Open Journal of Gastroenterology, 2013, 3, 259-266 OJGas
http://dx.doi.org/10.4236/ojgas.2013.35044 Published Online September 2013 (http://www.scirp.org/journal/ojgas/)
Prognostic factors after palliative resection for colorectal
cancer with incurable synchronous liver metastasis*
Kiichi Sugimoto, Kazuhiro Sakamoto, Yuichi Tomiki, Michitoshi Goto,
Yutaka Kojima, Hiromitsu Komiyama, Makoto Takahashi, Yukihiro Yaginuma,
Shun Ishiyama, Koichiro Niwa, Kiichi Nagayasu, Shingo Ito, Masaya Kawai,
Kazuhiro Takehara, Yoshihiko Tashiro, Shinya Munakata
Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University, Tokyo, Japan
Received 28 July 2013; revised 24 August 2013; accepted 31 August 2013
Copyright © 2013 Kiichi Sugimoto et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Purpose: With the improvements in newer chemo-
therapeutic agents, there is currently no consensus
regarding the validity of palliative resection of the
primary tumor for colorectal cancer with incurable
distant metastasis. We retrospectively analyzed prog-
nostic factor in patients with colorectal cancer ac-
companied by incurable synchronous liver metastasis.
Methods: 82 patients with incurable synchronous
liver metastases, who underwent primary tumor re-
section alone, were enrolled. Results: The multivari-
ate analysis revealed that the presence of ascites (P =
0.001, Hazard ratio = 2.96) and differentiation (P =
0.003, Hazard ratio = 3.68) were found to be signifi-
cant independent prognostic factors. The median sur-
vival time among the patients with ascites was 4.8
months and that among the patients with poorly-dif-
ferentiated or mucinous adenocarcinoma, or signet
ring cell carcinoma (high grade differentiation) was
1.4 months, respectively. Conclusion: The presence of
ascites and differentiation were prognostic factors in
the patients with incurable liver metastases. There-
fore, because prognosis is generally poor after pri-
mary tumor resection in the patients with ascites or
high grade differentiation, the introduction of sys-
temic chemotherapy with alleviation of symptoms re-
lated to the primary tumor should be taken into ac-
count as one of the therapeutic strategies.
Keywords: Colorectal Carcinoma; Liver Metastasis;
Primary Tumor Resection; Palliative Resection;
Systemic Chemotherapy; Postoperative Morbidity
1. INTRODUCTION
With the improvements in newer chemotherapeutic
agents, there is currently no consensus regarding the
validity of palliative resection of the primary tumor for
colorectal cancer with incurable distant metastasis, be-
cause there are many risks of postoperative mortality and
morbidity due to highly-advanced tumor-bearing condi-
tion [1,2]. Therefore, we determine whether or not re-
section of the primary tumor should be performed, ac-
cording to the symptom of the primary tumor, the status
of distant metastasis and the patient’s status. In particular,
in colorectal cancer patients with extensive metastatic
lesions within the liver, the selection of a therapeutic
strategy for the primary tumor is difficult because liver
dysfunction, jaundice and ascites are occasionally seen
preoperatively. This study was undertaken to retrospec-
tively analyze the prognosis of primary tumor resection
and its prognostic factor in patients with colorectal
cancer accompanied by incurable synchronous liver me-
tastasis and to identify patients requiring care in eva-
luating the indication for primary tumor resection.
2. METHODS
2.1. Patient Selection
Of the 1557 consecutive patients who underwent surgery
for colorectal cancer at our department between Decem-
ber 1998 and March 2009, 149 (9.6%) presented with
synchronous colorectal liver metastases (Figure 1). In
this study, synchronous metastases were defined as
nodules that had been diagnosed before the primary
colorectal surgery. The patients with synchronous color-
ectal liver metastases were divided into two groups ac-
cording to whether or not they underwent simultaneous
curative liver resection for synchronous colorectal liver
*Conflict of interest: The authors declare that they have no conflicts o
f
interest.

K. Sugimoto et al. / Open Journal of Gastroenterology 3 (2013) 259-266 260
Figure 1. Patient selection.
metastases (n = 58; 38.9%, and n = 91; 61.1%, res-
pectively). Among the patients with incurable synchro-
nous liver metastases, 9 underwent colostomy or bypass
alone. The remaining 82 patients who underwent primary
tumor resection alone were enrolled in this study. Cases
that underwent emergency operation or died of non-
cancer-related causes were excluded from this study.
None of the patients received preoperative adjuvant
therapy. The median observation period was 13.9 months
(range: 0.5 - 121.7 months) in all patients with incurable
synchronous liver metastases. On the other hand, among
the 56 patients who died of cancer during the observation
period, the median survival period was 12.6 months
(range: 0.5 - 45.9 months). With respect to the indication
for liver resection in our hospital, there were no limi-
tations regarding the number or size of liver metastases.
In this series, liver resection was indicated for liver
metastases when the following 3 conditions were met: 1)
the primary tumor, liver metastases and extrahepatic dis-
tant metastases were curatively resected; 2) liver func-
tional reserve was likely to be acceptable after liver
resection; 3) tolerance for operation was adequate. Pa-
tients who did not meet these criteria only underwent
surgery for the primary tumor (resection of the primary
tumor, colostomy or bypass). With respect to the thera-
peutic strategies for the patients with curable liver meta-
stasis, we did not perform preoperative adjuvant chemo-
therapy before liver resection for the patients with
curable liver metastasis. The reason for this is that during
the study period, preoperative systemic chemotherapy
was not popular in Japan. In addition, tumor progression
during preoperative chemotherapy could reduce the
opportunity for liver resection and introduce a risk of
liver dysfunction. Therefore, at our department we per-
formed liver resection immediately after diagnosis.
2.2. Clinicopathological Analysis
Clinicopathological factors, i.e., patient background, pre-
operative laboratory data, intraoperative findings, patho-
logical findings, postoperative factors and survival data
were analyzed to determine prognostic factors related to
the prognosis after primary tumor resection. For the pa-
tient backgrounds, age, gender, symptoms, preoperative
comorbidity, body mass index (BMI), performance status
criteria outlined by the Eastern Cooperative Oncology
Group (ECOG), location, extent of liver metastasis and
extrahepatic distant metastasis were investigated. In the
preoperative laboratory data, white blood cell (WBC),
aspartate aminotransferase (AST), alanine aminotrans-
ferase (ALT), total bilirubin (T-Bil), albumin (Alb), C-
reactive protein (CRP), carcinoembryonic antigen (CEA)
and Child classification were investigated. Among the
intraoperative findings, ascites and peritoneal metastasis
were investigated. Regarding the pathological findings,
primary tumor diameter, differentiation, invasion depth,
lymphatic invasion, venous invasion and lymph node
metastasis were investigated. With respect to postopera-
tive factors, postoperative complications and chemothe-
rapy were investigated.
2.3. Statistical Analysis
Survival was measured from the time of primary tumor
resection, and death was the end point. The survival rate
was calculated using the Kaplan-Meier method accord-
ing to each of the clinicopathological factors. Univariate
analyses were performed using the log-rank test. Dif-
ferences were considered statistically significant at P <
0.05. With regard to the clinicopathological factors for
which there were statistically significant differences in
the univariate analyses, mutual correlation coefficients
(r) were calculated using Spearman rank correlation
coefficient. When |r| was >0.6, a strong correlation was
detected among the clinicopathological factors. Clinico-
pathological factors that achieved lower P-values in the
log-rank test were used as covariables for the multi-
variate analysis. For the multivariate analysis, the Cox
proportional-hazard model was used with the Hazard
ratio. Data were statistically analyzed using JMP 9.0.2
software (SAS Institute Inc., Cary, NC, USA). Values are
expressed as the median (min. - max.).
3. RESULTS
3.1. Patient Characteristics
The patient characteristics are shown in Table 1. The
median age was 68 years (34 - 86 years). The most
frequently encountered location was sigmoid colon in 25

K. Sugimoto et al. / Open Journal of Gastroenterology 3 (2013) 259-266 261
Table 1. Patient characteristics.
No. of patients (%)
Total 82
Age 68 years (34 - 86)
Location
Cecum 6 (7.3%)
Ascending colon 11 (13.4%)
Transverse colon 12 (14.6%)
Descending colon 7 (8.5%)
Sigmoid colon 25 (30.5%)
Rectosigmoid 11 (13.4%)
Rectum 10 (12.2%)
Extrahepatic distant metastasisa
Lung 21 (25.6%)
Peritoneum 15 (18.3%)
Para-aortic lymph node 3 (3.7%)
Spleen 1 (1.2%)
Bone 1 (1.2%)
Postoperative complicationa
Wound infection 12 (14.6%)
Ileus 8 (9.8%)
Anastomotic leakage 5 (6.1%)
Intrapelvic abscess 5 (6.1%)
DIC 4 (4.9%)
Others 3 (3.7%)
Postoperative chemotherapy
FOLFOX/FOLFIRI 27 (32.9%)
Transcatheter arterial infusion (TAI) 17 (20.7%)
IV 5FU/LV 12 (14.6%)
Others (oral administration etc.) 8 (9.8%)
None 18 (22.0%)
aWith some duplication.
patients (30.5%). Extrahepatic distant metastases were
lung metastasis in 21 patients (25.6%), peritoneal meta-
stasis in 15 patients (18.3%), para-aortic lymph node
metastasis in 3 patients (3.7%), spleen metastasis in one
patient (1.2%) and bone metastasis in one patient (1.2%).
Postoperative complications were recognized in 31 pa-
tients (37.8%). The most frequently encountered post-
operative complication was wound infection in 12 pa-
tients (14.6%); followed by ileus in 8 patients (9.8%),
anastomotic leakage in 5 patients (6.1%), intrapelvic
abscess in 5 patients (6.1%), disseminated intravascular
coagulation (DIC) in 4 patients (4.9%) and other in 3
patients (3.7%). Sixty-four patients (78.0%) underwent
postoperative chemotherapy. The most frequently en-
countered chemotherapy was FOLFOX or FOLFIRI in
27 patients (32.9%); followed by transcatheter arterial
infusion (TAI) in 17 patients (20.7%), intravenous in-
jection of 5FU/LV in 12 patients (14.6%), and other in 8
patients (9.8%). On the other hand, 18 patients (22.0%)
received no chemotherapy because of poor general status
or advanced age.
3.2. Prognostic Factors Related to the Outcome
Comparisons of the survival rates according to clinico-
pathological factors are shown in Tables 2-4. Significant
differences in comparisons of survival rates were recog-
nized in the extent of liver metastasis (P = 0.02), abnor-
mal AST (P = 0.01), abnormal ALT (P = 0.001), ascites
(P = 0.0001) and differentiation (P = 0.01).
Next, with respect to these clinicopathological factors
for which there were significant differences in the log-
Table 2. Comparisons of the survival rates according to clini-
copathological factors (1).
Clinicopathological
factors Variables No. of patients
Median
survival
time (month)
P-value
75≤ 17 14.3
Age <75 65 13.8 0.77
Male 48 15.7
Gender Female 34 13.5 0.79
+ 60 13.1
Symptom
− 22 19.9
0.19
+ 60 13.2
Preoperative
comorbidity − 22 15.1
0.59
25.0< 21 16.8
Body mass index
(BMI) ≤25.0 61 13.1
0.96
0 47 15.7
Performance status
1, 2 35 9.1
0.87
Colon 72 13.9
Location
Rectum 10 15.2
0.86
High 23 8.9
Extent of liver
metastasisa Low 59 15.7
0.02
+ 25 15.7
Extrahepatic distant
metastasis b − 57 13.2
0.98
aHigh: five or more metastatic tumors at least one of which is more than 5
cm in maximum diameter, Low: except for high grade. bExcept for perito-
neal metastasis.

K. Sugimoto et al. / Open Journal of Gastroenterology 3 (2013) 259-266 262
Tab l e 3. Comparisons of the survival rates according to clini-
copathological factors (2).
Clinicopathological
factors Variables No. of patients
Median
survival
time (month)
P-value
9000< 30 12.2
WBC (/mm3) ≤9000 52 14.7 0.80
37< 33 8.0
AST (IU/l) ≤37 49 15.7 0.01
43< 22 4.2
ALT (IU/l) ≤43 60 16.4 0.001
1.2< 10 6.2
T-Bil (mg/dl) ≤1.2 72 14.6 0.12
4.0≤ 17 19.7
Alb (g/dl) <4.0 65 13.2 0.08
0.3< 70 12.6
CRP (mg/dl) ≤0.3 12 17.9 0.16
3.0< 78 13.9
CEA (ng/dl) ≤3.0 4 14.0 0.06
A 58 15.7
Child classification B, C 24 10.2 0.07
Abbreviations: WBC: White blood cell, AST: Aspartate aminotransferase,
ALT: Alanine aminotransferase, T-Bil: Total bilirubin, Alb: Albumin, CRP:
C-reactive protein, CEA: Carcinoembryonic antigen.
Table 4. Comparisons of the survival rates according to clini-
copathological factors (3).
Clinicopathological
factors Variables No. of patients
Median
survival
time (month)
P-value
+ 25 4.8
Ascites − 57 16.8 0.0001
+ 15 9.1
Peritoneal
metastasis − 67 14.9
0.11
50< 51 14.0
Primary tumor
diameter (mm) ≤50 31 13.8
0.28
Low gradea 73 14.3
Differentiation High gradeb 9 1.4 0.01
T3 27 15.9
Invasion depth T4 55 12.0 0.17
+ 75 13.8
Lymphatic invasion − 7 17.8 0.61
+ 79 13.8
Venous invasion − 3 16.8 0.87
+ 71 13.4
Lymph node
metastasis − 11 16.0
0.61
+ 31 13.2
Postoperative
complication − 51 14.3
0.91
+ 27 17.8
Chemotherapy
with novel agents c − 37d 14.9
0.62
aWell- and moderately-differentiated adenocarcinoma; bPoorly-differentiated
or mucinous adenocarcinoma or signet ring cell carcinoma; cPostoperative
chemotherapy with novel agents, such as oxaliplatin or irinotecan; dExcept
for the patients without chemotherapy due to poor general status.
rank test, mutual correlation coefficients were calculated
using Spearman rank correlation coefficient (Table 5).
As a result, a strong correlation between abnormal AST
and abnormal ALT was recognized (r = 0.626). Because
there was a lower P-value for abnormal ALT compared
with the abnormal AST, four clinicopathological factors
except for abnormal AST were used as co-variables for
the multivariate analysis. Consequently, the presence of
ascites (P = 0.001, Hazard ratio = 2.96) and differentia-
tion (P = 0.003, Hazard ratio = 3.68) were found to be
significant independent prognostic factors (Table 6).
Comparisons of the cumulative survival rates accord-
ing to the prognostic factors are shown in Figure 2. The
median survival time among the patients with ascites was
4.8 months and that among the patients with poorly-dif-
ferentiated or mucinous adenocarcinoma, or signet ring
cell carcinoma (high grade differentiation) was 1.4 months,
respectively. Therefore, it was shown that the prognosis
among the patients with these prognostic factors was
poor.
4. DISCUSSION
The liver is the most common organ of distant metastases
from colorectal cancer and the incidence of synchronous
liver metastases in colorectal cancer has been reported to
be 13% - 25% [3-5]. Surgical resection is the most effec-
tive therapy for liver metastases and it has been reported
that the 5-year survival rate after liver resection in pa-
Figure 2. Comparision of the cumulative survival rate accord-
ing to the prognostic factors. (a) Ascites; (b) Differentiation.

K. Sugimoto et al. / Open Journal of Gastroenterology 3 (2013) 259-266 263
Table 5. Correlation coefficients among clinicopathological
factors using Spearman rank correlation coefficient.
Extent of liver
metastasis
AST ALT Ascites Differentiation
Extent of liver
metastasis - 0.539 0.418 0.235 0.128
AST - 0.626 0.213 0.189
ALT - 0.316 0.228
Ascites - 0.107
Differentiation -
Table 6. Prognostic factors related to the outcome using Cox’s
proportional hazards model.
Prognostic factor P-value Hazard
ratio
95% confidence
interval
Extent of liver
metastasis (High) 0.13 1.59 0.87 - 2.89
ALT (>43IU/l ) 0.06 1.87 0.98 - 3.57
Ascites (+) 0.001 2.96 1.55 - 5.64
Differentiation
(High gradea) 0.003 3.68 1.55 - 8.71
aPoorly-differentiated or mucinous adenocarcinoma or signet ring cell car-
cinoma.
tients with synchronous liver metastases is 19% - 38%,
and that the prognosis of the patients with resectable syn-
chronous liver metastases is better than for those with
non-resectable liver metastases [6-9]. However, up to
70% - 80% of these patients have incurable disease, so
the proportion of the patients with incurable liver metas-
tases is greater than that of the patients with curable liver
metastases [10-12]. On the other hand, due to recent ad-
vances in systemic chemotherapy, the prognosis of the
patients with distant metastases has been improved re-
markably [13,14]. Therefore, it would appear that there is
a possibility that the patients with incurable liver me-
tastases could achieve a relatively good prognosis by
systemic chemotherapy instead of primary tumor resec-
tion [15,16]. Thus it is important to identify the patients
with a poor prognosis who are unlikely to enjoy the
benefits of primary tumor resection. Therefore, we ret-
rospectively investigated the prognosis of primary tumor
resection in patients with incurable synchronous liver
metastasis and analyzed prognostic factors related to the
prognosis.
With respect to the prognosis after primary tumor
resection in the patients with incurable distant metastases,
some authors have reported median survival periods of
7.0 - 30.0 months [1,17-19] and mean survival periods of
10.6 - 13.9 months [2,20,21]. In this study the subjects
were limited to the patients with incurable liver meta-
stases, and consequently, the median survival period was
13.9 months. Because it is generally expected that the
prognosis is poor in the patients with highly-advanced
tumor-bearing condition, the identification of prognostic
factors could possibly help us to decide the indication for
operation.
Only the presence of ascites and differentiation were
prognostic factors in the patients with incurable liver
metastases. The patient backgrounds and the extent of
primary tumor and liver metastases were not prognostic
factors in this study. In addition to this study, there has
been a report that the presence of ascites was associated
significantly with the prognosis [19]. The report con-
cluded that the presence of ascites reflected a highly-
advanced tumor-bearing condition. Because we studied
patients with incurable synchronous liver metastasis, it
was considered that there was likely to be liver dys-
function due to extensive metastatic lesions within the
liver or undernutrition due to the highly-advanced tumor-
bearing underlying state of the patients with ascites and
that this might significantly affect the prognosis. With
regard to differentiation of the primary tumor, some
authors have reported that the prognosis among patients
with high grade differentiation was significantly poorer
than that with well- and moderately-differentiated adeno-
carcinoma [21-24]. The prognosis was extremely poor in
this study, which suggested that differentiation also
provided useful prognostic information among patients
who underwent non-curative resection. Therefore, it is
thought that the patients with high grade differentiation
are unlikely to enjoy the benefits of primary tumor
resection.
The extent of liver metastases was not an independent
prognostic factor in a multivariate analysis. Previously,
Katoh et al. [25] reported that the extent of liver meta-
stases was a significant independent factor in multi-
variate analysis using the JCCC (Japanese Classification
of Colorectal Cancer) staging system [26]. With respect
to the extent of liver metastases, there was a significant
difference in a univariate analysis, however, it was not a
significant independent factor in the multivariate analysis
conducted in this study. The reason for this was con-
sidered that the criteria for incurable liver metastases
included the resectability of extrahepatic distant meta-
stases and general status in this study. Therefore, if the
investigation was conducted with only the patients in
whom liver metastasis itself was unresectable, it is be-
lieved that the extent of liver metastases would be a
prognostic factor for outcome. However, because in cli-
nical practice there are many patients who cannot un-
dergo liver resection due to the presence of unresectable
extrahepatic distant metastases and poor general status,
these patients were included in this study.
In the patients with postoperative complications after

K. Sugimoto et al. / Open Journal of Gastroenterology 3 (2013) 259-266 264
curative resection of colorectal carcinoma, long-term
survival is poor [27-29]. We investigated whether or not
postoperative complications after primary tumor resec-
tion were determinants of prognosis among the patients
with incurable liver metastases. Some authors have re-
ported that the incidence of postoperative complications
among the patients with incurable liver metastases was
18.3% - 23.9% [2,19]. In this study, the incidence of
postoperative complications was 37.8%, which was higher
than previous reports. There was no significant differ-
ence in long-term survival between the patients with or
without postoperative complications. It has been demon-
strated that postoperative complications could lead to a
period of immunosuppression, resulting in proliferation
of free tumor cells and occult malignant cells that would
worsen the prognosis [27,30]. However, because the re-
sidual metastatic lesions themselves strongly affect prog-
nosis among the patients with incurable liver metastases,
it was thought that the effects based on the presence of
postoperative complications were small. Furthermore,
there were no deaths related to grave postoperative com-
plications and there were no patients who required re-
operation. However, the incidence of grave postoperative
complications could lower the quality of life among the
patients and delay the introduction of systemic chemo-
therapy [31]. Prognosis can be improved through efforts
to reduce postoperative complications.
Some authors have reported that 76.0% - 79.0% of the
patients with incurable liver metastases underwent chemo-
therapy after primary tumor resection, which was equi-
valent to this study. These reports concluded that the
introduction of chemotherapy after primary tumor resec-
tion was a significant prognostic factor and was impor-
tant in order to improve the prognosis. However, there
were some patients to whom chemotherapy could not be
introduced because their general status was poor after the
primary tumor resection. 22.0% of the patients were also
unable to receive chemotherapy in this study. Therefore,
it must be considered there was a bias that the patients
who were able to receive chemotherapy after primary
tumor resection had a good general status. In addition,
we compared outcomes between the patients who re-
ceived chemotherapy with novel agents, such as oxali-
platin or irinotecan and those who received chemo-
therapy with other regimen. In this study, the proportion
of the patients who received chemotherapy with novel
agents after primary tumor resection was 32.9%, while
the proportion treated with oxaliplatin was 27.5% in the
previous report [32]. The median survival time among
the patients who received chemotherapy with novel
agents was longer than that for the others, but there was
no significant difference between the two groups. It was
supposed the reason for this is that the patient back-
grounds, i.e., the extent of extrahepatic distant metastasis
and the regimens of chemotherapy after the primary
tumor resection, were varied, because this study was
retrospective in nature.
Recently, with the improvements in systemic chemo-
therapy, some authors have reported that non-operative
management by systemic chemotherapy with novel
agents and molecular target drugs was recommended for
patients who had relatively asymptomatic colorectal can-
cer with incurable distant metastases [17,33,34]. It was
reported that when the patients who had relatively
asymptomatic colorectal cancer with incurable distant
metastases underwent FOLFOX or FOLFIRI treatment,
not only metastatic lesions but also primary tumor could
be well controlled and the rate of complications related
to the non-resected primary tumor was very low. How-
ever, because these reports had a small number of pa-
tients, further investigations with larger numbers of pa-
tients will be needed. Therefore, because prognosis is
generally poor after primary tumor resection in the pa-
tients with ascites or high grade differentiation, the intro-
duction of systemic chemotherapy with alleviation of
symptoms related to the primary tumor should be taken
into account as one of the therapeutic strategies.
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