Ann Surg Oncol DOI 10.1245/s10434-014-3885-1
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Surgical Approaches to Advanced Gallbladder Cancer A 40-Year Single-Institution Study of Prognostic Factors and Resectability Ryota Higuchi, MD, PhD1, Takehiro Ota, MD, PhD1, Tatsuo Araida, MD, PhD2, Hideki Kajiyama, MD1, Takehisa Yazawa, MD, PhD1, Toru Furukawa, MD, PhD3, Tatsuya Yoshikawa, MD, PhD1, Ken Takasaki, MD, PhD1, and Masakazu Yamamoto, MD, PhD1 Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan; 2Department of Surgery, Division of Gastroenterological Surgery, Yachiyo Medical Center, Tokyo Women’s Medical University, Tokyo, Japan; 3Department of Pathology, and International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Tokyo, Japan 1
ABSTRACT Purpose. The aim was to evaluate prognostic factors and factors associated with the resectability of advanced gallbladder cancer (GBC). Methods. This was a single-institution retrospective review of 274 consecutive surgically-treated cases of advanced GBC (excluding incidental GBC and early GBC). Univariate and multivariate analysis were performed to assess prognostic variables. R0 resection and survival rates were investigated for each local extension factor. Results. Long-term survival was uncommon among patients with multiple liver metastases (H2–3: n = 22; 2-year survival, 0 %), dissemination (P1–3: n = 16; 3-year survival, 0 %), invasion through the hepatoduodenal ligament (Binf3: n = 45; 5-year survival, 4.6 %), or group 3 lymph node (LN) metastasis including of the para-aortic LN (N3: n = 52; 13.7 %). Long-term survival rates did not differ significantly between patients who did and did not undergo bile duct resection or pancreaticoduodenectomy. Survival did not differ significantly according to the type of hepatectomy performed.
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3885-1) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 19 February 2014 M. Yamamoto, MD, PhD e-mail:
[email protected]
Conclusion. Surgery may not be indicated for patients with multiple liver metastasis, dissemination, Binf3, or visible para-aortic LN metastasis. Furthermore, it is important to achieve R0 surgery in cases of GBC.
Gallbladder cancer (GBC) is a rare disease that usually has a late presentation1 and poor prognoses in its advanced stage.2–5 GBC progression can include lymph node (LN) metastasis, liver invasion, hepatoduodenal ligament (HDL) invasion, liver metastasis, and peritoneal metastasis.5 However, there is no consensus regarding the resectability of advanced GBC. Here, we investigated factors that are unfavorable to the resection of advanced GBC. We sought to identify indications for surgery and appropriate surgical procedures. Because GBC is a rare cancer, it has been difficult to obtain sample sizes that are sufficient for detailed analyses of resection and prognosis. For this study, we collected data on cases treated between 1969 and 2012. Variations in treatment over this period naturally pose a limitation to our analysis. Yet, there is a critical need for evidence regarding the treatment of advanced GBC, and data from recent years are insufficient to address this need. Therefore, we designed this 40-year retrospective study to provide preliminary evidence on the treatment of advanced GB. METHODS We retrospectively examined records from 274 consecutive patients who underwent surgery for pathologically confirmed advanced GBC (excluding 26 incidental GBC and 89 early GBC) between 1969 and 2012 at our
R. Higuchi et al.
institution. Early GBC can be defined histologically as follows: the deepest invasion is limited to the mucosa or muscularis propria of the gallbladder wall, regardless of LN metastasis. Intraepithelial cancer of any layers of the Rokitansky-Aschoff sinus can be defined as early cancer. Cases with deepest invasion beyond the muscularis propria were defined as advanced GBC.6 We selected factors for further investigation based on the 5th version of the Japanese Society of Biliary Surgery (JSBS) classification system.6 Definitions of these factors can be found in the electronic supplementary Table 1. We also stratified the patients by treatment era to evaluate secular changes in surgical approaches, morbidity, and mortality [Group A: 1969–1989 (n = 88); Group B: 1990–1999 (n = 76); and Group C: 2000–2012 (n = 110)]. The Clavien–Dindo classification was used in our evaluation of morbidity.7 Postoperative hospital stay and 30-day readmission were calculated in cases without mortality. The Institutional Review Board of Tokyo Women’s Medical University approved this retrospective study. Changes in Diagnostic and Surgical Strategies by Era Angiography, computed tomography (CT), and multidetector row CT were introduced at our institution during 1969, 1986, and 2005, respectively. Percutaneous transhepatic biliary drainage was mainly performed from 19688 until 2002, while the use of endoscopic biliary drainage gradually increased after 2002, and is now the first-choice therapy for obstructive jaundice. Portal vein (PV) embolization was introduced at our institution in 1992, and is indicated when the predicted remnant liver is\30 % of the total liver volume. Hemihepatectomy with extrahepatic bile duct resection (BDR) was introduced in 1978 to increase curability. Hepato-pancreaticoduodenectomy (HPD) was introduced in 1982 and was performed in 101 cases, including nine cases of hepato-ligament-pancreaticoduodenectomy, which itself was introduced in 1988. Resection and reconstruction of the PV began to be performed in 1980, and resection and reconstruction of the hepatic artery (HA) began to be performed in 1986. Until 1996, we had actively performed PD when the depth of mural cancer and its location indicated the possibility of LN metastasis.9 However, extensive surgeries, such as major hepatectomy with PD, resulted in poor short-term surgical results and high hospital mortality.10 Since 1997, we have therefore avoided major hepatectomy with PD, instead performing PD when LN metastasis has either been proven by intraoperative pathology or obviously exists without invasion of the HDL.9 Resection of the PV and HA was only performed if invasion was suggested at laparotomy. The basic LN dissection was D2 (electronic supplementary Table 1). Most D3 dissections were
performed in patients with concomitant PD cases (Table 1). D1 dissections were performed (i) in patients with curative resections that could not be accomplished as a result of HDL invasion, hepatic invasion, or liver or peritoneal metastasis (n = 20); (ii) in patients with limited hepatic resection for small cancer (n = 14); and (iii) in elderly patients with poor general condition or another severe disease (n = 12; note that these categories overlap). Since 1984, we have determined the indication for hepatectomy by assessing expected remnant liver function, using the resection rate of the liver and the indocyanine green (ICG) clearance test. Since 2011, we have also used the Fuji Film (Tokyo, Japan) SYNAPSE VINCENT highspeed three-dimensional (3D)-image analysis system for 3D liver volumetry. When possible, patients were seen every 1 and 2 months for the first 6 months, every 1–3 months for the following year, and every 2 and 3 months thereafter. Among patients with LN metastasis, residual cancer, and good postoperative condition, adjuvant chemotherapy was used according to the physician’s preference. Adjuvant therapy consisted of titanium silicate (TS)-1 (since 2001) and/ or gemcitabine (since 2003) within 12 weeks postoperatively. Statistical Analysis Survival analyses were performed using the Kaplan– Meier method, log-rank test, and Cox proportional hazards model in the R environment (R version 2.12.0; The R Foundation for Statistical Computing). Associations among qualitative variables were analyzed by using Fisher’s exact test, specifically by testing the independence of contingency tables. p-Values \0.05 were considered to indicate statistically significant differences. RESULTS Overall, 116 men and 158 women were included. The mean age was 64 years (range 31–90 years). Mean and median observational periods were 35.1 and 14.0 months (range 0–294 months). The use of BDR increased over time (Group A, 23.9 %; Group B, 38.2 %; Group C, 59.1 %; p \ 0.0001), while the use of simultaneous PD decreased over time (Group A, 54.5 %; Group B, 50.0 %; Group C, 14.5 %; p \ 0.0001) [electronic supplementary Fig. 1]. Cholecystectomy (Gb) was performed in 16 cases (10 D1 and 6 D2 LN dissections), and Gb with BDR was performed in 15 cases (1 D1 and 14 D2; Table 1). Gb was selected in cases with small tumors of the peritoneal and fundus side that also involved (n = 11), poor general condition (n = 13) or had been diagnosed as early cancer by intraoperative finding or frozen section diagnosis
29
6
15
16
274 36/10/10
RGB
PD
Gb with BDR
Gb
Total number
4/3/3
0/1/20/46/1
0/4/4/8/0 1/0/4/4/0
9/7/0/0/0
8/3/4/0/0
1/1/1/3/0
9/12/2/5/1
1/7/3/7/1
16/0/0
8/7/0
4/2/0
27/2/0
12/7/0
11/16/0
8/1/0
12/4/0
2/1/0 25/10/0
27/39/2
16/15/0
87 33/50/46/141/4 168/104/2
0
0
5
0
0
23 2/5/3/17/0
0
0
0 0/1/0/2/0 28 2/8/4/21/0
2
29 0/1/1/28/1
35/274
0/16 (0)
0/15 (0)
0/6 (0)
0
2 (11)
1 (3.7)
0
1 (6.3)
1 (33) 2 (5.7)
13 (19)
15 (48)
14
21
34
22
26
35
21
34
79 43
31
66
4/110 (3.6) 29
0/8 (0)
0/8 (0)
0/1 (0)
0/14 (0)
1/10 (10)
0/4 (0)
0/6 (0)
0/6 (0)
0/1 (0) 0/9 (0)
3/42 (7.1)
0/1 (0)
20/239
1/16
1/15
0/6
1/29
0/17
2/26
0/9
0/15
0/2 3/33
9/55
3/16
35.1
81.7
44.7
85.0
48.3
25.4
39.1
37.0
30.2
74.3 57.0
11.7
11.2
22 (17–41)
NA (66–NA)
67 (47–NA)
NA (NA–NA)
NA (40–NA)
49 (17–NA)
13 (9–NA)
NA (21–NA)
9 (7–NA)
3 (3–NA) 27 (17–NA)
12 (11–15)
11 (9–43)
37.0 (30.8–44.4)
85.9 (69.5–100)
61.9 (36.6–100)
83.3 (58.3–100)
57.2 (39.4–82.9)
17.0 (3.20–90.3)
26.9 (14.3–50.7)
64.8 (39.3–100)
24.1 (9.08–64.0)
50.0 (12.5–100) 36.1 (22.6–57.7)
14.7 (6.98–31.1)
7.06 (1.07–46.5)
Postoperative 30-day Disease-specific survival (months) hospital stay readmission Median; (days) Mean MST (95 % CI) 5-year (95 % CI)
Postoperative hospital stay and 30-day readmission were calculated in cases without mortality MH major hepatectomy, PD pancreaticoduodenectomy, BDR bile duct resection, S4b5 resection of segment IVB and V, RGB resection of the gallbladder bed, Gb cholecystectomy (all-layer excision of the gallbladder), PV portal vein, HA hepatic artery, HANR hepatic artery resection and not reconstruction, D3 complete dissection of Group 1, 2 and 3 lymph nodes, JSBS Japanese Society of Biliary Surgery,8 MST median survival time, CI confidence interval, NA not applicable
0/0/0
0/0/1
0/0/0
0/0/0
0/0/1
27
19
RGB with BDR
0/0/0
1/0/1
0/0/0 7/1/2
13/2/0
11/4/2
(PV/HA/HANR)
Resection Mortality status (2/3/4a/4b/NA) (R0/1 or 2/NA) Overall (%) 2000- (%)
Vascular resection D3 JSBS stage
RGB with PD
16
9
3 35
MH S4b5 with PD
S4b5
68
MH with BDR
S4b5 with BDR
31
MH with PD
Surgical procedure n
TABLE 1 Details of operative procedures performed: stage, resection status (R0, R1, or R2), mortality, and survival
Outcomes in Advanced Gallbladder Cancer
R. Higuchi et al. P < 0.001
Stage II
Fisher’s exact test n
R0 resection (%)
a
P-Value
0.8
Regional and distant factors
1.0
TABLE 2 Rates of R0 resection in patients with advanced gallbladder cancer according to invasion, metastasis, and Japanese Society of Biliary Surgery classification
5-year survivors (n)
10
N2
81
47 (58)
10
N3
52
17 (33)
4
30
Liver invasion (Hinf) \0.0001
Hinf0
66
54 (82)
Hinf1a
56
38 (68)
21
Hinf1b
28
18 (64)
3
Hinf2 Hinf3
38 84
19 (50) 39 (46)
3 1
Binf0
131
107 (82)
Binf1
35
23 (66)
2
Binf2
58
24 (41)
4
27
HDL invasion (Binf)
n
5 years (95% Cl)
MST
Stage II
33
0.85 (0.72–1.00)
NA (NA–NA)
Stage III
50
0.67 (0.53–0.84)
NA (61–NA)
Stage IVa 46
0.28 (0.16–0.49)
20 (15–47)
Stage IVb 141
0.11 (0.06–0.21)
11 (9–13)
Stage IVa Stage IVb
0
50
100
150
200
250
300
month No. at risk
45
\0.0001
13 (29)
49
1
Liver metastasis (H) \0.0001
H0
211
156 (74)
H1
39
12 (44)
H2
8
0
0
H3
14
0
0
52 4
Peritoneal metastasis (P) \0.0001
P0
254
P1
8
0
0
P2 P3
4 4
0 0
0 0
167 (66)
56
HDL hepatoduodenal ligament, JSBS Japanese Society of Biliary Surgery a
(%)
34 (71)
0.4
68 (82)
48
0.2
83
0.0
\0.0001
N0 N1
Binf3
Stage III
0.6
JSBS8 (N)
Fisher’s exact test for n 9 2 tables for the n values of each factor
(n = 7). There were 17 patients with R0 resection in N3 (Table 2). Five received major hepatectomy with PD, four underwent S4b5 resection with PD, five underwent resection of the gallbladder bed (two with PD, two with BDR, and one without BDR), two underwent PD and one underwent Gb with BDR. Patients for whom it was supposed that a few N3 LN metastases would all be resected with negative surgical margins were classified as having received R0 resection, as follows: superior mesenteric artery (n = 9), para-aortic (n = 6), stomach (n = 2), peripancreatic without superior retropancreatic (n = 2), and celiac (n = 1, repetition ?). Regarding Binf 3, R0 resection was achieved in 13 of the 45 patients (Table 2). Thirteen patients underwent 11 major hepatectomies with PD and two major hepatectomies with BDR.
0M
60M
120M
Stage II
33
21
8
Stage III
50
20
9
Stage IVa
46
6
2
Stage IVb
141
7
2
FIG. 1 Disease-specific survival rates according to Japanese Society of Biliary Surgery stage. Five-year survival rates and MSTs are presented. Four cases (one T2 and three T4) were excluded from this figure because the status of lymph node metastasis was unclear. MST median survival time, NA not applicable
Thirty-four patients died in the hospital following postoperative complications, resulting in an overall surgical mortality rate of 12.4 %. Over the years, morbidity greater than Clavien–Dindo classification 3a decreased gradually 7 from 60.2 % (53/88) in Group A to 57.9 % (44/ 76) in Group B and 30.9 % (34/110) in Group C (p \ 0.0001). The rate of [3a morbidity rate was 26.4 % (14/53) during 2007–2012. Surgical mortality also decreased gradually from 19.3 % (17/88) in Group A and 17.1 % (13/76) in Group B to 3.6 % (4/110) in Group C (p = 0.00063). The surgical mortality rate was 1.9 % (1/ 53) during 2007–2012. Table 1 shows details of operative procedures, postoperative stay, 30-day readmission rate, and mortality. Of the patients who tolerated surgery, 139 (50.7 %) died from causes related to the original disease, and 10 died of other causes (3.6 %). At the time of data collection, 12 patients were alive with recurrence (4.4 %) and 79 patients were alive and disease-free (28.8 %). Survival curves for various JSBS stages (Fig. 1) and surgical procedures (Table 1) are shown.
Outcomes in Advanced Gallbladder Cancer TABLE 3 Univariate and multivariate analyses of prognostic factors in patients with advanced gallbladder cancer
n
Univariate
Multivariate a
5-year DSS [% (95 % CI)]
P-Value
Hazard ratio (95 % CI)
P-Valueb
\75
225
35.8 (29.2–44.0)
0.18
1.00
C75
49
40.5 (26.0–62.9)
Men
116
29.4 (20.6–42.0)
Women
158
41.8 (33.7–51.7)
Type of hepatectomy Gb 37
77.6 (63.9–94.2)
Age (years) 1.16 (0.66–2.03)
0.61
Sex 0.11
1.00 0.61 (0.39–0.98)
\0.0001
0.042
1.00
RGB
75
39.1 (28.3–54.1)
1.99 (0.88–4.52)
0.10
S4b5
60
36.4 (25.2–52.6)
1.23 (0.46–3.29)
0.68
MH
102
12.7 (6.02–26.6)
1.67 (0.62–4.55)
0.31
BDR \0.0001
Absent
58
67.1 (54.7–82.3)
Present
117
23.1 (14.7–36.4)
1.18 (0.58–2.40)
0.64
99
30.6 (21.8–43.0)
0.93 (0.33–2.60)
0.89
PD
1.00
LND D1
41
43.3 (28.6–65.7)
D2
143
38.7 (30.2–49.7)
0.85 (0.44–1.63)
0.62
D3
87
31.3 (21.8–44.9)
0.55 (0.20–1.56)
0.26
157
52.3 (44.1–62.0)
C2000 116 Surgery time (min)
13.2 (7.42–23.5)
0.51
1.00
Bleeding (min) \2000
\360
136
49.9 (41.0–60.7)
C360
138
23.6 (16.5–33.9)
\0.0001
1.00 1.82 (1.09–3.04)
0.0003
0.021
1.00 1.12 (0.63–1.99)
0.70
Histology \0.0001
G1
85
60.1 (49.1–73.5)
G2
93
28.0 (18.8–41.6)
1.09 (0.61–1.95)
1.00 0.76
G3
56
26.3 (15.9–43.7)
2.78 (1.50–5.16)
0.0012
G4
39
18.7 (8.03–43.5)
3.75 (1.79–7.86)
0.0005
Liver invasion (Hinf) \0.0001
0
66
66.4 (54.3–81.3)
1a
56
50.9 (38.5–67.2)
1.24 (0.58–2.09)
1.00 0.55
1b
28
32.9 (16.8–64.7)
2.01 (0.92–5.09)
0.14
2
38
13.8 (5.46–34.9)
1.68 (0.67–3.30)
0.23
3
84
7.30 (2.23–23.8)
1.38 (0.64–2.80)
0.41
1.00 1.63 (0.87–3.05)
0.13
HDL invasion (Binf) \0.0001
0 1
131 35
57.2 (48.5–67.5) 21.6 (9.08–51.5)
2
58
11.9 (5.07–28.0)
1.80 (0.92–3.53)
0.087
3
45
4.63 (0.74–29.0)
1.32 (0.56–3.15)
0.53
Absent
219
43.0 (36.1–51.3)
Present
43
pA \0.0001
0 (2 ys 10.7)
1.00 1.03 (0.51–2.11)
0.93
pV Absent
212
44.2 (37.1–52.7)
Present
44
9.01 (2.58–31.5)
\0.0001
1.00 1.69 (0.90–3.18)
0.10
R. Higuchi et al. TABLE 3 continued
n
Univariate 5-year DSS [% (95 % CI)]
Multivariate a
P-Value
Hazard ratio (95 % CI)
P-Valueb
\0.0001
1.00
JSBS8 (N) N0
83
54.6 (43.9–67.9)
N1
48
46.2 (31.1–68.6)
1.30 (0.67–2.51)
0.43
N2
81
24.3 (15.2–38.9)
2.01 (1.14–3.57)
0.016
N3
52
13.7 (6.12–30.7)
2.67 (1.30–5.47)
0.0074
1.00 1.09 (0.61–1.95)
0.78
Liver metastasis (H) DSS disease-specific survival, Gb cholecystectomy (all-layer excision of the gallbladder), RGB resection of the gallbladder bed, S4b5 resection of segment IVB and V, MH major hepatectomy, BDR bile duct resection, PD pancreaticoduodenectomy, LND lymph node dissection, HDL hepatoduodenal ligament, pA invasion to the hepatic artery, pV invasion to the portal vein, JSBS Japanese Society of Biliary Surgery 8 a b
Log-rank test
Cox proportional hazard model
\0.0001
H0 H1
211 39
H2
8
0 (2 ys 0)
1.40 (0.41–4.77)
0.59
H3
14
0 (2 ys 0)
1.64 (0.67–4.03)
0.28
43.4 (36.2–52.0) 18.9 (8.35–42.9)
Peritoneal metastasis (P) P0
39.2 (32.7–47.1)
0.0002
1.00
P1
8
0 (3 ys 0)
1.92 (0.70–5.23)
0.20
P2
4
0 (2 ys 0)
1.21 (0.34–4.32)
0.76
P3
4
0 (2 ys 0)
22.8 (2.05–253)
0.011
R 0
168
52.4 (44.3–62.0)
1 or 2
104
8.37 (3.36–20.8)
\0.0001
1.00 2.08 (1.12–3.86)
0.020
Adjuvant chemotherapy Absent
243
36.2 (29.8–44.0)
Present
28
32.5 (12.6–83.6)
There were no long-term survivors among patients with multiple liver metastases (2-year survival 0 %) or dissemination (3-year survival 0 %; Tables 2, 3). The 5-year survival rate was 18.9 % (N = 4) for patients with solitary liver metastasis. In patients with distant LN metastasis (N3), as defined by the JSBS classification, the 5-year survival rate was 13.7 % (N = 4). With respect to liver invasion, 5-year survival rates for Hinf2 and Hinf3 cases were 13.8 % (N = 3) and 7.3 % (N = 1), respectively. Among patients with HDL invasion, the 5-year survival rates were 21.6 % (N = 2) for Binf1 cases, 11.9 % (N = 4) for Binf2 cases, and 4.6 % (N = 1) for Binf3 cases (Tables 2, 3). The following were independent prognostic factors of disease-specific survival (DSS) in our multivariate analysis (Table 3): female sex (hazard ratio [HR] 0.61), bleeding (HR 1.82), G3 histology (HR vs. G1 2.78), G4 histology (HR vs. G1 3.75), JSBS N2 (HR vs. N0 2.01), JSBS N3 (HR vs. N0 2.67), P3 (HR vs. P0 22.8), and R1/2 resection (HR vs. R0, HR 2.08). A detailed analysis of LN metastasis was also performed (Table 4). When the analysis was limited to T2 patients, supra-retropancreatic, superior mesenteric, celiac, and para-aortic LN metastases were seen in 16.9 % (13/77), 2.6 % (2/77), 1.3 % (1/77), and 2.6 % (2/77) of cases,
0.14
1.00 0.54 (0.25–1.14)
0.11
respectively. The associated 5-year DSS rates were 91.7, 50, 0, and 50 %, respectively. DISCUSSION There is no consensus regarding the factors that make GBC unresectable. Therefore, we began by investigating factors associated with the resectability of advanced GBC. Because the Union for International Cancer Control (UICC) classification11 does not include a detailed classification of regional factors, we also examined how liver invasion, HDL invasion, liver metastasis, and peritoneal metastasis affected resectability using the JSBS classification (Tables 2, 3). The UICC11 defines metastasis in the hepatic hilus nodes (including nodes along the common bile duct, common HA, PV, and cystic duct) as regional LN metastasis. Furthermore, metastasis in the celiac, periduodenal, peripancreatic, or superior mesenteric artery nodes is defined as distant metastasis (M1). Many authors recommend against surgical resection in patients with para-aortic LN metastasis.12,13 Kishi et al..14 found that posterosuperior pancreatic LN metastases were associated with a significantly better prognosis than other distant metastases. The 5-year survival rate was significantly higher for
Outcomes in Advanced Gallbladder Cancer
patients with metastasis restricted to these nodes (35 %, N = 20) than it was for patients with metastasis beyond these nodes (17 %, N = 46; p = 0.0400). In our study, among patients who had T2 disease and supra-retropancreatic LN metastasis (N = 13), the 5-year survival rate was 91.7 % (N = 7; Table 4). Regarding the American Joint Committee on Cancer UICC staging system, we would therefore like to propose to that supra-retropancreatic LN may be handled as a regional LN of the GBC. Several previous studies have reported that invasion of the HDL (Binf) is an independent predictor of poor outcomesperformed. Currently15–23, and few of these studies recommended surgical resection.15,19,20,23 The associated rates of R0 resection and 5-year survival were reported to be 5–84 % and 0–23 %, respectively.15–17,19–23 Data from the present study indicated a 66 % R0 resection rate for Binf1, a 41 % rate for Binf2, and a 29 % rate for Binf3 (Table 3). Five-year survival among these patients was 21.6 % (N = 2) for Binf1, 11.9 % (N = 4) for Binf2, and 4.6 % (N = 1) for Binf3. Based on the low R0 resection and survival rates, it does not appear that there is a surgical indication for patients with Binf3 (invasion through the HDL). Kang et al. have reported results for 94 patients with stage IV GBC, of whom 22.3 % underwent surgery.24 In that report, curative surgery resulted in a survival benefit for patients with stage IVb disease (median survival, 8 months), patients with an isolated liver metastasis near the gallbladder bed (median survival, 31 months vs. 9 months; p \ 0.0010), and patients with a limited number of peritoneal implantations (median survival, 20 months vs. 6 months; p = 0.0020). In the present study, there were no long-term survivors among patients with multiple liver metastasis (n = 22; 2-year survival rate, 0 %) or dissemination (n = 16; 3-year survival, 0 %; Tables 2, 3). Therefore, we propose that there is probably no surgical indication for patients with multiple liver metastasis or dissemination. In cases of GBC with direct liver invasion, at least a limited hepatectomy is necessary to facilitate R0 resection. Liver invasion is known to be an important prognostic factor 25,26, but liver invasion alone is not viewed as precluding the resection of GBC. If residual liver function is expected to be sufficient, liver invasion does not need to be viewed as contraindicating resection, although surgical outcomes tend to be poor (Tables 2, 3). R0 resection is widely recognized as an important prognostic factor for GBC.5,16,18,27–31 The results of our multivariate analysis also suggest that it is necessary to perform R0 surgery by combining various procedures, with specific choices depending on the depth of tumor and the progressive pattern of the GBC. However, there were no significant differences in outcomes according to the type of hepatectomy performed, or whether BDR or PD was
TABLE 4 Rates of R0 resection and 5-year disease-specific survival in patients with advanced gallbladder cancer, according to regional lymph node metastasis Regional LN metastasis
n
R0 resection (%)
Supra-retropancreatic 73
33 (45)
5-year DSS [% (95 % CI)]
5-year survivors (n)
22.7 (13.8–37.4)
10
[91.7 (77.3–100)]
7
[T2 disease alone]
13 [12 (92)]
Superior mesenteric
23
9 (39)
24.1 (10.3–56.4)
3
2
[1 (50)]
[50.0 (13.0–100)]
1
[T2 disease alone] Coeliac
4
1 (25)
0
0
[T2 disease alone]
1
[1 (100)]
0
[0]
Para-aortic [T2 disease alone]
22
6 (27)
2
[1 (50)]
17.2 (5.14–57.4)
2
[50.0 (13.0–100)] [0]
DSS disease-specific survival, LN lymph node, R0 microscopically margin-negative resection
performed. Currently, the type of hepatectomy performed5,30,32,33, BDR30,34–37, or PD38–40 for lymphadenectomy in patients with GBC is controversial. Our co-author previously reported that, in cases of GBC, HPD was useful for lymphadenectomy around the pancreatic head among patients who had LN metastasis without HDL invasion (Binf).9 The survival rates were 87 % in the HPD group (N = 16) and 17 % (N = 10) in the non-HPD group (p \ 0.0500). [Note that this study cohort overlapped with the present study.] In recent studies of a high-volume center30,39,41–43, it has been reported that progressing surgical techniques, perioperative management, and strict indication (careful patient selection) have resulted in improved hospital stays, morbidity, and mortality after major procedures. On the other hand, high operative risks of GBC surgery have still been reported. Jin et al. reported that the mortality associated with extensive hepatectomy for GBC is 16 %. Their study used data from 424 patients with GBCs that were curatively resected at 243 hospitals belonging to the American College of Surgeons–National Surgical Quality Improvement Program (2005-2009).32 Kenjo et al. 44 also reported that 90-day mortality after hepatectomy for GBC (n = 107) was 13.1 %, based on an analysis of 7,732 hepatectomy cases from the national clinical database of Japan, 2011. Based on these prior findings and our own data, it appears that patients with GBC are best managed at high-volume centers. There are several limitations to our retrospective study, which extends across four decades, particularly because of changes in therapies for GBC. These changes encompass operative approaches, techniques of perioperative management, and advances in adjuvant therapy (including various chemotherapy agents). Nevertheless, our results suggest that there may be no indication for surgery in
R. Higuchi et al.
patients who have GBC with multiple liver metastasis, dissemination, Binf3 (invasion through the HDL), or visible para-aortic LN metastasis. Furthermore, it is important to achieve R0 surgeries in cases of GBC. ACKNOWLEDGMENT The authors are indebted to Prof. Naohito Yamaguchi (Department of Public Health, Tokyo Women’s Medical University), who performed a statistical review of this manuscript. DISCLOSURE Ryota Higuchi, Takehiro Ota, Tatsuo Araida, Hideki Kajiyama, Takehisa Yazawa, Toru Furukawa, Tatsuya Yoshikawa, Ken Takasaki, and Masakazu Yamamoto have no commercial interests, financial support, or material support to declare.
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