International Surgery Aggressive surgical management of gallbladder cancer: long-term results from a retrospective study of 315 Chinese patients

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1 International Surgery Aggressive surgical management of gallbladder cancer: long-term results from a retrospective study of 315 Chinese patients --Manuscript Draft-- Manuscript Number: Full Title: Article Type: Keywords: Corresponding Author: INTSURG-D R1 Aggressive surgical management of gallbladder cancer: long-term results from a retrospective study of 315 Chinese patients Original Article Gallbladder cancer; extended radical surgery; radical surgery yong zeng Sichuan University West China Hospital Chengdu, CHINA Corresponding Author Secondary Information: Corresponding Author's Institution: Sichuan University West China Hospital Corresponding Author's Secondary Institution: First Author: nengwen ke First Author Secondary Information: Order of Authors: nengwen ke yong zeng Order of Authors Secondary Information: Abstract: Objective: To investigate which is the best surgical treatment for the gallbladder cancer patient. Summary Background Data: Up to now, the aggressive surgery for advanced gallbladder cancer is controversial. In this study, we analyzed gallbladder cancer patients' data retrospectively and want to find out which is the best surgical treatment for the patient. Methods: From 2009 to 2013, 315 cases of gallbladder carcinoma were identified. Data were analyzed retrospectively. The review included analysis of survival rate, postoperative complications, operative mortality rate, and correlation between local extent of the primary tumor and frequency of nodal metastases. Results: Postoperative complications occurred in 15 (6.2%) patients. 3% of patients who underwent a radical surgery procedure had complications, but in extended radical surgery group, it was 9.8%. Operative mortality rate is 4.94%. No lymph node metastases were found in patients with T1 tumors. Nodal involvement in patients with T3 (55.22%) and T4 (82.50%) tumors was significantly higher than that in patients with T2 (44.12%) tumors. In stage I and II patients, radical resection group had a better survival rate than simple cholecystectomy. In stage III patients, extend radical surgery group and radical surgery group showed a better survival rates than others. In stage IV patients, extend radical surgery group showed 4% survival rate at 2 year, but other group was 0. Conclusions: Simple cholecystectomy may decrease the long survival rates in stage I and II patients. In more advanced stages, extended radical resection should be performed if the R0 resections could be achieved. Powered by Editorial Manager and ProduXion Manager from Aries Systems Corporation

2 Title Page Click here to download Title Page title page.docx The full title: Aggressive surgical management of gallbladder cancer: long-term results from a retrospective study of 315 Chinese patients Authors: Ke Nengwen MD Hepato-bilio-pancreatic Surgery, West China Hospital, SichuanUniversity, Chengdu, Sichuan , China. kenengwen@scu.edu.cn Zeng Yong MD Hepato-bilio-pancreatic Surgery, West China Hospital, SichuanUniversity, Chengdu, Sichuan , China. keiske@126.com Corresponding Author's name: Zeng Yong Corresponding Author's address: Hepato-bilio-pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan , China Corresponding Author's Tel: ; fax: Corresponding Author's keiske@126.com Conflict of interest statement We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled, Aggressive surgical management of gallbladder cancer: long-term results from a retrospective study of 315 Chinese patients A running headline: Aggressive surgery management of gallbladder tumor

3 Manuscript Click here to download Manuscript manuscript for internationnal surgery.doc 1 Aggressive surgical management of gallbladder cancer: long-term results from a retrospective study of 315 Chinese patients Abstract patient. Objective: To investigate which is the best surgical treatment for the gallbladder cancer Summary Background Data: Up to now, the aggressive surgery for advanced gallbladder cancer is controversial. In this study, we analyzed gallbladder cancer patients data retrospectively and want to find out which is the best surgical treatment for the patient. Methods: From 2009 to 2013, 315 cases of gallbladder carcinoma were identified. Data were analyzed retrospectively. The review included analysis of survival rate, postoperative complications, operative mortality rate, and correlation between local extent of the primary tumor and frequency of nodal metastases. Results: Postoperative complications occurred in 15 (6.2%) patients. 3% of patients who underwent a radical surgery procedure had complications, but in extended radical surgery group, it was 9.8%. Operative mortality rate is 4.94%. No lymph node metastases were found in patients with T1 tumors. Nodal involvement in patients with T3 (55.22%) and T4 (82.50%) tumors was significantly higher than that in patients with T2 (44.12%) tumors. In stage I and II patients, radical resection group had a better survival rate than simple cholecystectomy. In stage III patients, extend radical surgery group and radical surgery group showed a better survival rates than others. In stage IV patients, extend radical surgery group showed 4% 1

4 2 survival rate at 2 year, but other group was 0. Conclusions: Simple cholecystectomy may decrease the long survival rates in stage I and II patients. In more advanced stages, extended radical resection should be performed if the R0 resections could be achieved. Key words: gallbladder cancer; extended radical surgery; radical surgery Introduction Gallbladder carcinoma is a highly lethal disease. The 5-year survival rate for this type of cancer lies between 0% and 10% in most reported series [1]. The only potentially curative therapy for gallbladder carcinoma is surgical resection. However, the use of aggressive surgical resection is controversial. Most surgeons believe that radical resection should be performed in patients with stage T1b and T2 disease [2, 3]. However, others who have reported a 10-year survival rate of 75% to 85% for simple cholecystectomy for patients with T1b gallbladder carcinoma [4, 5] advocate for this procedure [6, 7]. The seventh American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging guidelines recommend radical resection for patients with stage T2 or T3 tumors [8]. But Principe et al. reported that a simple cholecystectomy is a feasible and effective surgical strategy in patients with T2 gallbladder carcinoma [9]. For patients with stage III and IV gallbladder carcinoma, both metastases to the para-aortic lymph node and distant metastases are normally considered a contraindication for surgery, but some researchers suggest that more aggressive surgical resections including common bile duct resection [10], resection of half of the liver [11], or even a pancreaticoduodenectomy [12] can benefit patients with advanced gallbladder 2

5 3 carcinoma [13,14,15]. To determine the best surgical treatment for gallbladder carcinoma, we conducted a retrospective study of patients with gallbladder carcinoma treated at the Department of General Surgery, West China Hospital, from January 2009 to December Materials and Methods Patients This study was approved by the Human Subject Research Committee of the West China Hospital. Our team collected data on all patients with gallbladder carcinoma who underwent general surgery from 2009 to We identified 315 cases of gallbladder carcinoma in this study, which enrolled 110 men and 205 women with a mean age of years (range, years). (Table I) Surgical procedures Our retrospective analysis revealed that 243 patients underwent surgical procedures, 43 underwent chemical therapy or interventional therapy, and 29 refused therapy. Among the 243 patients who underwent surgical procedures, 35 underwent simple cholecystectomy and 94 underwent radical surgery. The standard radical surgical procedure consisted of a cholecystectomy, en bloc resection of the regional lymphatics, and adequate resection of adjacent liver tissue. The regional lymph nodes, including level N1 nodes in the hepatoduodenal ligament, were also resected. For some patients, resection included the level N2 peripancreatic nodes. Fifty-two of the 94 patients underwent extended radical surgery, which included the following: right hepatectomy in 17 patients; left hepatectomy in 13 patients; resection of the middle lobe of the liver in 8 patients; radical surgery plus a resection of the transverse colon in 8 patients; and radical surgery plus a pancreaticoduodenectomy in 6 3

6 4 patients. The level N2 lymph nodes were resected in all of the patients who underwent extended radical surgery. Of the 243 patients who opted for surgery, 62 underwent palliative surgery, including exploratory laparotomy in 23 patients, biliary-enteric anastomosis in 18, external biliary drainage in 14, and gastro-enteric anastomosis in 7 (Table II). Tumor staging All of the resected specimens underwent color doppler ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) scans before operation and histopathologic examination after operation. The depth of the tumor invasion was determined by means of serial sectioning of the entire gallbladder. The surrounding organs and lymph nodes were also examined histologically to determine the presence or absence of metastases, residual tumor, or both. The TNM system of the AJCC was used for staging, and the patients cancers were classified into 1 of 4 stages. As a result, the TNM staging system used in this report was equivalent to the pathologic TNM (ptnm) system. The resections were classified in accordance with the following criteria: R0, a curative resection with complete removal of the locoregional tumor by a radical procedure without distant metastases; and R1, an incomplete resection with residual microscopic tumor at the surgical stump or tumor in resected distant tissues. The distant tissues included metastatic tumor in the liver (excluding direct invasion of the liver by the tumor) and distant lymph nodes beyond the N2 region (M1). If the patients underwent palliative surgery or did not undergo surgery, the stage of the tumor was decided based on the information obtained from computed tomography (CT) or magnetic resonance imaging (MRI) scans. Follow-up and statistical analysis 4

7 5 Clinical records and follow-up data were obtained for 268 patients; 47 patients were lost to follow-up. The cumulative survival rates were estimated with the Kaplan-Meier method. Differences among the survival curves were compared with the generalized Wilcoxon test or log-rank test. A p value less than 0.05 was considered significant. Results Morbidity and mortality Postoperative complications occurred in 15 patients (6.2%) and included bile leakage in 6 patients, lung infection in 3, intra-abdominal infections in 2, hepatic insufficiency in 2, intra-abdominal hemorrhages in 1, and deep vein thrombosis in 1. The complication rate among patients who underwent a radical surgical procedure was 3%, while among patients who underwent an extended radical surgical procedure it was 9.8 %. Twelve deaths occurred within the first 30 postoperative days, yielding an operative mortality rate of 4.94 % in patients who underwent a surgical procedure. Correlation between local extent of the primary tumor (T) and frequency of nodal metastases (N) As shown in Table III, the frequency of lymph node metastasis correlated with the depth of invasion of the tumor. No lymph node metastases were found in patients with T1 tumors. Nodal involvement in patients with T3 or T4 tumors (55.22% and 82.50%, respectively) was significantly higher than that in patients with T2 tumors (44.12%). There was also a significant difference in the N0/N1/N2 ratios between patients with T2 tumors and those with T3 or T4 tumors. Survival 5

8 6 Figure 1 shows the survival rates of patients with different stages of cancer. The mean follow-up was 13.6 months (range, 1.0 to 60.0 months). The actuarial survival rates of patients with stage I gallbladder carcinoma were 83% at 1 year, 58% at 3 years, and 38% at 5 years. The median survival was 47 months. The survival rates of patients with stage II gallbladder carcinoma were 65% at 1 year, 39% at 3 years, and 12% at 5 years. The median survival was 23 months. Among patients with stage III or IV gallbladder carcinoma, the survival rates decreased significantly. Patients with stage IV gallbladder carcinoma had 3- and 5-year survival rates of 0%. The median survival was 7 months in patients with stage III gallbladder carcinoma, but only 4 months in those with stage IV gallbladder carcinoma. All of the patients with stage I gallbladder carcinoma underwent surgery. Seven patients underwent simple cholecystectomy, while 5 underwent radical resection. Among the five patients who underwent radical resection, only two of them were diagnosis gallbladder carcinoma in interoperation, three of them were diagnosis after simple cholecystectomy. The three patients were called back to hospital to do the radical resection. The survival rates of patients in the simple cholecystectomy group were 71% at 1 year, 43% at 3 years, and 14% at 5 years. The median survival was 25 months. Among patients in the radical resection group, the survival rates were 100% at 1 year, 80% at 3 years, and 60% at 5 years. The median survival was 60 months. The differences in the survival rates for patients in these 2 groups were not statistically significant (p = 0.151) (Fig. 2). Among the patients with stage II gallbladder carcinoma, those in the radical surgery group experienced longer survival than did those in the simple cholecystectomy group. In the radical surgery group, the survival rates were 75% at 1 year, 44% at 3 years, and 16% at 5 6

9 7 years. The median survival was 30 months. In the simple cholecystectomy group, the survival rates were 43% at 1 year, 29% at 3 years, and 0% at 5 years. The median survival was 10.5 months. The survival rates for patients in these 2 groups were significantly different (p = 0.049) (Fig. 3). Among the patients with stage III gallbladder carcinoma, those in the extended radical surgery group and the radical surgery group experienced longer survival than did those in the palliative and non-surgery groups. In the radical surgery group, the survival rates were 36% at 1 year, 5% at 3 years, and 3% at 5 years. The median survival was 9.4 months. In the extended radical surgery group, the survival rates were 53% at 1 year, 16% at 3 years, and 5% at 5 years. The median survival was 13.2 months. None of the patients in the palliative and non-surgery groups were still alive after 1 year (Fig. 4). Among the patients with stage IV gallbladder carcinoma, the extended radical surgery group experienced the longest survival. The survival rates for this group were 18% at 1 year, 4% at 2 years, and 0% at 3 years. In the radical surgery group, the survival rates were 13% at 1 year, and 0% at 2 and 3 years. None of the patients in the other groups survived beyond 1 year (Fig. 5). Discussion Gallbladder carcinoma carries a poor prognosis, and the only chance of being cured lies in early detection and complete surgical resection. However, the extent of resection that is required to cure a patient remains controversial. Most surgeons agree that stage I disease only requires a simple cholecystectomy, which is associated with an overall 5-year survival rate of 80% [16,17]. In our series, we 7

10 8 documented a 5-year survival rate of only 14% for patients with stage I disease after simple cholecystectomy. However, a 5-year survival rate of 60% was observed for the radical resection group. We feel that use of such an aggressive approach is warranted, given the lymphatic or venous invasion rate of 28% reported by Ouchi et al. [16] for ptlb tumors. In the present study, neither lymph node metastasis nor lymphovascular infiltration was observed in patients of the T1 group. However, other researchers have found that the incidence of lymphatic invasion will be significantly increased if the cancer invades the muscular layer [1]. The muscular layer is breached in most cases of T1b gallbladder carcinoma; therefore, patients with stage I disease may benefit from radical surgery because this procedure can decrease the incidence of lymphatic invasion. For patients with stage II gallbladder carcinoma, most surgeons believe that radical surgery is needed. Pilgrim et al. [6] analyzed 4 comparable studies. Their results showed that patients with a T2 stage tumor who had a simple cholecystectomy had lower 5-year survival rates than did those who underwent a radical resection. However, Principe et al. [9] reported a 5-year survival rate of 75% for patients with stage II disease after simple cholecystectomy. Our study documented a lymphatic invasion rate of 46.5% in those with a T2 stage tumor. Thus, in patients with stage II gallbladder carcinoma, simple cholecystectomy may lead to approximately 50% more patients progressing to an incurable status because of tumor metastasis and recurrence. In this study, the 5-year survival rate of the radical resection group was 33.3%; however, it was 0% in the simple cholecystectomy group. Therefore, radical resection should be performed for patients with stage II disease to decrease the incidence of lymph node metastasis and ensure negative margins. 8

11 9 Other studies, as well as our own, found a high incidence of complications after extended radical resection for patients with stage III or IV disease, with the published rates ranging from 9.8% to 100% [12,18,19]. The poor long-term survival of patients with stage III or IV disease is another reason why some surgeons are unwilling to perform an extended radical resection procedure. Although our study did have a high incidence of complications (9.8%), all were cured by conservative treatment. The 1- and 2-year survival rates of patients in the extended radical resection group were significantly better than those in the radical resection, palliative surgery, and non-surgery groups, but the 5-year survival rates were not significantly different among these groups. Kai et al. demonstrated that the 5-year survival of patients with stage III disease was significantly better after extended radical resection [20]. Therefore, we believe that patients with stage III or IV disease could benefit from extended radical resection, given that an R0 resection is achieved. This study has several potential limitations. This is a retrospective study of gallbladder cancer patients. We compared surgical, nontreatment, chemotherapy only and survival outcomes in the later 5 years. Because of the rarity of gallbladder cancer and the difficulties of early diagnosis, it is impossible to study a large group of patients in each TNM stage at a single centre. We just included 12 patients in stage I and 19 patients in stage II. The small cohort size may lead to a bias. Furthermore, only a few patients treated by chemotherapy in this cohort study; this represents an element of selection bias. Nevertheless, we believe that this study can provide valuable information of surgical treatment for gallbladder cancer. In comparison with other studies, we provided 315 gallbladder cancer patients data at a single centre, and we also analyzed the survival outcomes in patients who treated by different 9

12 10 surgical procedures. The results showed patients with stage I and II may benefit from radical resection. In more advanced stages, extended radical resection should be performed if the R0 resections could be achieved. In conclusion, patients with stage I or II gallbladder carcinoma can be successfully treated by radical resection. Simple cholecystectomy may decrease survival in these patients. If an R0 resection can be achieved, extended radical resection should be performed for patients with more advanced disease. References: 1. Misra S, Chaturvedi A, Misra N C, Sharma ID. Carcinoma of the gallbladder. Lancet Oncol, 2003 Mar; 4(3): doi: /s (03) Mekeel KL, Hemming AW. Surgical management of gallbladder carcinoma: a review. J Gastrointest Surg 2007 Sep;11(9): doi; /s Dixon E, Vollmer CM Jr, Sahajpal A, Cattral M, Grant D, Doig C, et al. An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: a 12-year study at a North American Center. Ann Surg Mar;241(3): doi: /01.sla ef 4. Kang CM, Lee WJ, Choi GH, Kim JY, Kim KS, Choi JS, et al. Does clinical R0 have validity in the choice of simple cholecystectomy for gallbladder carcinoma? J Gastrointest Surg 2007 Oct;11(10): doi: /s Shirai Y, Yoshida K, Tsukada K, Muto T, Watanabe H. Early carcinoma of the gallbladder. Eur J Surg 1992 Oct;158(10): C. Pilgrim, Val Usatoff, Peter M. A review of the surgical strategies for the management of 10

13 11 gallbladder carcinoma based on T stage and growth type of the tumour. EJSO, 2009 Sep;35(9): doi: /j.ejso Sun CD, Zhang BY, Wu LQ, Lee WJ. Laparoscopic cholecystectomy for treatment of unexpected early-stage gallbladder cancer. J Surg Oncol 2005 Sep;91(4): doi: /jso Edge SB, Compton CC. AJCC cancer staging manual, th edition. Springer, New York 9. Principe A, Del Gaudio M, Ercolani G, Golfieri R, Cucchetti A, Pinna AD. Radical surgery for gallbladder carcinoma: possibilities of survival. Hepatogastroenterology, 2006 Sep-Oct;53(71): Choi SB, Han HJ, Kim WB, Song TJ, Suh SO, Choi SY. Surgical strategy for T2 and T3 gallbladder cancer: is extrahepatic bile duct resection always necessary? Langenbecks Arch Surg Dec;398(8): doi: /s Reddy SK, Marroquin CE, Kuo PC, Pappas TN, Clary BM. Extended hepatic resection for gallbladder cancer. Am J Surg Sep;194(3): doi: /j.amjsurg Tsukada K, Yoshida K, Aono T, Koyama S, Shirai Y, Uchida K, et al. Major hepatectomy and pancreatoduodenectomy for advanced carcinoma of the biliary tract. Br J Surg, 1994 Jan;81(1): doi: /bjs Choi SB, Han HJ, Kim CY, Kim WB, Song TJ, Suh SO, et al. Fourteen year surgical experience of gallbladder cancer: validity of curative resection affecting survival. Hepatogastroenterology Jan-Feb;59(113): doi: /hge Sakata J, Shirai Y, Wakai T, Ajioka Y, Hatakeyama K. Number of positive lymph nodes 11

14 12 independently determines the prognosis after resection in patients with gallbladder carcinoma. Ann Surg Oncol Jul;17(7): doi: /s Nasu Y, Tanaka E, Hirano S, Tsuchikawa T, Kato K, Matsumoto J, et al. The prognosis after curative resection of gallbladder cancer with hilar invasion is similar to that of hilar cholangiocarcinoma. J Hepatobiliary Pancreat Sci May;19(3): doi: / s Ouchi K, Owada Y, Matsuno S, Sato T. Prognostic factors in the surgical treatment of gallbladder carcinoma. Surgery Jun; 101(6): Morrow CE, Sutherland DE, Florack G, Eisenberg MM, Grage TB. Primary gallbladder carcmoma: significance of subserosal lesions and results of aggressive surgical treatment and adjuvant chemotherapy. Surgery,1983 Oct;94(4): Miwa S, Kobayashi A, Akahane Y, Nakata T, Mihara M, Kusama K, et al. Is major hepatectomy with pancreatoduodenectomy justified for advanced biliary malignancy? J Hepatobiliary Pancreat Surg, 2007 Mar;14(2): doi: /s Nimura Y, Hayakawa N, Kamiya J, Maeda S, Kondo S, Yasui A, et al. Hepatopancreatoduodenectomy for advanced carcinoma of the biliary tract. Hepatogastroenterology 1991 Apr;38(2): Kai M, Chijiiwa K, Ohuchida J, Nagano M, Hiyoshi M, Kondo K. A curative resection improves the postoperative survival rate even in patients with advanced gallbladder carcinoma. J Gastrointest Surg Aug;11(8): doi: /s

15 Table1 Click here to download Table Table 1.doc Table 1. Patient characteristics and TNM classification. Patient characteristics Gender Age, years, median(range) abdominal pain jaundice cholecystolithiasis CEA (ng/ml) CA 19-9 (U/ml) CA 125 (U/ml) T factor Patients (n=315) male 110 (34.92%) female 205 (65.08%) < (58.10%) (41.90%) positive 31 (9.84%) negative 284 (90.16%) positive 110 (34.92%) negative 205 (65.08%) positive 263 (83.49%) negative 52 (16.51%) < (80%) (20%) <22 96 (30.48%) (69.52%) <35 34 (10.79%) (89.21%) T1a 3 (0.95%) T1b 9 (2.86%) T2 34 (10.79%)

16 T3 171 (54.29%) T4 98 (31.11%) N factor N0 183 (58.10%) N1 102 (32.38%) N2 30 (9.52%) M factor M0 290 (92.06%) M1 25 (7.94%) TNM stage I 12 (3.81%) II 19 (6.03%) IIIA 91 (28.89%) IIIB 65 (20.63%) IVA 73 (23.17%) IVB 55 (17.46%)

17 Table2 Click here to download Table table 2.doc Table 2. Treatment for gallbladder carcinoma. Procedure No. of patients Surgical 243 Simple cholecystectomy 35 Radical surgery 94 Extend radical surgery 52 right hepatectomy 17 left hepatectomy 13 middle liver resection 8 radical surgery plus transverse colon resection 8 radical surgery plus pancreaticoduodenectomy 6 Palliative surgery 62 exploratory laparotomy 23 biliary-entero anastomosis 18 external biliary drainage 14 gastro-entero anastomosis 7 Chemical therapy or interventional therapy 43 No therapy 29 Total 315

18 Table3 Click here to download Table table 3.doc Table 3. Correlation between local extent of the primary tumor (T) and frequency of nodal metastases (N). T stage number of nodal metastases N1 N2 lymph node metastasis T1a(n=2) T1b(n=3) T2(n=34) % T3(n=67) % T4(n=40) % Totle(n=146) %

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24 Figure legend Click here to download Figure legend.doc Figure 1. Kaplan-Meier overall survival estimates stratified for gallbladder cancer in patients with different stage. (p<0.05) Figure 2. Kaplan-Meier overall survival estimates stratified for stage I patients who underwent simple cholecystectomy or radical cholecystectomy.(p=0.151) Figure 3. Kaplan-Meier overall survival estimates stratified for stage II patients who underwent simple cholecystectomy or radical cholecystectomy.(p<0.05) Figure 4. Kaplan-Meier overall survival estimates stratified for stage III patients who underwent different treaments. (p<0.05) Figure 5. Kaplan-Meier overall survival estimates stratified for stage IV patients who underwent different treaments. (p<0.05)

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