close

Вход

Забыли?

вход по аккаунту

?

000444097

код для вставкиСкачать
Original Paper
Received: September 18, 2015
Accepted: January 17, 2016
Published online: April 27, 2016
Dig Surg 2016;33:382–391
DOI: 10.1159/000444097
Clinicopathological Factors Associated with
Recurrence and Prognosis after R0 Resection for
Stage IV Colorectal Cancer with Peritoneal Metastasis
Harunobu Sato a Kenjiro Kotake c Kenichi Sugihara d Hiroshi Takahashi b
Kotaro Maeda a Ichiro Uyama a on behalf of the Study Group for Peritoneal
Metastasis from Colorectal Cancer By the Japanese Society for Cancer of the Colon
and Rectum Departments of a Surgery and b Medical Statistics, Fujita Health University School of Medicine, Toyoake, c Department
of Surgery, Tochigi Cancer Center, Utsunomiya, and d Department of Surgery, Tokyo Medical and Dental University,
Tokyo, Japan
Abstract
Background/Aims: Peritoneal metastasis (PM) is a wellknown predictor of poor prognosis. This study aims at identifying factors affecting recurrence and prognosis after R0
resection for colorectal cancer (CRC) with synchronous PM.
Methods: A multi-institutional, retrospective analysis of 172
patients with R0 surgery for CRC with PM was conducted.
Clinicopathological variables were analyzed for their significance in contributing toward recurrence and prognosis. Results: Lymph node (LN) metastasis was an independent factor affecting recurrence as indicated by logistic regression
analyses. The following factors were independent predictors
of poor prognostic using the Cox proportional hazard model: LN metastasis, no postoperative adjuvant chemotherapy,
five or fewer dissected LNs, and preoperative high serum
carbohydrate antigen 19-9 levels. Of the patients undergoing postoperative adjuvant chemotherapy, no significant
differences were observed in recurrence rate and disease-
© 2016 S. Karger AG, Basel
0253–4886/16/0335–0382$39.50/0
E-Mail karger@karger.com
www.karger.com/dsu
free interval between those with intensive adjuvant chemotherapy and those with non-intensive chemotherapy. After
R0 surgery for PM, 90 patients (76.3%) experienced recurrence by 18 months, and hematogenous recurrence occurred significantly more often than peritoneal recurrence.
Conclusion: Harvesting of more than 5 LNs and administration of postoperative adjuvant chemotherapy after R0 surgery are recommended for prognosis improvement. Intensive follow-up should be performed within 18 months after
R0 surgery for CRC with synchronous PM.
© 2016 S. Karger AG, Basel
Introduction
Colorectal cancer (CRC) is the third most common
cause of cancer death in Japan, and its incidence is increasing. Synchronous peritoneal metastasis (PM), found
in 4–10% of primary CRC patients, is a well-known predictor of poor prognosis in CRC patients [1, 2]. The TNM
classification of malignant tumors classifies CRC with
PM as stage IV-B, which includes patients with multiple
organ metastases [3]. Appropriate treatment for synchroDr. Harunobu Sato
Department of Surgery, School of Medicine
Fujita Health University, 1-98 Dengakugakubo
Kustukake-cho, Toyoake, Aichi 470-1192 (Japan)
E-Mail harsato @ hotmail.co.jp
Downloaded by:
Kings's College London
137.73.144.138 - 10/29/2017 8:48:40 AM
Key Words
Colorectal cancer · Peritoneal metastases · R0 surgery ·
Recurrence · Prognosis
Methods
Patients
Data were collected from 1,217 consecutive patients with CRC
and synchronous PM who underwent an initial surgery between
January 1997 and December 2007 using the databases of 16 referral
hospitals of the Japanese Society for Cancer of the Colon and Rectum (JSCCR). Of the 1,217 patients, 224 received R0 resections,
and 172 of them had sufficient background records for the final
analysis. No patients underwent HIPEC in our series.
Parameters
The parameters used in this study were as follows: age, gender,
location of primary tumor (PT), distant metastases, liver metastasis, size of PT, lymph node dissection, number of dissected lymph
nodes, histology, depth of tumor invasion, lymph node metastases,
postoperative adjuvant chemotherapy, lymphatic invasion, venous invasion, grade of PM according to JSCCR classification,
maximum size of PM, number of PM, extent of PM, and preoperative serum levels of the carcinoembryonic antigen (CEA) and
carbohydrate antigen 19-9 (CA19-9). Clinical and pathological
data were recorded according to the JSCCR classification system
[10]. The depth of tumor invasion and lymph node metastases was
classified according to the seventh TNM classification system [3].
The cutoff values for CEA and CA19-9 were 5.0 ng/ml and 37.0
U/ ml, respectively. Serial univariate analyses were conducted on
all dissected lymph nodes (66 times in total), all metastatic lymph
nodes (30 times in total), all PM nodules (cases including all cases
with 11 or more PM nodules 10 times in total), and all regional PM
(8 times in total) to determine cut-off values in the analysis of factors that affected recurrence and prognosis. The lowest p value for
Peritoneal Metastases of CRC
the number of dissected lymph nodes, metastatic lymph nodes,
PM nodules, and number of regional PM cases was defined as the
cut-off value for each. Surgical charts were thoroughly reviewed
and scrutinized with respect to narrative descriptions, figures, and
comments. Patients were classified according to the size of the
largest disseminated lesions, number of disseminated lesions, and
number of regional disseminated lesions. The number and size of
the PM nodules were converted to numerical data based on the
original descriptions provided in the surgical charts. For example,
‘a few’ disseminated lesions were recorded as ‘≤3’, ‘miliary’ and
‘rice-sized’ lesions as ‘≤5 mm’, and ‘azuki bean-sized’ and ‘thumbsized’ lesions as ‘5–20 mm’. The PM site was classified into 9 areas,
and the extent of the PM was evaluated as the number of sites as
described in a previous study [14]. The grade of PM was classified
using the Japanese PM classification defined by JSCCR as follows:
P0, no PM; P1, metastasis localized to the adjacent peritoneum; P2,
metastases limited to the distant peritoneum; and P3, diffuse metastases in the distant peritoneum [10]. Intensive chemotherapy
was defined as the regimen that contained fluorouracil (5FU) or
5FU derivatives and camptothecin (CPT-11) or oxaliplatin. The
median follow-up period was 27.2 months (range 0.5–209.0
months).
Statistical Analysis
Differences between continuous variables and categorical variables were identified using the Mann–Whitney U test and the chisquare test or Fisher’s exact test, respectively. Factors affecting recurrence were analyzed using binomial logistic regression analyses. All data are expressed as medians and ranges, and survival
rates were calculated using the Kaplan–Meier method and compared using the log-rank test to examine the associations between
survival and the clinical and pathological variables. Survival analyses were performed using Cox regression models for factors that
influenced the survival of patients in the Kaplan–Meier analysis,
and the differences were identified using the log-rank test. Multiple comparisons were performed by Bonferroni adjustment. The
differences between groups and the associations with the survival
of CRC patients with PM were considered significant when p <
0.05. All analyses were performed using JMP 11 Statistical Software (SAS Institute Inc., Cary, N.C., USA).
Results
Patient Characteristics (Table 1)
The median age of the 172 patients was 62.0 (range
18–91). Of the 172 patients, 66 had a PT in the right colon,
including the cecum, ascending colon, and transverse colon; 79 in the left colon, including the descending colon,
sigmoid colon, and rectosigmoid colon; and 27 in the rectum. Synchronous distant metastases as well as PM were
found in 54 patients (31.4%). Synchronous liver metastases were found in 27 patients (15.7%), distant lymph node
metastases in 13 (7.6%), and other organ metastases in 21
(12.2%). The number of patients with P1, P2, and P3 was
103 (59.9%), 56 (32.6%), and 13 (7.6%), respectively.
Dig Surg 2016;33:382–391
DOI: 10.1159/000444097
383
Downloaded by:
Kings's College London
137.73.144.138 - 10/29/2017 8:48:40 AM
nous PM can improve the prognosis of CRC patients; in
this regard, aggressive cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy
(HIPEC) has been performed [4–7], and recent intensive
chemotherapies are expected to improve the prognosis.
Most PM classifications determine the degree of PM
based on focal number, range, and size of PM and are
used to make prognostic predictions and decisions about
treatment strategies [7–11]. Previous reports have identified histological types, presence of lymph node metastases, and R0 surgery as prognostic variables for CRC with
PM [12, 13]. However, there has been no detailed report
regarding the clinical outcomes of CRC with PM after R0
surgery. Factors affecting recurrence and prognosis are
important for postoperative follow-up and decisions
about adjuvant chemotherapy administration, yet such
factors have not yet been identified for CRC with PM.
The aim of this study was to identify the factors associated with recurrence and prognosis in stage IV CRC with
synchronous PM after R0 resection for determining appropriate postoperative follow-up and treatment strategies.
Table 1. Univariate and multivariate analyses of factors affecting recurrence in CRC patients with peritoneal metastases after R0 resec-
tion
Univariate analysis
number
Age, years
≤70
70<
Gender
Male
Female
Tumor location
Colon
Rectum
Distant metastases
+
–
Liver metastasis
+
–
Size of PT, mm
≤70
70<
LN dissection
D1
D2, D3
Number of dissected LN
≤5
5<
Unknown
Histology
Differentiated type
Undifferentiated type
Depth of invasion
T1–T3
T4
LN metastases
–
+
Postoperative chemotherapy
+
–
Unknown
Lymphatic invasion
–
+
Venous invasion
0+1
2+3
JSCCR classification of PM
P1
P2
P3
Size of PM, mm
≤5
6–20
21≤
384
recurrence, %
Multivariate analysis
p value
HR
95% CI
p value
3.02
1.60–5.69
0.0007
0.005
3.44
0.82–14.3
0.88
0.004
2.24
0.95–5.30
0.07
0.53
122
50
98 (80.3)
38 (76.0)
80
92
63 (78.8)
73 (79.3)
145
27
113 (77.9)
23 (85.2)
54
118
47 (87.0)
89 (75.4)
27
145
22 (81.5)
114 (78.6)
130
42
104 (80.0)
32 (76.2)
9
163
7 (77.8)
129 (79.1)
8
162
2
7 (87.5)
128 (79.0)
1 (50.0)
135
37
108 (80.0)
28 (75.7)
44
128
31 (70.5)
105 (82.0)
27
145
13 (48.1)
123 (84.8)
117
35
20
101 (86.3)
26 (74.3)
9 (45.0)
14
158
7 (50.0)
129 (81.6)
92
80
65 (70.7)
71 (88.8)
103
56
13
77 (74.8)
48 (85.7)
11 (84.6)
95
59
18
75 (78.9)
44 (74.6)
17 (94.4)
0.92
0.39
0.08
0.74
0.60
0.92
0.56
0.57
0.10
0.00001
0.09
0.10
0.62
Dig Surg 2016;33:382–391
DOI: 10.1159/000444097
Sato et al.
Downloaded by:
Kings's College London
137.73.144.138 - 10/29/2017 8:48:40 AM
Variable
Table 1. (continued)
Univariate analysis
number
Number of PM
1
2≤
Regional number of PM
1
2≤
Preoperaive CEA level
High
Low
Unknown
Preoperative CA19-9 level
High
Low
Unknown
recurrence, %
p value
HR
95% CI
p value
0.03
1.81
0.74–4.44
0.55
0.02
1.93
0.83–4.51
0.13
0.06
68
104
49 (72.1)
87 (83.7)
108
64
81 (75.0)
55 (85.9)
104
54
14
88 (84.6)
38 (70.4)
10 (71.4)
73
81
18
64 (87.7)
59 (72.8)
13 (72.2)
0.07
Ninety-five patients (55.2%) had PM measuring 5 mm or
smaller. Although 104 patients (60.5%) had <4 PM, 38
patients (22.1%) had ≥10 PM. One regional dissemination lesion was observed in 108 of 172 patients (62.8%).
Postoperative adjuvant chemotherapy was administered
in 117 patients (68.0%) after R0 surgery, and involved intensive chemotherapy in 28 patients (16.3%) and oxaliplatin in 9 (5.2%). Oral postoperative adjuvant chemotherapy, such as carmofur, UFT ± Uzel, TS-1, and doxifluridine, was administrated in 40 patients (23.3%), and
regimes using intravenous 5FU ± leucovorin were used in
49 patients (28.5%).
Factors Affecting Recurrence after R0 Surgery
Recurrence was found in 136 patients (79.1%) after R0
surgery. An association between lymph node metastases
(p = 0.00001), lymphatic invasion (p = 0.005), venous invasion (p = 0.004), preoperative high serum CEA levels
(p = 0.03), and preoperative high serum CA19-9 levels
(p = 0.02) was revealed using the chi-square test (table 1).
Logistic regression analyses revealed that, of these factors,
only lymph node metastases independently affected recurrence (table 1).
Although there was no significant association between
the recurrence rate and postoperative adjuvant chemotherapy, the median disease-free interval was 10.9 months
(range 0.9–99.6) in patients with postoperative adjuvant
chemotherapy and 9.5 months (range 1.4–39.5) in those
without (p = 0.07). Among the patients who received
postoperative adjuvant chemotherapy, there was no significant difference in the recurrence rate or disease-free
Peritoneal Metastases of CRC
Multivariate analysis
interval between those who received intensive postoperative adjuvant chemotherapy and those who received nonintensive postoperative adjuvant chemotherapy. Furthermore, among the patients who received postoperative intensive adjuvant chemotherapy, there was no significant
difference in the recurrence rate between those treated
with oxaliplatin as the postoperative adjuvant chemotherapy (88.9%) and those not treated with oxaliplatin (89.5%).
There was no significant difference in the recurrence
site between patients with PM alone and patients with PM
plus metastases to other organs. Hematogenous recurrence occurred in 44.8% of all patients who experienced
recurrence; 29.7% of these patients experienced peritoneal recurrence (table 2). The median disease-free interval was 10.8 months (range 0.9–99.6) in 118 patients
whose recurrence day was known. Of them, 67 (56.8%)
had a recurrence within 12 months after R0 surgery, and
90 (76.3%) within 18 months (fig. 1). Surgery for recurrent lesions after R0 surgery was performed in 25 patients
(21.2%), more commonly in patients who had a recurrence after 18 months (10 of 28 cases; 35.7%) than in the
patients who had a recurrence within 18 months (15 of 90
cases; 16.7%; p = 0.03; fig. 1).
Factors Affecting Prognoses after R0 Surgery
The overall 3- and 5-year survival rates of patients with
PM after R0 surgery were 42.0 and 36.2%, respectively.
Five or fewer dissected lymph nodes (p = 0.01), lymph
node metastases (p = 0.008), postoperative chemotherapy
(p = 0.008), lymphatic invasion (p = 0.02), venous invasion (p = 0.049), regional number of PM (p = 0.04), and
Dig Surg 2016;33:382–391
DOI: 10.1159/000444097
385
Downloaded by:
Kings's College London
137.73.144.138 - 10/29/2017 8:48:40 AM
Variable
90 cases (76.3%)
67 cases
(56.8%)
11 cases
(9.3%)
Number
40
30
20
10
0
0–6
6–12
12–18
18–24
24–30
30–36
36–42
42–48
48–54
54–60
60–66
Months
Number
26
41
23
8
4
5
3
4
2
1
1
Surgery
(%)
5
(19.2)
5
(12.2)
5
(21.7)
3
(37.5)
1
(25.0)
1
(20.0)
2
(66.7)
1
(25.0)
2
(100)
0
0
Fig. 1. Disease-free interval after R0 surgery in patients with peritoneal metastases of CRC and the surgery rate
for recurrent lesions according to the disease-free interval.
Table 2. Recurrence site after R0 surgery
PM
PM + others
Total
Number Recurrence,
%
Via blood,
%
Liver,
%
Lung,
%
Others,
%
PM,
%
118
54
172
50 (42.4)
27 (50.0)
77 (44.8)
31 (26.3)
18 (33.3)
49 (28.5)
19 (16.1)
9 (16.7)
28 (16.3)
9 (7.6)
4 (7.4)
13 (7.6)
37 (31.4) 10 (8.5) 14 (11.9)
14 (25.9) 7 (13.0) 6 (11.1)
51 (29.7) 17 (9.9) 20 (11.6)
89 (75.4)
47 (87.0)
136 (79.1)
LN,
%
Local,
%
Multiple
organ, %
30 (25.4)
13 (24.1)
43 (25.0)
Others include hematogenous matastases and distant lymph node metastases.
386
Dig Surg 2016;33:382–391
DOI: 10.1159/000444097
the patients with five or fewer dissected lymph nodes (2
of 8 patients, 25.0%; p = 0.01).
The prognosis was significantly better in patients who
underwent surgery after 2005 than in those who underwent surgery before 2004 (fig. 2a); there was no significant difference in the follow-up periods after surgery between those treated after 2005 (median 34.5 months;
range 1.0–70.3) and those treated up until 2004 (median
23.7 months; range 0.5–209.0; p = 0.55). Furthermore,
among the patients with postoperative adjuvant chemotherapy, prognosis was significantly better in those who
received intensive postoperative adjuvant chemotherapy
using CPT-11 or oxaliplatin than in those who received
postoperative non-intensive adjuvant chemotherapy
(fig. 2b). Among the patients who received postoperative
intensive adjuvant chemotherapy, there was no significant difference in prognosis between those who were
treated with oxaliplatin as postoperative adjuvant chemoSato et al.
Downloaded by:
Kings's College London
137.73.144.138 - 10/29/2017 8:48:40 AM
preoperative high serum CA19-9 levels (p = 0.045) were
associated with poor prognosis using the log-rank test
(table 3). Of these factors, lymph node metastases, no
postoperative adjuvant chemotherapy, five or fewer dissected lymph nodes, and preoperative high serum CA199 levels were independent poor prognostic factors using
the Cox proportional hazard model (table 3).
The median number of metastatic lymph nodes was 4
in 172 patients. Fifty-two patients (30.2%) had seven or
more metastatic lymph nodes, and 35 (20.3%) had 10 or
more metastatic lymph nodes. The number of lymph
node metastases was significantly higher in patients with
more than five dissected lymph nodes (median 7; range
0–79) than in patients with five or fewer dissected lymph
nodes (median 1; range 0–3) (p = 0.005). There were significantly more patients with more than one lymph node
metastases among the patients with more than five dissected lymph nodes (115 of 162 patients, 71.0%) than in
Table 3. Univariate and multivariate analyses of factors affecting survival in CRC patients with peritoneal metastases
Univariate analysis
number
Gender
Male
Female
Tumor location
Colon
Rectum
Distant metastases
+
–
Liver metastasis
+
–
Size of PT, mm
≤70
70<
LN dissection
D1
D2, D3
Number of dissected LN
≤5
5<
Unknown
Histology
Differentiated type
Undifferentiated type
Depth of invasion
T1–T3
T4
LN metastases
–
+
Postoperative chemotherapy
+
–
Unknown
Lymphatic invasion
–
+
Venous invasion
0+1
2+3
JSCCR classification of PM
P1
P2
P3
Size of PM, mm
≤5
6–20
21≤
Number of PM
1
2≤
Peritoneal Metastases of CRC
Multivariate analysis
3-year SR, %
5-year SR, %
80
92
39.1
44.4
31.1
33.8
145
27
42.4
40.0
34.3
23.3
54
118
41.0
42.5
31.7
33.1
27
145
39.0
42.5
29.7
33.2
130
42
43.3
37.9
32.3
33.7
9
163
25.0
42.9
25.0
33.0
8
162
2
12.5
42.7
12.5
32.6
135
37
44.8
31.0
33.4
31.0
44
128
47.1
40.3
38.8
30.3
27
145
60.2
37.7
55.2
26.7
117
35
20
44.2
28.4
33.6
19.0
14
158
62.3
40.2
62.3
30.0
92
80
46.5
36.9
40.7
23.1
103
56
13
45.7
39.5
25.0
35.2
32.5
16.7
95
59
18
40.5
46.9
33.3
28.6
42.9
22.2
68
104
49.7
36.9
42.2
26.2
p value
HR
95% CI
p value
2.84
1.20–6.69
0.02
0.008
2.55
1.06–6.11
0.03
0.008
1.75
1.11–2.78
0.02
0.02
1.32
0.99–2.29
0.28
0.049
1.34
0.89–2.04
0.16
0.95
0.61
0.097
0.21
0.84
0.43
0.01
0.68
0.71
0.32
0.13
0.13
Dig Surg 2016;33:382–391
DOI: 10.1159/000444097
387
Downloaded by:
Kings's College London
137.73.144.138 - 10/29/2017 8:48:40 AM
Variable
Table 3. (continued)
Variable
Univariate analysis
Regional number of PM
1
2≤
Preoperaive CEA level
High
Low
Unknown
Preoperative CA19-9 level
High
Low
Unknown
Multivariate analysis
number
3-year SR, %
5-year SR, %
108
64
46.7
34.2
36.9
25.4
104
54
14
36.9
42.9
24.7
40.5
73
81
18
33.1
44.9
23.8
36.4
After 2005
Until 2004
0.8
0.6
95% CI
p value
0.04
1.50
0.99–2.29
0.06
1.58
1.05–2.38
0.03
0.26
1.0
Intensive postoperative chemotherapy
Non-intensive postoperative chemotherapy
0.8
0.6
53.8%
41.4%
0.4
0.4
28.6%
0.2
a
HR
0.045
1.0
0
p value
p = 0.03
0
50
26.3%
0.2
60
100
150
200
0
250
Months
b
p = 0.01
0
50
60
100
150
200
250
Months
Fig. 2. Overall survival curves according to the eras (a, p = 0.03) and the regimen of adjuvant chemotherapy after
R0 surgery (b, p = 0.01).
Discussion
Synchronous PM is a poor prognostic factor for primary CRC patients [15]. A majority of patients with synchronous PM of CRC have hematogenous metastases, and
388
Dig Surg 2016;33:382–391
DOI: 10.1159/000444097
most patients with PM are exclusively managed with palliative care for symptom relief with or without chemotherapy [12]. However, aggressive surgery improves the prognosis of synchronous PM of CRC if performed as an R0
surgery. To improve the treatment outcomes of CRC patients with PM, CRS combined with HIPEC has been attempted [4–7], with significant prognostic improvement
shown in a randomized controlled trial [16]. However, this
approach has not been performed as a standard treatment
due to frequent and significant morbidity and mortality.
Furthermore, a recent retrospective international registry
study showed that a complete CRS was associated with
overall survival, while HIPEC was not [17]. Intensive systemic chemotherapy is expected to improve survival.
Retrospective multicenter analyses have reported that
R0 resection is an independent favorable prognostic facSato et al.
Downloaded by:
Kings's College London
137.73.144.138 - 10/29/2017 8:48:40 AM
therapy and those who were not (p = 0.94). In the patients
with recurrence, the 3- and 5-year survival rates after recurrence were 12.3 and 3.5%, respectively. The prognosis
after recurrence was significantly better for patients who
underwent surgery for recurrent lesions than in those
who underwent other treatments (fig. 3) and was significantly better in those who had recurrence within 18
months than in those who had recurrence after 18 months
(fig. 4).
1.0
Others
0.8
0.6
0.4
17.3%
0.2
0
p = 0.0005
0%
0
10
20
30
40
50
60
70
80
Months
Fig. 3. Overall survival curves after recurrence according to treat-
ment for recurrent disease (p = 0.0005).
DFI >18 months
1.0
DFI •18 months
0.8
0.6
0.4
0.2
0
14.3%
p = 0.002
0%
0
10
20
30
40
50
60
70
80
Months
Fig. 4. Overall survival curves after recurrence according to the
disease-free interval (p = 0.002).
tor in patients with synchronous PM caused by CRC [12,
13]. However, recurrence occurs frequently, even if R0
surgery is performed. The recurrence rate in the present
study was 79%. Lymph node metastasis was an independent factor that affected recurrence after R0 resection in
patients with synchronous PM caused by CRC in the present study. Lymph node metastases, no postoperative adjuvant chemotherapy, five or fewer dissected lymph
nodes, and preoperative high serum CA19-9 levels were
independent poor prognostic factors. Focal number,
Peritoneal Metastases of CRC
range, and size of PM have been used to classify the progression of PM [8–11]; the JSCCR classification according
to the focal number and range of PM is reported to be one
of the factors affecting R0 resection and prognostic factors
[12]. However, the number of patients eligible for R0 surgery is limited – most belonged to P1 or P2 in the present
study. As a result, the focal number, range, and size of PM,
which are used in many classifications, were not associated with recurrence and prognosis in patients after R0
surgery. Hematogenous metastasis is reportedly associated with R0 resection, and liver metastasis is an independent poor prognostic factor in CRC patients with PM [12].
However, in this study, neither distant metastasis nor liver metastasis was a prognostic factor in the R0 surgery
case. The TNM classification of malignant tumors classifies CRC with PM as stage IV-B, which includes patients
with multiple organ metastases [3]. We believe that there
was no difference in the recurrence rate or prognosis between patients with and without distant metastases because the treatment outcome was poor in CRC patients
with PM, regardless of distant metastases. On the other
hand, among these patients with nodal metastasis, more
than 35% actually had seven or more nodal metastasis and
included patients who underwent R0 surgery. For this
reason, lymph node metastasis was an independent factor
affecting recurrence and poor prognosis. Five or fewer
dissected lymph nodes constitute one of the poor prognostic factors in this study. Among the patients with five
or fewer dissected lymph nodes, the number of node metastases and the fraction of patients with node metastasis
≤1 were significantly lower than those among the other
patients. Examination of a minimum of 12 lymph nodes
is recommended to prevent stage migration and to accurately identify the N stage, particularly in stage II disease
[18]. In synchronous PM cases in which R0 surgery was
possible, our outcomes suggest that the harvest of more
than five lymph nodes through suitable lymph node dissection was important in the prediction of prognosis [10].
Although there was no significant association between
the recurrence rate and postoperative adjuvant chemotherapy, we believe that postoperative adjuvant chemotherapy contributed to prognostic improvement by extending the disease-free interval, although it did not prevent recurrence. A pooled analysis of two large prospective
randomized trials (N9741 and N9841) investigating the
efficacy of chemotherapy for metastatic CRC showed that
the median survival time of patients with PM was significantly shorter than that of patients without PM [19]. Actually, the efficacy of chemotherapy (even intensive chemotherapy such as FOLFOX/FOLFIRI ± bevacizumab/
Dig Surg 2016;33:382–391
DOI: 10.1159/000444097
389
Downloaded by:
Kings's College London
137.73.144.138 - 10/29/2017 8:48:40 AM
Surgery
cetuximab) for the treatment of PM has not been demonstrated [19–21]. However, in this study, hematogenous
recurrence occurred more frequently than peritoneal recurrence after R0 surgery for PM of CRC, even in patients
without distant metastases. Most patients who underwent R0 surgery belonged to P1 or P2 in this study. Furthermore, 84.3% of patients had lymph node metastasis,
which was one of the risk factors for hematogenous recurrence. These facts are thought to underlie the frequent
hematogenous recurrence observed in these patients and
may explain why postoperative adjuvant chemotherapy
after R0 surgery was effective in decreasing recurrence
and improving prognosis. The prognosis was significantly better in patients who received postoperative intensive
adjuvant chemotherapy than in those who received nonintensive adjuvant chemotherapy, although there were
no significant differences in recurrence rate and diseasefree interval between the two groups. Furthermore, the
prognosis was significantly better in patients who underwent surgery after 2005 than in those who underwent surgery before 2004, when oxaliplatin was approved for use
in CRC in Japan. These outcomes suggest that intensive
chemotherapy better improves the prognosis of patients
with PM after R0 surgery. Thus, intensive chemotherapy
such as oxaliplatin might not be necessary as postoperative adjuvant chemotherapy for stage IV CRC patients
with PM who have undergone R0 surgery.
Recurrence occurred in almost 60% of patients with
PM within 12 months after R0 surgery and in 75% within
18 months. Recurrence, particularly hematogenous recurrence, should be a significant concern until 18 months
after R0 surgery for CRC with PM. The disease-free interval has been associated with the resection rate of recur-
rent disease and prognosis after recurrence, and the resection rate was lower and prognosis was poor in patients
who had a recurrence within 18 months after R0 surgery.
Complete cancer removal by surgery followed by postoperative adjuvant therapy may extend the disease-free interval and improve prognosis.
There are several potential limitations to this retrospective study. The first involves the accuracy of data due
to the inconsistent format of surgical records collected at
16 institutions. Some patients had to be excluded from
further analysis due to lack of sufficient background records. To ensure the accuracy of our data, we carefully
omitted all inappropriate and uncertain data, thereby, unfortunately, decreasing the data by as much as 23%. Therefore, our observations warrant further consideration and
validation in a larger series of patients with CRC.
In conclusion, lymph node metastasis was an independent factor for recurrence and prognosis after R0 resection in patients with synchronous PM of CRC. In addition, the number of dissected lymph nodes, postoperative
adjuvant chemotherapy, and preoperative serum CA19-9
levels were independent prognostic factors. In PM cases
of CRC, the harvesting of more than five lymph nodes
through suitable curative lymph node dissection and the
administration of adjuvant chemotherapy after R0 surgery are recommended for the prediction and improvement of prognosis.
Disclosure Statement
All authors declare that there is no conflict of interest in this
study.
References
390
Dig Surg 2016;33:382–391
DOI: 10.1159/000444097
toreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J
Clin Oncol 2009;27:681–685.
5 Franko J, Ibrahim Z, Gusani NJ, Holtzman
MP, Bartlett DL, Zeh HJ 3rd: Cytoreductive
surgery and hyperthermic intraperitoneal
chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis. Cancer 2010;116:3756–3762.
6 Pestieau SR, Sugarbaker PH: Treatment of
primary colon cancer with peritoneal carcinomatosis: comparison of concomitant vs.
delayed management. Dis Colon Rectum
2000;43:1341–1346; discussion 1347–1348.
7 Sugarbaker PH: Successful management of
microscopic residual disease in large bowel
cancer. Cancer Chemother Pharmacol 1999;
43(suppl):S15–S25.
8 Gilly FN, Carry PY, Sayag AC, Brachet A,
Panteix G, Salle B, Bienvenu J, Burgard G,
Guibert B, Banssillon V, et al: Regional chemotherapy (with mitomycin C) and intra-operative hyperthermia for digestive cancers
with peritoneal carcinomatosis. Hepatogastroenterology 1994;41:124–129.
9 Jacquet P, Sugarbaker PH: Clinical research
methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer
Treat Res 1996;82:359–374.
10 Japanese Society for Cancer of the Colon and
Rectum: Japanese Classification of Colorectal
Carcinoma, ed 2. Tokyo, Kanehara and Co.,
Ltd., 2009.
Sato et al.
Downloaded by:
Kings's College London
137.73.144.138 - 10/29/2017 8:48:40 AM
1 Jayne DG, Fook S, Loi C, Seow-Choen F: Peritoneal carcinomatosis from colorectal cancer.
Br J Surg 2002;89:1545–1550.
2 Kobayashi H, Enomoto M, Higuchi T, Uetake
H, Iida S, Ishikawa T, Ishiguro M, Sugihara K:
Validation and clinical use of the Japanese
classification of colorectal carcinomatosis:
benefit of surgical cytoreduction even without hyperthermic intraperitoneal chemotherapy. Dig Surg 2010;27:473–480.
3 Sobin LH, Gospondarowicz MK, Wittekind
C: TNM Classification of Malignant Tumors.
UICC International Union against Cancer, ed
7. New York, Wiley, 2009, pp 100–105.
4 Elias D, Lefevre JH, Chevalier J, Brouquet A,
Marchal F, Classe JM, Ferron G, Guilloit JM,
Meeus P, Goéré D, Bonastre J: Complete cy-
Peritoneal Metastases of CRC
14 Kobayashi H, Kotake K, Sugihara K: Enhancing the objectivity of the Japanese classification of peritoneal metastases from colorectal
cancer. Jpn J Clin Oncol 2014;44:898–902.
15 Japanese Society for Cancer of the Colon and
Rectum: JSCCR Guidelines 2014 for the
Treatment of Colorectal Cancer. Tokyo,
Kanehara & Co., Ltd., 2014.
16 Verwaal VJ, van Ruth S, de Bree E, van
Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA: Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy
and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J
Clin Oncol 2003;21:3737–3743.
17 Chua TC, Moran BJ, Sugarbaker PH, Levine
EA, Glehen O, Gilly FN, Baratti D, Deraco M,
Elias D, Sardi A, Liauw W, Yan TD, Barrios P,
Gómez Portilla A, de Hingh IH, Ceelen WP,
Pelz JO, Piso P, González-Moreno S, Van Der
Speeten K, Morris DL: Early- and long-term
outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated
by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J
Clin Oncol 2012;30:2449–2456.
Dig Surg 2016;33:382–391
DOI: 10.1159/000444097
18 Le Voyer TE, Sigurdson ER, Hanlon AL, Mayer RJ, Macdonald JS, Catalano PJ, Haller DG:
Colon cancer survival is associated with increasing number of lymph nodes analyzed: a
secondary survey of intergroup trial INT0089. J Clin Oncol 2003;21:2912–2919.
19 Franko J, Shi Q, Goldman CD, Pockaj BA, Nelson GD, Goldberg RM, Pitot HC, Grothey A,
Alberts SR, Sargent DJ: Treatment of colorectal
peritoneal carcinomatosis with systemic chemotherapy: a pooled analysis of north central
cancer treatment group phase III trials N9741
and N9841. J Clin Oncol 2012;30:263–267.
20 Klaver YL, Simkens LH, Lemmens VE, Koopman M, Teerenstra S, Bleichrodt RP, de
Hingh IH, Punt CJ: Outcomes of colorectal
cancer patients with peritoneal carcinomatosis treated with chemotherapy with and without targeted therapy. Eur J Surg Oncol 2012;
38:617–623.
21 Sadahiro S, Suzuki T, Maeda Y, Tanaka A,
Makuuchi H, Kamijo A, Haruki Y, Murayama
C: Prognostic factors in patients with synchronous peritoneal carcinomatosis (PC)
caused by a primary cancer of the colon. J
Gastrointest Surg 2009;13:1593–1598.
391
Downloaded by:
Kings's College London
137.73.144.138 - 10/29/2017 8:48:40 AM
11 Witkamp AJ, de Bree E, Kaag MM, Boot H,
Beijnen JH, van Slooten GW, van Coevorden
F, Zoetmulder FA: Extensive cytoreductive
surgery followed by intra-operative hyperthermic intraperitoneal chemotherapy with
mitomycin-C in patients with peritoneal carcinomatosis of colorectal origin. Eur J Cancer
2001;37:979–984.
12 Kobayashi H, Kotake K, Funahashi K, Hase K,
Hirata K, Iiai T, Kameoka S, Kanemitsu Y,
Maeda K, Murata A, Ohue M, Shirouzu K,
Takahashi K, Watanabe T, Yano H, Yatsuoka
T, Hashiguchi Y, Sugihara K; Study Group for
Peritoneal Metastasis from Colorectal Cancer
by the Japanese Society for Cancer of the Colon and Rectum: Clinical benefit of surgery
for stage IV colorectal cancer with synchronous peritoneal metastasis. J Gastroenterol
2014;49:646–654.
13 Ozawa H, Kotake K, Kobayashi H, Kobayashi
H, Sugihara K: Prognostic factors for peritoneal carcinomatosis originating from colorectal cancer: an analysis of 921 patients from a
multi-institutional database. Surg Today
2014;44:1643–1650.
Документ
Категория
Без категории
Просмотров
0
Размер файла
131 Кб
Теги
000444097
1/--страниц
Пожаловаться на содержимое документа