Outcomes of Radical Surgery for Gallbladder Cancer Patients with Lymphatic Metastases

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1 Outcomes of Radical Surgery for Gallbladder Cancer Patients with Lymphatic Metastases Hua Meng 1, Xin Wang 2,3, Yuman Fong 1, Zi-Han Wang 1, Yu Wang 1 and Zhong-Tao Zhang 1,* Jpn J Clin Oncol 2011;41(8) doi: /jjco/hyr072 Advance Access Publication 28 June Department of Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, 2 Department of Medical Oncology, Zhongshan Hospital, affiliated to Xiamen University, Xiamen and 3 Department of Medical Oncology, Shanghai Changzheng Hospital, affiliated to The Second Military Medical University, Shanghai, China *For reprints and all correspondence: Zhong-Tao Zhang, Department of Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong an Lu Road, Xuanwu District, Beijing , China. zhangztmd@yeah.net Received December 7, 2010; accepted May 6, 2011 Objective: The objective of this study was to investigate whether radical surgical treatment can be associated with reasonable survival for patients with Stage IV gallbladder cancer with distant lymph node metastasis. Methods: Fifty-five patients (20 men and 35 women) with complete clinical and follow-up data for Japanese Society of Biliary Surgery TNM system Stage IV gallbladder cancer were included in our study. Patients were divided into three treatment groups for clinical analysis: Group A (radical resection, n ¼ 24), Group B (chemotherapy, n ¼ 8) and Group C (other palliative treatment, n ¼ 23). Results: The survival rate in Group A was significantly higher when compared with Groups B (P ¼ 0.008) and C (P ¼ 0.004). Moreover, the prognosis of patients with distant lymph node metastasis (Group A2, Japanese Society of Biliary Surgery N3; American Joint Committee on Cancer M1) was significantly worse versus those with local lymph node metastasis (Group A1, Japanese Society of Biliary Surgery N1 N2; American Joint Committee on Cancer N1) (P ¼ 0.007). Most importantly, no significant difference in the survival rate was observed between patients in Group A2 and Groups B (P ¼ 0.47) or C (P ¼ 0.74). Conclusions: Radical resection might result in a reasonable prognosis for gallbladder cancer patients with local metastasis of the lymph nodes (Japanese Society of Biliary Surgery N1 N2), but was not effective when distant lymph nodes (Japanese Society of Biliary Surgery N3) were involved. Key words: biliary cancer hepatectomy liver resection INTRODUCTION Gallbladder cancer is not only the most common biliary tract cancer, but also a highly lethal malignancy, with a 5-year survival rate of,5% for those patients with disease not amenable to surgical resection (1). Treatment options for gallbladder cancer have evolved over the last decade, as it has become well accepted that patients benefit from radical resection (2 5). The reported 5-year survival across all stages is % (6,7). Radical surgery is advocated for patients with Stages II and III disease, and includes cholecystectomy, lymphadenectomy and en bloc hepatic resection, with or without bile duct resection (2,8,9). However, such a radical resection has relatively high morbidity and mortality rates. Given the poor prognosis of Stage IV patents, debate continues as to the relative risk-benefits of radical surgery for such advanced stage patients. In this study, we seek to determine criteria upon which to base the decision for surgical resection. A comparison of the American Joint Committee on Cancer-International Union Against Cancer (AJCC-UICC) TNM staging system (10) and the Japanese Society Biliary Surgery (JSBS) system (11) isshownin Table 1. In the present study, we examined clinical outcomes of patients in Stage IV with nodal metastases. PATIENTS AND METHODS From October 1997 to May 2004, a total of 79 patients with Stage IV primary gallbladder cancer were admitted to the # The Author (2011). Published by Oxford University Press. All rights reserved.

2 Jpn J Clin Oncol 2011;41(8) 993 Table 1. Classification systems for staging gallbladder carcinoma by the AJCC and JSBS AJCC JSBS Lymph node metastasis N0: no reginal lymph node metastasis N0: no reginal lymph node metastasis N1: metastasis in hepatoduodenal ligament N1: metastasis to Group 1 lymph nodes, but no metastasis to Groups 2 and 3 lymph nodes N2: metastasis in peripancreatic (head only), periduodenal, N2: metastasis to Group 2 lymph nodes, but no metastasis to Group 3 lymph nodes periportal, celiac and/or superior mesenteric lymph nodes N3: metastasis to Group 3 lymph nodes Stage I: T1N0M0 I: T1N0M0 II: T2N0M0 II: T1N1M0, T2N0M0, T2N1M0 III: T1N1M0, T2N1M0, T3N0M0, T4N0M0 III: T1N2M0, T2N2M0, T3N0M0, T3N1M0 IVA: T4N0M0, T4N1M0 IVA: T4N0M0, T4N1M0, T4N2M0 IVB: anytn2m0, anyt anynm1 IVB: anytn3m0, any T anynm1 T is essentially similar in AJCC and JSBS and explained in the text. AJCC, American Joint Committee on Cancer; JSBS, Japanese Society of Biliary Surgery; M0 and M1, absence and presence of distant metastasis, respectively. Department of Surgery, Beijing Friendship Hospital. Fifty-five patients with complete clinical and follow-up data (20 men and 35 women) were included in our study. The mean age was 64.1 years (range, years). Mean follow-up after hospitalization was 7.9 months (range, 1 64 months). Clinical and pathologic staging was achieved with the JSBS TNM system. Staging of non-operative patients was determined from ultrasound, computed tomography and magnetic resonance imaging. Thirty patients (55.6%) were categorized as Stage IVa and 25 (45.5%) as Stage IVb. RADICAL SURGERY Demographic and clinical parameters are presented in Table 2. A surgical approach aimed at achieving a cure was employed in all patients with gallbladder cancer unless they refused surgical exploration for economic or other personal reasons, or the left hepatic artery was involved. Twenty-four patients (43.6%) underwent a standard radical cholecystectomy consisting of the following procedures: (1) extended cholecystectomy, including at least 2 cm of normal liver parenchyma beyond the cancer; (2) regional lymphadenectomy encompassing the lymph nodes within the hepatoduodenal ligament, behind the head of the pancreas and along the common hepatic artery medial to the celiac. Pancreaticoduodenectomy was employed in seven patients with apparent lymph node involvement in the hepatoduodenal ligament and around the common hepatic artery for more complete lymphadenectomy around the pancreas head. Similarly, anatomic wedge resection of the gallbladder bed was performed for 13 patients (54.2%) and extended hepatectomies for 9 patients (37.5%). Extended hepatectomy comprised either the excision of segment (Sg)4 þ Sg5 or Sg4 þ Sg5 þ Sg6 (n ¼ 7) or extended right hepatectomy (n ¼ 1). All these operations were performed by the same operation group in our department of surgery. The Brisbane 2000 terminology system was used for describing hepatic resections (12). PALLIATION Eight patients with advanced gallbladder cancer who refused surgical exploration for economic or other personal reasons were treated by chemotherapy systemically (five patients) and via hepatic arterial infusion (HAI) (three patients). The regimen of systemic chemotherapy was 5-flurouracil (5-FU) 160 mg/m 2 intravenously as a continuous infusion on days 1 7andcisplatin(CDDP)3mg/m 2 intravenously on days 1 5 for four consecutive weeks followed by 1 week rest (13). The arterial catheter was inserted into the proper hepatic artery by the Seldinger method. HAI chemotherapy was administered monthly with local chemotherapy (CDDP mg/m 2, and 5-FU 300 mg/m 2, via the hepatic arterial catheter) (14). This therapy was continued until doselimiting toxicities were observed. Twenty-three patients with unresectable locally advanced and/or metastatic diseases accepted simple exploratory laparotomies, palliative approaches or best supported care (T-tube drainage, bypass operation procedures, biliary stent, percutaneous transhepatic drainage). STATISTICAL ANALYSIS All statistical analysis was performed using the SPSS 12.0 software package for Windows (SPSS Inc., Chicago, IL, USA). The x 2 test was used for the comparison of two groups. Survival curves were calculated by the Kaplan Meier method, and the differences in survival were evaluated

3 994 Radical surgery for gallbladder cancer Table 2. Demographic and clinical parameters in Stage IV (JSBS) gallbladder carcinoma (n ¼ 24) Patient Age (years) Sex Follow-up (months) ptnm (JSBSa) Stage Surgecal procedures (CC þ SHL þ LPPCH) Complication 1 68 F 7.5 died T4N2M0 IVa þbdr þ PVR Bile leakage 2 68 M 3.0 died T4N3M0 IVb þrh þ BDR 3 71 F 5.5 died T4N2M0 IVa þgbr þ BDR 4 64 M 0.5 died T4N2M0 IVa þsg4 þ Sg5 þ Sg6 þ BDR Hepatic failure 5 69 M 6.5 died T4N2M0 IVb þsg4 þ Sg5 þ PD 6 50 F 4.0 died T4N2M0 IVa þgbr þ BDR 7 59 F 3.5 died T4N2M0 IVa þgbr Renal failure 8 61 F 8.0 died T3N3M1 IVb þgbr 9 36 M 49.0 alive T4N2M0 IVa þgbr þ PD M 5.0 died T4N3M1 IVb þgbr Wound infection F 1.5 died T4N3M0 IVb þgbr Wound infection M 13.0 died T3N3M0 IVb þgbr Wound infection M 6.0 died T4N2M0 IVa þgbr þ bile duct desection M 4.5 died T3N2M0 IVa þgbr F 6.0 died T3N2M0 IVa þgbr þ PD F 46.0 alive T4N2M0 IVa þsg4 þ Sg5 þ PD F 4.0 died T3N3M0 IVb þsg4 þ Sg5 þ PD Bile leakage M 5.5 died T4N2M0 IVa þgbr F 15.0 died T4N2M0 IVa þsg4 þ Sg5 þ Sg6 þ PppD F 36.0 alive T4N2M0 IVa þsg4 þ Sg5 þ PD F 5.0 died T3N2M0 IVa þgbr F 34.5 alive T4N1M0 IVa þbdr þ PVR F 11.0 alive T3N3M1 IVb þsg4 þ Sg5 þ G þ DWR M 64.0 alive T4N2M0 IVa þsg4 þ Sg5 þ Sg6 þ BDR CC, cholecystectomy; SHL, skeletonization of hepatoduodenum ligament; LPPCH, lymphadenectomy in the posterosuperior pancreatic region and along the common hepatic artery; BDR, bile duct reconstruction; PVR, portal vein reconstruction; RH, right hepatectomy; GBR, gallbladder bed resection; PD, pancreatoduodenectomy; PppD, pylorus-preserving pancreatoduodenectomy; G, gastrectomy; DWR, duodenal wedge resection. by the log-rank test. A probability value,0.05 was considered significant. RESULTS MORBIDITY AND MORTALITY The morbidity rate in patients with radical resection was 29.2% (7/24). One patient died of acute hepatic failure on postoperative day 18. Another patient died of gastrointestinal bleeding and renal failure on day 34, yielding an operative mortality rate of 8.3% (2/24). No chemotherapy-related death occurred in this series. SURVIVAL SURVIVAL CORRELATED WITH RADICAL PROCEDURES Patients were divided into three groups for the survival analysis: Group A [radical surgery, n ¼ 24 (Table 2)], Group B (chemotherapy, n ¼ 8) and Group C (other palliative treatment, n ¼ 23). The 1-, 3- and 5-year survival rates in Group A were 29.5, 12.0 and 5%, respectively. On the other hand, no patient in Group B survived over 1 year. In Group C, only one patient was a 1-year survivor and he died in the 13th month after treatment. The prognosis of patients in Group A was significantly better when compared with those in Groups B (P ¼ 0.008) and C (P ¼ 0.004) (Fig. 1). There was no significant difference in survival between Groups B and C (P ¼ 0.80) (Fig. 1). All the deaths were cancer-related. Although these data are not part of a randomized study, there was no statistically significant difference among the Group A, Group B and Group C with regard to the distributions of variables, including age, sex, disease stage or additional health problems (Table 3). In addition, none of the investigated clinicalopathological parameters (histological type) or comorbidities (Child-Pugh-Turcotte classification, ASA Classification, MELD Score) showed a

4 Jpn J Clin Oncol 2011;41(8) 995 Figure 1. The patients with Japanese Society of Biliary Surgery (JSBS) Stage IV gallbladder carcinoma were divided into three groups for the survival analysis: Group A (radical resection), Group B (chemotherapy) and Group C (other palliative treatment). The prognosis of patients in Group A was significantly better than that in Group B (P ¼ 0.008) and Group C (P ¼ 0.004). statistically significant difference between Group A1 and Group A2 (Table 4). SURVIVAL CORRELATED ON LYMPH INVOLVEMENT The radical patients in Group A were further divided into two subgroups: Group A1 included those with local lymph node metastasis (JSBS N1 N2, n ¼ 12; AJCC N1), while Group A2 comprised those with distant lymph node metastasis (JSBS N3, n ¼ 9; AJCC N2; three patients who had distant metastasis were excluded). The 1-, 3- and 5-year accumulative survival rates of patients in Group A1 were 50.5, 26.0 and 8.5%, respectively. Meanwhile, only one of the patients in Group A2 survived over 1 year. The survival of Group A1 was significantly better when compared with GroupA2(P ¼ 0.007) and Group B (P ¼ ) (Fig. 2). No significant difference in the survival rate was observed between the patients in Group A2 and Groups B (P ¼ 0.47) or C (P ¼ 0.75) (Fig. 3). DISCUSSION With the increasing safety of hepatic and pancreatic surgery, various radical procedures have been advocated to improve the curative outcome for advanced gallbladder cancer. Recent data suggest that aggressive resection may improve long-term survival, even in patients with advanced stage disease (7,15). Radical cholecystectomy includes more substantial liver resections, from segmentectomies (4b/5) to right hepatectomies, even trisectionectomy. Extended radical Table 3. Tumor stage classified by JSBS a in each group Group Stage No. of patients Group A (n ¼ 24) Radical resection: M, 10; F, 14; mean age 61 Group B (n ¼ 8) Chemotherapy: M, 3; F, 5; mean age 66 Group C (n ¼ 23) Palliative treatment: M, 8; F, 15; mean age 65 Stage IVa 17 Stage IVb 7 Stage IVa 4 Stage IVb 4 Stage IVa 10 Stage IVb 13 a Japanese Society of Biliary Surgery TNM system (10); M, male; F, female. resection also includes regional lymphadenectomy of the porta hepatis and periduodenal and pancreatic nodes. To completely clear the lymphatics in the porta hepatis, many surgeons perform a resection of the bile duct. Sometimes, a pancreaticoduodenectomy is added to achieve R0 resection status (16). In our study, the prognosis of patients with Stage IV disease who accepted radical surgery (Group A) was significantly better than those who accepted chemotherapy (Group B) or another palliative treatment (Group C). Therefore, surgical resection remains the only curative treatment for gallbladder. Only two patients died of fatal

5 996 Radical surgery for gallbladder cancer Table 4. Patients comorbidities and histological type in Groups A1 and A2 Characteristics No. of patients (%) in A1 A2 All cases 12 9 Histology Endometrioid adenocarcinoma Grade 1 4 (33.3) 3 (33.3) Grade 2 6 (50.0) 4 (44.4) Grade 3 2 (16.7) 1 (11.1) Adenosquamous carcinoma 0 (00.0) 1 (11.1) ASA classification 1 7 (58.3) 6 (66.6) 2 5 (41.7) 3 (33.3) 3 0 (00.0) 0 (00.0) 4 0 (00.0) 0 (00.0) 5 0 (00.0) 0 (00.0) Child-pugh score 5 A 9 (75.0) 7 (77.7) B 3 (25.0) 2 (22.2) C 0 (00.0) 0 (00.0) MELD score (mean) ASA, American Society of Anesthesiologists; MELD score, model for end-stage liver disease. complications, and no patient in Groups B and C survived over 13 months. The results are consistent with recent studies (6,17) in which radical resection is the only parameter associated with a cure for advanced gallbladder cancer. Adjuvant chemoradiation therapy was an independent prognostic factor for survival, and recommended for lymph node-positive T2/T3 gallbladder cancer following surgical resection (18). However, radical resection has been associated with a high morbidity (53%) and mortality (5%) (19). In our study, the morbidity rate in patients with radical resection was 29.2%, and the operative mortality rate was 8.3%. At the same time, the 5-year survival rate of patients after radical resection has been reported at only 8% for Stage IV (20 22). Kokudo et al. (23) have discussed the validity of surgical resection in patients with posterosuperior peripancreatic and/or perihaeptaic artery lymph node metastasis. This led us to explore possible clinical and pathologic characteristics that would improve patient selection for better outcome. Our data indicate that if only patients with local lymph node metastasis (JSBS N1 N2; AJCC N1) were chosen for surgery, 40% of 30-month survival would be seen rather than the 20% seen for distant lymph node metastasis (JSBS N3; AJCC N2). In fact, for N3 disease, there were no 2-year survivors. Unfortunately, even the more stringent selection of only N1 and N2 patients did not result in high cure rates, since 5-year survival was still seen in only 8% of patients. Thus, radical resection is reasonable in JSBS N1 N2 or AJCC N1 tumors Figure 2. The patients in Group A were divided into two subgroups, those with local lymph involvement (Group A1, JSBS N1 N2) and those with distant lymph involvement (Group A2, JSBS N3). The survival in Group A1 was significantly better when compared with than in Group A2 (P ¼ 0.007).

6 Jpn J Clin Oncol 2011;41(8) 997 Figure 3. No significant difference in the survival rate was observed between the patients in Group A2 and Group B (P ¼ ). No significant difference in the survival rate was observed between the patients in Group A2 and Group C (P ¼ ). because it is associated with prolongation of survival, but does not improve eventual cure. This highlights the importance of research in systemic therapies for this disease and that resectable patients with Stage IV disease are prime candidates for clinical trials with promising agents. Many authors have discussed the relationship of lymph node involvement and outcome of advanced gallbladder cancer (24,25). At the Beijing Friendship Hospital, we use the JSBS staging system (10) because it allows for detailed segregation of lymphatic involvement by cancer. In the JSBS TNM system, the definitions of T and M are essentially similar to those of the AJCC-UICC TNM system, but the extent of N varies greatly (Table 3). In the JSBS system, the nodes along the gallbladder and cystic duct are classified as N1, while the hepatoduodenal ligament nodes are classified as N2. Whether this splitting of AJCC-UICC N1 nodes into two stations has clinical relevance cannot be discerned from the present study, since too few patients presented with only JSBS N1 nodes to allow a meaningful analysis. That superior parapancreatic nodes are also classified as N2 in the JSBS system is a major philosophic departure from the AJCC-UICC system where they are considered advanced metastatic disease. An acceptance of the high parapancreatic nodes as regional metastases drives aggressive local resection, including pancreaticoduodenectomy. In our study, since no superior parapancreatic node was involved in all patients, we made it one group for JSBS N1 2 patients and AJCC-UICC N1 patients. Chijiiwa et al. (25) reported a 5-year survival rate of 28% in patients with lymph node metastasis confined to the hepatoduodenal ligament, posterosuperior pancreaticoduodenal region or along the common hepatic artery. It is intriguing that three of the seven patients subjected to pancreaticoduodenectomy in the current series are still alive during follow-up (median survival: 46 months; longest survival at present: 49 months). In our study, the survival of patients with distant lymph node metastasis (JSBS N3, Group A2) was significantly worse than those with local lymph node metastasis (JSBS N1 N2, Group A1). No significant difference in the survival rate was observed between the patients in Group A2 and Groups B (P ¼ ) or C (P ¼ ). Almost all patients with N3 lymph node metastasis died of recurrence within 1 year, whether or not they underwent radical resection. Consequently, our data indicated that patients with lymph node metastasis confined to N1 N2 by the JSBS or N1 by the AJCC are good candidates for radical resection. On the contrary, to balance the benefit and risk, patients with N3 by the JSBS or N2 by the AJCC should be treated with chemotherapy or other palliative treatment. Conflict of interest statement None declared. References 1. Shukla PJ, Neve R, Barreto SG, Hawaldar R, Nadkarni MS, Mohandas KM, et al. A new scoring system for gallbladder cancer

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