in 20 cases (61%)，extrahepatic disease in 13 cases (39%)， aging or comorbidity in 7 cases (20%)， and concurrent he -patic resection in 7 cases (20%) (Overlapping rea -ヮ “ a 司 p uses defined by the ]SCC
R
.
There were 25 cases with H，
l
6 cases with H2， and 2 cases with H3. There were 8 cases with grade A， 7 cases with grade B， 14 cases with grade C， and 4 unknown Patients' characteristics Sex (number of patients) Male : Female 14: 12 Synchronous: Metachronous (number ofcases)10: 23 Age atablation (:tSD)(years) 63.6 (:t 10.8) CRC factorsT (numberofpatients) T1 T2 T3 T4 CRC factors N (number of patients)NO
N1 N2 N3 Unknown Histological type ofCRC (number of patients) Well differentiated adenocarcinoma Moderately differentiatedadenocarcinoma Poorly differentiated adenocarcinoma Unknown Liver metastasisat ablation(number of cases) ~ 0 H1 25m
6m
2 Grade classification of liver metastasis (numberofcases) A 8 B 7 C 14 Unknown4
Extrahepatic metastasisat ablation(number of cases) None 21 Distant lymph node metastasis Peritoneum L~ 8 Lung+ lymph node metastases 1 Local recurrence Change in theCEA level (number of cases) Decrease Increase Unknown Table 1 cases. Eleven cases underwent MCT. 14 cases under -went RFA， and8
cases underwent combination MCT and RF A. Overall， 25 cases were performed under laparotomy， and8
cases underwent percuta -neous local ablation. The median follow-up period after treatment was 402 days. Postoperative compli -cations included 2 cases of liver abscess in the MCT ハU n u p o n u つ 臼 F O ヴ ioo っ “ q υgroup， one case in the RF A group， and 1 case in the RF A and MCT group， with 1 case of pulmonary in -farction in the MCT group. Q d d A τ ハ u q u 可 。 ム 2. Methods
Images obtained by enhanced computed mography (equipment: Asteion and Aquilion， Toshiba， Tokyo， ]apan; HiSpeed CT， Proseed SA， and LightSpeed Ultra 16， GE Healthcare UK， Ltd， Little Chalfont， Buckinghamshire， UK) were used for preoperative diagnosis and measurement of tu -mor diameter. Superparamagnetic iron oxide or gadolinium-enhanced magnetic resonance imaging was also used for preoperative diagnosis (equip -ment: Signa
1
.
5T， GE Healthcare UK， Ltd， Litt
1
e Chalfon，
t
Buckinghamshire， UK). Biopsies were not performed for preoperative diagnosis of lesions di -agnosed clinically as CRLM.The distance between the tumor and major he -patic vessels was defined as the shortest distance between the tumor margin and major hepatic ves -sels. Major hepatic vessels were defined as subseg -mental and seg-mental portal vein branches， lef
，
t
right， middle， and accessory right inferior hepatic veins， and inferior vena cava. The distance between the tumor and major hepatic vessels was defined as close when it was less than or equal to 1 cm， and as to -口 δ q υ 円 L n 4 SD， standard deviation;CRC， colorectal cancer;CEA， carci -noembryonicantigen. sons are included). Cases with inadequate ablation according to the operative findings were excluded.The male to female ratio was 14: 12. The T and
N
distant when greater than 1 cm.
As the general criteria for selecting MCT or RF A factors of the primary colorectal cancers (CRCs) are
reported in Table
1
.
There were 10 cases of syn-chronous liver metastases. and 23 cases were me- at laparotomy， MCT was used for tumors in which the deepest location of the tumor from the liver sur -face was within 2 cm， and RF A was used for deeper lesions. Percutaneous MCT was not performed af -ter 2003. Percutaneous local ablation tachronous. Synchronous metastases were defined as CRLMs identified at the time or within 6 months per -was of the diagnosis of CR
C
.
H classification and Grade classification are the classifications of liver metasta --E343-formed whenever t
h
e
CRLM c
o
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p
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u
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a
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and n
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b
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a
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p
a
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-s
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c
t
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.
P
r
i
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'
s
maneuver was n
o
t
p
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d
d
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-i
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.
An
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，Osaka
，]
a
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was u
s
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f
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，and a
n
RIT
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A
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was p
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.
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System was 8
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W
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，and t
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a
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was 1
2
m
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s
f
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e
s
s
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n
.
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t
was a
l
s
o
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n
-d
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w
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tumor was a
b
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by c
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.
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r
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，i
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f
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e
n
t
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a
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was o
b
t
a
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d
f
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m
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p
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a
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t
.
A
f
t
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r
t
r
e
a
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nt
，
p
a
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n
t
s
were f
o
l
l
o
w
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d
up a
t
t
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o
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c
o
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c
e
a
month by c
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k
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n
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tumor m
a
r
k
e
r
s
，and r
e
c
u
r
r
e
n
c
e
was
r
e
g
u
l
a
r
l
y
c
h
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c
k
e
d
by p
e
r
f
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i
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g
a
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n
-h
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e
d
computed tomography o
r
u
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t
r
a
s
o
n
o
g
r
a
p
h
y
o
n
c
e
w
i
t
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i
n
a
n
i
n
t
e
r
v
a
l
o
f
3
t
o
6
m
o
n
t
h
s
.
T
h
i
s
s
t
u
d
y
was a
p
p
r
o
v
e
d
by t
h
e
E
t
h
i
c
s
Board o
f
Tokyo Women's M
e
d
i
c
a
l
U
n
i
v
e
r
s
i
t
y
.
3
.
A
n
a
l
y
s
i
s
1
)
C
o
m
p
a
r
i
s
o
n
between r
e
c
u
r
r
e
n
t
and n
o
n
-r
e
c
u
r
r
e
n
t
l
e
s
i
o
n
s
a
t
t
h
e
s
i
t
e
o
f
a
b
l
a
t
i
o
n
Maximal tumor d
i
a
m
e
t
e
r
and p
o
s
i
t
i
o
n
a
l
r
e
l
a
t
i
o
n
-s
h
i
p
s
t
o
t
h
e
m
a
j
o
r
v
e
s
s
e
l
s
were compared a
c
c
o
r
d
-i
n
g
t
o
r
e
c
u
r
r
e
n
c
e
a
t
t
h
e
s
i
t
e
o
f
a
b
l
a
t
i
o
n
(
t
r
u
e
l
o
c
a
l
r
e
c
u
r
r
e
n
c
e
)
.
The 3
・y
e
a
rl
o
c
a
l
r
e
c
u
r
r
e
n
c
e
-
f
r
e
e
r
a
t
e
s
were a
l
s
o
a
n
a
l
y
z
e
d
.
2
)
I
d
e
n
t
i
f
y
i
n
g
t
h
e
b
e
s
t
i
n
d
i
c
a
t
i
o
n
s
f
o
r
l
o
c
a
l
a
b
l
a
-t
i
o
n
The t
h
r
e
s
h
o
l
d
o
f
tumor maximal d
i
a
m
e
t
e
r
f
o
r
r
e
-c
u
r
r
e
n
c
e
a
t
t
h
e
s
i
t
e
o
f
a
b
l
a
t
i
o
n
was c
a
l
c
u
l
a
t
e
d
u
s
i
n
g
t
h
e
r
e
c
e
i
v
e
r
o
p
e
r
a
t
i
n
g
c
h
a
r
a
c
t
e
r
i
s
t
i
c
(ROC) c
u
r
v
e
，and t
h
e
g
r
o
u
p
w
i
t
h
t
u
m
o
r
s
h
a
v
i
n
g
a
s
i
z
e
l
e
s
s
t
h
a
n
t
h
e
t
h
r
e
s
h
o
l
d
was d
e
f
i
n
e
d
a
s
t
h
e
s
m
a
l
l
g
r
o
u
p
，a
n
d
t
h
e
g
r
o
u
p
w
i
t
h
t
u
m
o
r
s
h
a
v
i
n
g
a
s
i
z
e
g
r
e
a
t
e
r
t
h
a
n
t
h
e
t
h
r
e
s
h
o
l
d
was d
e
f
i
n
e
d
a
s
t
h
e
l
a
r
g
e
g
r
o
u
p
.
F
u
r
-t
h
e
r
m
o
r
e
，t
h
e
tumor g
r
o
u
p
was f
u
r
t
h
e
r
d
i
v
i
d
e
d
i
n
t
o
a
c
l
o
s
e
g
r
o
u
p
and a
d
i
s
t
a
n
t
g
r
o
u
p
d
e
p
e
n
d
i
n
g
o
n
t
h
e
p
o
s
i
t
i
o
n
a
l
r
e
l
a
t
i
o
n
s
h
i
p
w
i
t
h
m
a
j
o
r
v
e
s
s
e
l
s
.
I
n
o
r
d
e
r
t
o
i
d
e
n
t
i
f
y
t
h
e
b
e
s
t
i
n
d
i
c
a
t
i
o
n
s
f
o
r
l
o
c
a
l
a
b
l
a
t
i
o
n
，t
h
e
i
n
d
i
c
a
t
i
o
n
s
were e
v
a
l
u
a
t
e
d
i
n
t
e
r
m
s
o
f
tumor m
a
x
i
-mal d
i
a
m
e
t
e
r
and d
i
s
t
a
n
c
e
f
r
o
m
m
a
j
o
r
h
e
p
a
t
i
c
v
e
s
司s
e
l
s
.
4
.
S
t
a
t
i
s
t
i
c
a
l
a
n
a
l
y
s
i
s
C
o
m
p
a
r
i
s
o
n
s
between t
h
e
maximal tumor d
i
a
m
e
-t
e
r
o
f
r
e
c
u
r
r
e
n
t
and n
o
n
-
r
e
c
u
r
r
e
n
t
l
e
s
i
o
n
s
and t
h
e
p
o
s
i
t
i
o
n
a
l
r
e
l
a
t
i
o
n
s
h
i
p
o
f
t
u
m
o
r
s
w
i
t
h
r
e
g
a
r
d
t
o
r
e
-c
u
r
r
e
n
c
e
a
t
t
h
e
s
i
t
e
s
o
f
a
b
l
a
t
i
o
n
were e
v
a
l
u
a
t
e
d
by
S
t
u
d
e
n
t's
t
-
t
e
s
t
.
The ROC c
u
r
v
e
f
o
r
t
h
e
r
e
l
a
t
i
o
n
s
h
i
p
between t
h
e
maximal tumor d
i
a
m
e
t
e
r
and t
h
e
p
r
e
s
-e
n
c
e
o
f
t
r
u
e
l
o
c
a
l
r
e
c
u
r
r
e
n
c
e
was e
x
a
m
i
n
e
d
.
The
t
h
r
e
s
h
o
l
d
was d
e
t
e
r
m
i
n
e
d
by f
i
n
d
i
n
g
t
h
e
h
i
g
h
e
s
t
v
a
l
u
e
o
b
t
a
i
n
e
d
u
s
i
n
g
t
h
e
e
q
u
a
t
i
o
n
s
e
n
s
i
t
i
v
i
t
y
-
(
l
-s
p
e
c
i
f
i
c
i
t
y
)
.
The 3
・y
e
a
rl
o
c
a
l
r
e
c
u
r
r
e
n
c
e
-
f
r
e
e
r
a
t
e
was
c
a
l
c
u
l
a
t
e
d
u
s
i
n
g
t
h
e
K
a
p
l
a
n
-
M
e
i
e
r
method
，i
n
w
h
i
c
h
t
h
e
d
i
f
f
e
r
e
n
c
e
between t
h
e
two g
r
o
u
p
s
was e
v
a
l
u
-a
t
e
d
by t
h
e
l
o
g
-
r
a
n
k
t
e
s
.
t
]MP v
e
r
s
i
o
n
1
1
.
0
was
u
s
e
d
f
o
r
t
h
e
c
a
l
c
u
l
a
t
i
o
n
s
，and d
i
f
f
e
r
e
n
c
e
s
w
i
t
h
p
<
0
.
0
5
were c
o
n
s
i
d
e
r
e
d
s
i
g
n
i
f
i
c
a
n
t
.
R
e
s
u
l
t
s
1
.
Comparison between r
e
c
u
r
r
e
n
t
and n
o
n
-r
e
c
u
r
r
e
n
t
l
e
s
i
o
n
s
a
t
t
h
e
s
i
t
e
o
f
a
b
l
a
t
i
o
n
There were 2
9
r
e
c
u
r
r
e
n
c
e
s
(
5
2
.
7
%
)
i
n
5
5
l
e
s
i
o
n
s
a
t
t
h
e
s
i
t
e
o
f
a
b
l
a
t
i
o
n
，and t
h
e
3
-
y
e
a
r
t
r
u
e
l
o
c
a
l
r
e
c
u
r
r
e
n
c
e
-
f
r
e
e
r
a
t
e
was 4
4
.
3
%
(
F
i
g
.
1
)
.
On a
n
a
l
y
s
i
s
o
f
t
h
e
maximal tumor d
i
a
m
e
t
e
r
s
o
f
t
h
e
r
e
c
u
r
r
e
n
t
and n
o
n
-
r
e
c
u
r
r
e
n
t
g
r
o
u
p
s
，t
h
e
mean maximal t
u
-mor d
i
a
m
e
t
e
r
was 2
0
.
2
m m
f
o
r
t
h
e
n
o
n
-
r
e
c
u
r
r
e
n
t
g
r
o
u
p
(
2
6
l
e
s
i
o
n
s
)
，w
h
i
l
e
t
h
e
mean maximal tumor
d
i
a
m
e
t
e
r
o
f
t
h
e
r
e
c
u
r
r
e
n
t
g
r
o
u
p
was 3
6
.
4
mm; t
h
e
d
i
旺e
r
e
n
c
ewas s
i
g
n
i
f
i
c
a
n
t
(p< 0
.
0
0
0
1
)
(
F
i
g
.
2
)
.
There
were 1
1
1
e
s
i
o
n
s
t
h
a
t
r
e
c
u
r
r
e
d
(
4
0
.
7
%
)
i
n
t
h
e
d
i
s
t
a
n
t
g
r
o
u
p
(
2
7
l
e
s
i
o
n
s
)
.
The r
a
t
e
o
f
t
r
u
e
r
e
c
u
r
r
e
n
c
e
was
h
i
g
h
e
r
i
n
t
h
e
c
l
o
s
e
g
r
o
u
p
(
1
8
o
f
2
8
l
e
s
i
o
n
s
:
6
4
.
3
%
)
，b
u
t
t
h
e
d
i
妊e
r
e
n
c
ewas n
o
t
s
i
g
n
i
f
i
c
a
n
t
(
p
=
0
.
l0
8
)
(
T
a
-b
l
e
2
)
.
1.0 0.6 。
H m
﹄ 00 ﹄ ﹄ ' o o c φ ﹄ ﹄ コ 。 。 ﹂ 一 6 0 0 -o コ ﹄ ト 0.4 ハ U i i i o n U 2 0.2 1500 1000 500 0.0-
1
0 No. of days post-ablation Kaplan-Meier curve of the true local recurrence-free rate (overall) The 3・yeartrue local recurrence-free rate is 44.3%. Fig. 1 100 80 20 60 40 ( E E Z O B E E 百﹄ O E コ ト Recurrent Fig. 2 Comparison of mean maximal tumor diameters between recurrent and non-recurrent lesions at the site ofablation The mean maximal tumor diameter is 20.2 mm for the non-recurrent group (26 lesions)， while the mean maximal tumor diameter of the recurrent group is 36.4mm; the differ -ence is significant (pく0.0001). Norトrecurrent。
sions of size lessthan 1.
8 cm (small group:1
4
le-sions)， and the
3
・yeartrue recurrence-free rate wassignificantly better than that of the large group
(
4
1
lesions) (small group vs large group:
100%
vs2
7
.
7
%
，p
<
O
.
O
O
O
l
)
.
Using the Kaplan-Meier method， the
3
・yeartrue2
.
Analysis of the best indications for local ab-lation
The threshold of maximal tumor diameter for
-E345-true recurrence according to the ROC curve analy
-sis was
1
.
8
cm (area under the curve : AUC=
0
.
8
3
)
-recurrence-free rate was significantlybeUer for the distant group than for the close group (33 % vs 60
.
1
%
，
p=
0.0152) (Fig. 4). In thelargegroup，
the truelocalrecurrence-free rate was also beUer for the distant group， but the difference was not signifi -cant (close 20.9% vs distant 37.7%， p=
0.0867) (Fig.5). DiscussionI
t
has been reported that the 5 O ぱfpatients who underwent curative hepatic resec -Table 2 Recurrence in the closegroup and thedis -tantgroup Close group Distantgroup Non-recurrent 10 16 26 Recurrent 18 11 29 Total 28 27 55 Therateoftrue recurrencesi higher in the closegroup(18 of 28 lesions:64.3%)， butthedifference is notsignificant (p= 0.108) (two-sided test). 1.00 ~ ~〆
0.90 0.80 0.70。
0.60 ;> >、 .~ -~'
w
.~ ~ ~ 0.50 ー ー と。
ω ?(f).
=
0
.40
0.30 0.20 0.10 0.00/
//
り
!
/
/
レ
ノ
r---'一
グ
tion for CRLM ranged from 35 % to 58 % 4)7)8)， and this implies that patients could be cured of the dis -ease if they underwent hepatic resection. However，
CRLM with bilobar distribution is prone to be unre -sectable due to the limited volume of remnant he -patic parenchyma， and， therefore， the prognosis in such cases is unfavorable. Local ablation isnow widely adopted for unresectable CRLMs to improve their clinical outcomes十円Theconsensus is that it is the treatment modality of choice for unresectable small HCCs山5).However， for CRLMs， there are pos
-sible drawbacks of local ablation.
A
higher local re -currence rate and a worse prognosis of patients who underwent localablationand more extensive surgical resection for local recurrence after radiof -requency ablation than primary resection have been reported山6)…
Onthe other hand， the possibil -ity of improving the prognosis of multiple CRLMs with localablation has also been suggested by ap -plying more suitable criteria18 )一
a 0.00 0.10 0.20 0.30 0.40 0.500.60 1-Specificity 0.70 0.80 0.90 1.00 F alse Positive Fig. 3 Receiver operating characteristics (ROC) curve for the maximal tumor diameter andtrue local recurrence The threshold of maximal tumor diameter for true recurrence according to the ROC curve analysis is1.8 cm (area under the curve: AUC = 0.83)1.0 0.8 0.6 0.4 0.2 。 H C ﹂ 。 。 ﹄ ﹄ ' O Q C O ﹄ ﹄ コ 00 ﹂ 一 句 。 。 一
ω
コ ﹄ ト ， n u n u nu 2000 Fig.4 Kaplan-Meier curves of the truelocalrecurrence-freerateby the distancefrom majorhepaticvessels(closeand distant) The 3-year true recurrence-free rateissignificantlybetterfor thedistantgroup than for the close group(33.0% vs 60.1，%log-ranktest p = 0.0152). -Close group， - Distantgroup. 1500 1000 No. of days post-ablation 500 1.0 0.8 0.6 0.4 0.2 。 H C﹂ ω φ ﹄ h a o o c o ﹄ ﹄ コ O ω ﹂ 一 ω 0 0 一 ω コ ﹄ ト 0.0 O 2000 Fig. 5 Kaplan-Meiercurve of the truelocalrecurrence-freeratesby distance from major hepatic vessels in thelarge tumor group Inthelargegroup， the truelocal recurrence-freerateisalsobetterfor thedistant sub -group， but the difference isnot significant (close 20.9% vsdistant37.7%， log-ranl王testp = 0.0867).一
Closesubgroupinthelarge group， - Distantsubgroupin the largegroup. 1500 1000 No. of days post-ablation 500satisfactory削20).With regard to the best indications
forlocalablationofCRLMs in terms of size， better
-E347
-advanced systemic chemotherapy， the prognosis of
s
u
r
v
i
v
a
l
was r
e
p
o
r
t
e
d
by G
i
l
l
a
m
s
e
t
a
F
O )f
o
r
tumors
l
e
s
s
t
h
a
n
5
cm o
n
m
u
l
t
i
v
a
r
i
a
t
e
a
n
a
l
y
s
i
s
and by V
e
l
-t
r
i
e
t
a
F
9 )e
s
p
e
c
i
a
l
l
y
f
o
r
t
u
m
o
r
s
l
e
s
s
t
h
a
n
2
.
5
c
m
;
t
h
u
s
s
m
a
l
l
e
r
CRLMs would b
e
n
e
f
i
t
f
r
o
m
l
o
c
a
l
a
b
l
a
t
i
o
n
.
I
n
t
h
e
p
r
e
s
e
n
t
s
t
u
d
y
，t
r
u
e
l
o
c
a
l
r
e
c
u
r
r
e
n
c
e
was
a
n
a
l
y
z
e
d
i
n
o
r
d
e
r
t
o
e
v
a
l
u
a
t
e
t
h
e
t
r
e
a
t
m
e
n
t
o
u
t
-come a
f
t
e
r
l
o
c
a
l
a
b
l
a
t
i
o
n
.
We b
e
l
i
e
v
e
t
h
a
t
d
i
s
e
a
s
e
-f
r
e
e
and o
v
e
r
a
l
l
s
u
r
v
i
v
a
l
may p
r
o
v
i
d
e
r
e
s
u
l
t
s
t
h
a
t
r
e
f
l
e
c
t
by tumor b
i
o
l
o
g
i
c
c
h
a
r
a
c
t
e
r
i
s
t
i
c
s
and o
t
h
e
r
t
r
e
a
t
m
e
n
t
s
s
u
c
h
a
s
c
h
e
m
o
t
h
e
r
a
p
y
.
G
l
e
i
s
n
e
r
e
t
a
1
6 )r
e
p
o
r
t
e
d
t
h
a
t
t
h
e
R
F
A
-
t
r
e
a
t
e
d
g
r
o
u
p
had d
i
f
f
e
r
e
n
t
b
a
s
e
l
i
n
e
tumor and t
r
e
a
t
m
e
n
t
-
r
e
l
a
t
e
d
f
a
c
t
o
r
s
a
f
f
e
c
t
-i
n
g
s
u
r
v
i
v
a
l
compared t
o
t
h
e
r
e
s
e
c
t
i
o
n
-
a
l
o
n
e
g
r
o
u
p
by p
r
o
p
e
n
s
i
t
y
s
c
o
r
e
methods
，and warned t
h
a
t
a
r
e
t
r
o
s
p
e
c
t
i
v
e
a
n
a
l
y
s
i
s
c
o
m
p
a
r
i
n
g
s
u
r
v
i
v
a
l
t
o
f
i
n
d
t
h
e
e
f
f
i
c
a
c
y
o
f
a
t
r
e
a
t
m
e
n
t
m
o
d
a
l
i
t
y
s
u
c
h
a
s
l
o
c
a
l
a
b
l
a
t
i
o
n
may b
e
c
o
n
f
o
u
n
d
e
d
by d
i
f
f
e
r
e
n
t
b
a
s
e
l
i
n
e
c
h
a
r
a
c
t
e
r
i
s
t
i
c
s
a
f
f
e
c
t
i
n
g
s
u
r
v
i
v
a
I
.
l
n
t
h
e
p
r
e
s
e
n
t
s
t
u
d
y
，t
h
e
l
a
r
g
e
r
tumor g
r
o
u
p
had a
h
i
g
h
e
r
t
r
u
e
1
0
-c
a
l
r
e
c
u
r
r
e
n
c
e
r
a
t
e
，and l
e
s
i
o
n
s
c
l
o
s
e
t
o
m
a
j
o
r
h
e
-p
a
t
i
c
v
e
s
s
e
l
s
had a
h
i
g
h
e
r
t
r
u
e
l
o
c
a
l
r
e
c
u
r
r
e
n
c
e
r
a
t
e
.
S
i
n
c
e
t
h
e
t
r
u
e
l
o
c
a
l
r
e
c
u
r
r
e
n
c
e
-
f
r
e
e
r
a
t
e
was
100%
i
n
t
h
e
s
m
a
l
l
g
r
o
u
p
，i
t
was a
n
a
l
y
z
e
d
f
o
r
t
h
e
d
i
s
-t
a
n
t
s
u
b
g
r
o
u
p
o
f
t
h
e
l
a
r
g
e
g
r
o
u
p
i
n
o
r
d
e
r
t
o
e
v
a
l
u
-a
t
e
t
h
e
e
f
f
e
c
t
o
n
r
e
c
u
r
r
e
n
c
e
o
f
p
o
s
i
t
i
o
n
a
l
r
e
l
a
t
i
o
n
-s
h
i
p
s
w
i
t
h
m
a
j
o
r
v
e
s
s
e
l
s
.
A
1
t
hough n
o
s
i
g
n
i
f
i
c
a
n
t
d
i
f
f
e
r
e
n
c
e
was o
b
s
e
r
v
e
d
，a
p
r
o
p
e
n
s
i
t
y
f
o
r
t
r
u
e
l
o
c
a
l
r
e
c
u
r
r
e
n
c
e
was e
v
i
d
e
n
t
.
T
h
e
r
e
f
o
r
e
，l
o
c
a
l
a
b
l
a
t
i
o
n
s
h
o
u
l
d
be r
e
s
t
r
i
c
t
e
d
f
o
r
t
h
e
l
a
r
g
e
r
tumor g
r
o
u
p
and
l
e
s
i
o
n
s
c
l
o
s
e
t
o
m
a
j
o
r
h
e
p
a
t
i
c
v
e
s
s
e
l
s
.
As f
o
r
t
h
e
e
x
-p
l
a
n
a
t
i
o
n
f
o
r
t
h
e
s
e
r
e
s
u
l
t
s
，i
n
a
d
e
q
u
a
t
e
a
b
l
a
t
i
o
n
o
f
l
a
r
g
e
tumors and t
h
e
h
e
a
t
s
i
n
k
e
f
f
e
c
t
却，which i
m
-p
e
d
e
s
a
b
l
a
t
i
o
n
n
e
a
r
v
e
s
s
e
l
s
，may b
e
r
e
s
p
o
n
s
i
b
l
e
.
S
i
n
c
e
Welp e
t
a
l
剖r
e
p
o
r
t
e
dt
h
a
t
t
h
e
r
e
was s
i
g
n
i
f
i
-c
a
n
t
t
e
m
p
e
r
a
t
u
r
e
l
o
s
s
a
t
a
n
a
b
l
a
t
i
v
e
e
l
e
c
t
r
o
d
e
d
i
s
-t
a
n
c
e
o
f
2
cm n
e
a
r
a
v
e
s
s
el
，
g
i
v
e
n
t
h
a
t
t
h
e
1
cm
z
o
n
e
o
f
s
u
r
r
o
u
n
d
i
n
g
l
i
v
e
r
parenchyma i
s
a
b
l
a
t
e
d
a
s
t
h
e
margin
，we h
y
p
o
t
h
e
s
i
z
e
d
t
h
a
t
a
tumor 1
cm
from h
e
p
a
t
i
c
v
e
s
s
e
l
s
i
s
j
e
o
p
a
r
d
i
z
e
d
by t
h
e
h
e
a
t
s
i
n
k
e
f
f
e
c
t
.
S
i
n
c
e
E
l
i
a
s
e
t
a
F
2 )r
e
p
o
r
t
e
d
t
h
a
t
a
h
i
g
h
e
r
l
o
c
a
l
r
e
c
u
r
r
e
n
c
e
r
a
t
e
a
f
t
e
r
i
n
t
r
a
o
p
e
r
a
t
i
v
e
r
a
d
i
o
f
r
e
q
u
e
n
c
y
a
b
l
a
t
i
o
n
was c
o
r
r
e
l
a
t
e
d
w
i
t
h
l
i
v
e
r
m
e
t
a
s
t
a
s
e
s
i
n
d
i
-r
e
c
t
c
o
n
t
a
c
t
w
i
t
h
l
a
r
g
e
v
e
s
s
e
l
s
，we a
l
s
o
b
e
l
i
e
v
e
d
t
h
a
t
a
tumor l
e
s
s
t
h
a
n
1
cm from h
e
p
a
t
i
c
v
e
s
s
e
l
s
would a
l
s
o
be j
e
o
p
a
r
d
i
z
e
d
by t
h
e
h
e
a
t
s
i
n
k
e
f
f
e
c
t
.
T
h
e
r
e
f
o
r
e
，we d
i
v
i
d
e
d
t
h
e
t
r
e
a
t
m
e
n
t
g
r
o
u
p
i
n
t
o
t
h
e
c
l
o
s
e
g
r
o
u
p
，whose d
i
s
t
a
n
c
e
between t
h
e
tumor and
m
a
j
o
r
h
e
p
a
t
i
c
v
e
s
s
e
l
s
was l
e
s
s
t
h
a
n
o
r
e
q
u
a
l
t
o
1
cm
，and t
h
e
d
i
s
t
a
n
t
g
r
o
u
p
，whose d
i
s
t
a
n
c
e
between
t
h
e
tumor and m
a
j
o
r
h
e
p
a
t
i
c
v
e
s
s
e
l
s
was g
r
e
a
t
e
r
t
h
a
n
1
cm
，i
n
o
r
d
e
r
t
o
d
e
t
e
c
t
t
h
e
i
n
f
l
u
e
n
c
e
o
f
t
h
e
h
e
a
t
s
i
n
k
e
旺'ec
t
.L
i
m
i
t
a
t
i
o
n
s
o
f
l
o
c
a
l
a
b
l
a
t
i
o
n
a
r
e
t
h
e
r
a
n
g
e
o
f
a
b
l
a
t
i
o
n
23)-25)，worse s
t
a
g
i
n
g
compared t
o
r
e
s
e
c
t
i
o
n
，and e
l
e
c
t
r
o
d
e
t
r
a
c
k
s
e
e
d
i
n
g
26).However
，i
n
k
e
e
p
i
n
g
w
i
t
h
t
h
e
s
e
f
a
c
t
s
，t
h
e
r
e
i
s
t
h
e
p
o
s
s
i
b
i
l
i
t
y
t
h
a
t
s
m
a
l
l
e
r
CRLMs and l
e
s
i
o
n
s
f
a
r
f
r
o
m
m
a
j
o
r
v
e
s
-s
e
l
s
d
o
b
e
t
t
e
r
w
i
t
h
l
o
c
a
l
a
b
l
a
t
i
o
n
t
h
a
n
l
a
r
g
e
r
and
c
l
o
s
e
r
CRLMs. A
l
t
h
o
u
g
h
some a
u
t
h
o
r
s
who f
o
c
u
s
e
d
on t
h
e
h
i
g
h
e
r
c
o
n
t
r
o
l
r
a
t
e
f
o
r
s
m
a
l
l
e
r
l
e
s
i
o
n
s
i
n
-s
i
s
t
e
d
on p
e
r
f
o
r
m
i
n
g
a
r
a
n
d
o
m
i
z
e
d
，c
o
n
t
r
o
l
l
e
d
t
r
i
a
l
f
o
r
r
e
s
e
c
t
a
b
l
e
CRLMs by RF
A and r
e
s
e
c
t
i
o
n
お，i
n
t
h
e
p
r
e
s
e
n
t
s
i
t
u
a
t
i
o
n
，we b
e
l
i
e
v
e
t
h
a
t
l
o
c
a
l
a
b
l
a
t
i
o
n
would p
r
o
v
i
d
e
l
o
c
a
l
c
o
n
t
r
o
l
i
n
t
e
r
m
s
o
f
t
h
e
t
h
e
r
a
-p
e
u
t
i
c
s
t
r
a
t
e
g
y
f
o
r
CLRMs by making u
s
e
o
f
i
t
s
m
i
n
i
m
a
l
l
y
i
n
v
a
s
i
v
e
n
a
t
u
r
e
when i
t
i
s
a
p
p
l
i
e
d
t
o
m
u
l
-t
i
p
l
e
CRLMSs
，u
n
r
e
s
e
c
t
a
b
l
e
o
r
r
e
s
e
c
t
a
b
l
e
CRLMs o
f
e
l
d
e
r
l
y
p
a
t
i
e
n
t
s
，o
r
p
a
t
i
e
n
t
s
w
i
t
h
c
o
m
o
r
b
i
d
i
t
y
.
A
l
-t
h
o
u
g
h
t
h
e
r
e
were few c
a
s
e
s
o
f
l
i
v
e
r
a
b
s
c
e
s
s
and
pulmonary i
n
f
a
r
c
t
i
o
n
，l
o
c
a
l
a
b
l
a
t
i
o
n
i
s
m
i
n
i
m
a
l
l
y
i
n
-v
a
s
i
v
e
i
n
t
e
r
m
s
o
f
c
o
m
p
l
i
c
a
t
i
o
n
s
compared t
o
h
e
-p
a
t
i
c
r
e
s
e
c
t
i
o
n
26).
