Extensive surgery for carcinoma of the gallbladder

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1 Original article Extensive surgery for carcinoma of the gallbladder S. Kondo, Y. Nimura, N. Hayakawa, J. Kamiya, M. Nagino and K. Uesaka First Department of Surgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya , Japan Correspondence to: Dr Y. Nimura Background: The purpose of this study was to clarify the ef cacy of, and de ne the indications for, extensive surgery for gallbladder carcinoma. Methods: Between 1979 and 1994, 116 patients with gallbladder carcinoma underwent operation. Radical resection was performed in 80 patients. Results: In 68 patients with stage III or IV disease, extensive resection including extended right hepatectomy n = 40), pancreaticoduodenectomy n = 23) and/or portal vein resection n = 23) was employed to achieve complete tumour excision. The hospital mortality rate was 18 per cent. The postoperative 3- and 5-year survival rates were 44 and 33 per cent respectively in the patients with stage III disease n = 9), and 24 and 17 per cent respectively in patients with stage IV M 0 ) disease n = 29). In contrast, the postoperative survival rate for the 30 patients with stage IV M 1 ) disease 7 per cent at 3 years and 3 per cent at 5 years) was worse than that for patients with stage III and stage IV M 0 ) disease P = and P = respectively). Conclusion: Radical resection should be undertaken for stage III and stage IV M 0 ) gallbladder cancer. Although portal vein resection and/or pancreaticoduodenectomy did not contribute to long-term survival, better survival was obtained than that for the unresected patients. Paper accepted 11 October 2001 British Journal of Surgery 2002, 89, 179±184 Introduction Although extensive surgery including major hepatic resection, pancreaticoduodenectomy and/or combined portal vein resection for advanced gallbladder carcinoma has been reported recently 1±3, its ef cacy and long-term outcome are unknown. Since 1979, the strict policy in this unit has been to employ radical surgery 4±6. The purpose of the present article was to appraise the results of this surgical treatment and to clarify the indications for extensive surgery for advanced gallbladder carcinoma. Patients and methods Between 1979 and 1994, 116 patients with gallbladder carcinoma underwent surgery. During this period, a surgical approach aimed at achieving a cure was employed in all patients with gallbladder carcinoma unless they had extensive distant metastasis or involvement of the proper and/or left hepatic artery Table 1). Informed consent was obtained before treatment. Distant metastasis was classi ed into extensive and limited metastasis, the latter being de ned as hepatic or peritoneal nodules con ned to areas near the gallbladder and lymph node metastasis in the abdominal para-aortic area. Limited distant metastases were resected with the primary tumour. En bloc resection of macroscopically involved neighbouring organs such as the duodenum, pancreas and portal vein was performed, so frozen sections were not used routinely except for hepatic or peritoneal nodules. Prophylactic resection of surrounding organs without apparent tumour invasion was not employed. Regional lymphadenectomy was performed routinely. The para-aortic lymph nodes were dissected extensively in most patients, except those with intramucosal cancer. The surgical plan was based on the results of preoperative imaging and modi ed according to the intraoperative ndings. All 70 patients with obstructive jaundice underwent percutaneous transhepatic biliary drainage before operation. They were operated on after the serum bilirubin level had decreased below 2 mg/dl. All resected specimens collected from 1979 were examined microscopically and restaged according to the Union Internacional Contra la Cancrum UICC) tumour node metastasis TNM) classi cation of There were ve patients with stage I, seven patients with stage II, nine patients with stage III and 95 patients with stage IV gallbladder carcinoma. Most of the patients with stage IV ã 2002 Blackwell Science Ltd British Journal of Surgery 2002, 89, 179±

2 180 Extensive surgery for carcinoma of the gallbladder S. Kondo, Y. Nimura, N. Hayakawa, J. Kamiya, M. Nagino and K. Uesaka disease had initially been diagnosed as having irresectable tumours at another institute. All of the patients with stage I± III tumours, and per cent) of the 95 patients with stage IV disease underwent radical resection that secured negative resection margins with no residual tumour. Limited distant metastases were con rmed microscopically in the resected specimens in 30 of the 59 patients with stage IV disease who underwent radical resection stage IV M 1 )), but not in the other 29 patients stage IV M 0 )). In the 30 patients with stage IV M 1 ) disease, limited distant metastases were found in the para-aortic lymph nodes n = 24), liver n = 10) and peritoneum n = 3). The remaining 36 patients with stage IV disease underwent palliative surgery. Grading of tumours was also performed according to the UICC classi cation 7. Among the 12 patients with stage I or II disease, 11 had well differentiated G1) and one had moderately differentiated G2) gallbladder carcinoma. Among the 68 patients who underwent radical resection for stage III or IV disease, four, 43 and 21 patients had G1, G2 and G3 poorly differentiated) carcinoma respectively. Neither adjuvant chemotherapy nor radiotherapy was administrated. The survival rates after surgery were calculated using the Kaplan±Meier method. Statistical comparisons of survival were performed with the log ranktest. Results Surgical procedures In the patients with stage I or II gallbladder carcinoma, curative resection was accomplished by simple cholecystectomy n = 6) or radical cholecystectomy including resection of the adjacent liver parenchyma and regional lymph nodes n = 6). One patient underwent pancreaticoduodenectomy because of a concomitant benign tumour intraductal papillary mucinous tumour) of the pancreatic head. In the 68 patients who underwent radical resection for stage III or IV disease, radical cholecystectomy with extended right hepatectomy n = 40; 59 per cent), pancreaticoduodenectomy n = 23; 34 per cent) and/or portal vein resection n = 23; 34 per cent) was necessary for complete removal of tumour Fig. 1). Palliative surgery included exploratory laparotomy n = 7), bypass operation n = 15) and palliative resection n = 14) that resulted in macroscopic and/or microscopic residual tumours or positive resection margins. Morbidity and mortality rates Hospital mortality calculations included all deaths within and over 30 days of operation Table 2). There were no deaths among patients with stage I±III disease. The morbidity and mortality rates for the 59 patients with stage IV tumours who underwent radical resection were 51 and 20 per cent respectively. Six patients with a stage IV M 0 ) tumour died in hospital 3, 10, 16, 20, 25 and 49 days after operation, and six patients with stage IV M 1 ) disease also died during their hospital stay 8, 8, 18, 42, 53 and 75 days after surgery. All 12 hospital deaths occurred after extended right hepatectomy Fig. 1). Obstructive jaundice was also a signi cant determinant of hospital death P = 0 005, c 2 test). Postoperative hepatic failure developed after extended right hepatectomy for a cholestatic liver and was the most common cause of death eight of 12 deaths). The patients who died from hepatic failure did not have ongoing cholangitis. Although the mortality rate was high after radical resection for patients with stage IV disease, it was lower than that 33 per cent) after palliative surgery for patients with stage IV disease. The main cause of death after palliative surgery was tumour progression rather than postoperative complications. Table 1 Guidelines employed for surgical treatment of gallbladder carcinoma Preoperative and/or intraoperative ndings Direct hepatic invasion Involvement of the hepatic hilum and the right portal pedicle Subserosal invasion at the neck of the gallbladder or evident nodal metastasis in the hepatoduodenal ligament Invasion of the duodenum and/or the head of the pancreas Invasion of the portal vein Invasion of the other neighbouring organs colon, stomach, abdominal wall, etc.) Evident and/or occult nodal metastasis Hepatic metastasis or peritoneal seeding con ned to areas near the gallbladder Procedure of choice Cholecystectomy plus resection of the adjacent liver depending on the degree of hepatic invasion varying from wedge resection to extended right hepatectomy) Extended right hepatectomy plus caudate lobectomy En bloc resection and reconstruction of the bile duct Pancreaticoduodenectomy En bloc resection and reconstruction of the portal vein En bloc resection Routine dissection of the regional lymph nodes using a skeletonization technique and para-aortic lymphadenectomy En bloc resection British Journal of Surgery 2002, 89, 179±184 ã 2002 Blackwell Science Ltd

3 S. Kondo, Y. Nimura, N. Hayakawa, J. Kamiya, M. Nagino and K. Uesaka Extensive surgery for carcinoma of the gallbladder 181 Postoperative survival All of the 12 patients with stage I or II disease were alive without recurrence at the last follow-up, apart from three patients who died from causes other than the gallbladder cancer 3, 44 and 152 months after surgery Fig. 2). Six patients have survived for more than 5 years Fig. 1). Of the 68 patients with stage III or IV disease who underwent radical resection, 13 have survived for more than 3 years, of whom nine have survived for more than 5 years Fig. 1, Table 3). At the last follow-up, seven 5-year survivors were disease free. Obstructive jaundice was not a Radical or simple cholecystectomy (n = 27) Extended right hepatectomy (n = 40) Portal vein resection (n = 23) 5-year survivors (n = 15) 3-year survivors who died (n = 5) or were lost to follow-up (n = 2) within 5 years after surgery Patients who died in hospital after surgery (n = 12) Pancreaticoduodenectomy (n = 23) Patients who were discharged and died (n = 44) or were lost to follow-up (n = 2) within 3 years after surgery ( ) Fig. 1 Surgical procedures and outcome in 80 patients who underwent radical resection. Symbols in parentheses represent patients with stage I or II disease prognostic determinant; seven patients presenting with jaundice have survived for more than 3 years, of whom four have survived for more than 5 years. The presence of limited distant metastases had a negative impact on survival Fig. 2). There were some long-term survivors among the group of patients who underwent extended right hepatectomy Fig. 1). However, there was only one long-term survivor among the group of patients who underwent portal vein resection or pancreaticoduodenectomy. The postoperative 1- and 2-year survival rates were 39 and 13 per cent respectively in patients who underwent portal vein resection, and 48 and 17 per cent respectively in patients who had pancreaticoduodenectomy. These survival rates were signi cantly better than those of the 22 unresected patients, all of whom died within 1 year after operation P = and P < respectively). There was no statistically signi cant difference P = 0 294) between the survival rates for stage III 44 per cent at 3 years and 33 per cent at 5 years) and stage IV M 0 ) 24 per cent at 3 years and 17 per cent at 5 years) disease Fig. 2, Table 2). These survival rates were signi cantly worse than those for the patients with stage I or II disease P = and P < respectively). However, they were better than the survival rates for patients with stage IV M 1 ) disease P = and P = respectively) Fig. 2). All of the patients who underwent palliative surgery died within 1 year of operation despite various types of chemotherapy. The survival rate for this group was signi cantly worse than that for patients with stage IV M 1 ) disease who underwent radical surgery P = 0 004) Fig. 2). Sites of tumour recurrence There was no tumour recurrence in patients with stage I or II disease. Of the 68 patients who underwent radical resection for stage III or IV disease, 48 patients died from tumour recurrence. Two of them died more than 5 years after surgery; four died between 3 and 5 years after operation. Sites of tumour recurrence were identi ed by Table 2 Results of operation in 116 patients with gallbladder carcinoma Stage No. of patients Operative morbidity %) Hospital mortality %) Survival rate %) 1 year 3 years 5 years Median survival months) Radical resection I and II Ð III IV M 0 ) IV M 1 ) Palliative operation IV ã 2002 Blackwell Science Ltd Journal of Surgery 2002, 89, 179±184

4 182Extensive surgery for carcinoma of the gallbladder S. Kondo, Y. Nimura, N. Hayakawa, J. Kamiya, M. Nagino and K. Uesaka autopsy, relaparotomy or diagnostic imaging in 40 of the 48 patients. Abdominal tumour recurrence included seeding metastases in 13 patients, hepatic metastases in 12 patients, lymph node metastases mostly para-aortic nodes) in ten patients and local recurrence in nine patients. Sites of recurrence outside the peritoneal cavity were the neckand mediastinum in ve patients, the lung in ve patients and the bone in three patients. No. at risk Survival rate Time after operation (years) Stage I and II Stage III Stage IV (M 0 ) Stage IV (M 1 ) Palliative Stage I and II Stage III Stage IV (M 0 ) Stage IV (M 1 ) Palliative 36 0 Fig. 2 Postoperative survival of patients undergoing radical resection for gallbladder cancer according to Union Internacional Contra la Cancrum staging and patients undergoing palliative operation. P = stage I and II versus stage III); P = stage III versus stage IV M 0 )); P = stage IV M 0 ) versus stage IV M 1 )); P = stage IV M 1 ) versus palliative) log ranktest) 7 8 Discussion Satisfactory results were achieved by simple or radical cholecystectomy in patients with stage I or II disease. Extensive surgery is not necessary in these patients 8±12. However, poor outcomes have also been reported using this approach 13,14. These poor results might have been due to the inclusion of patients with stage III or IV disease with occult nodal metastases, because routine dissection and histological examination of the lymph nodes had not been performed. In contrast, the results of surgical treatment of stages III and IV gallbladder carcinoma have been reported to be extremely poor 8,13,15. Recently, the results have improved as a result of the introduction of extensive resection Table 3) 2,3,16±22, including en bloc resection of involved organs. A high resection rate of 65 per cent in patients with stage III or IV disease was achieved in the present study, in which extensive surgery was based on precise preoperative evaluation of tumour extension. Although the hospital mortality rate for patients with stage III or IV disease who had radical resection was high 18 per cent), it was lower than that 33 per cent) of patients who underwent palliative surgery. High mortality rates 20± 33 per cent) have been reported in some previous studies of radical surgery 2,8,14,18, but not in others 20,22,23. All 12 patients in this study who died after operation had undergone extended right hepatectomy. The majority n =8) died from postoperative hepatic failure; all of them had Table 3 Reports of extensive surgery and long-term survival in patients with stages III and IV gallbladder cancer No. of long-term survivors No. of extensive resections Stage III Stage IV Reference Year ERH PD PVR 3 years 5 years 3 years 5 years Gall et al Todoroki et al Chijiiwa and Tanaka Ruckert et al Bartlett et al Okamoto et al Miyazaki et al Tsukada et al Paquet Present study ERH, extended right hepatectomy; PD, pancreaticoduodenectomy; PVR, portal vein resection British Journal of Surgery 2002, 89, 179±184 ã 2002 Blackwell Science Ltd

5 S. Kondo, Y. Nimura, N. Hayakawa, J. Kamiya, M. Nagino and K. Uesaka Extensive surgery for carcinoma of the gallbladder 183 undergone major hepatectomy in the presence of liver damage due to obstructive jaundice, which has rarely been reported in other studies. Miyazaki et al. 2 used major hepatectomy in patients with cholestasis and also reported hepatic failure as the most common cause of postoperative death. Extended right hepatectomy of the cholestatic liver carries a high riskof postoperative hepatic failure even if the preoperative serum bilirubin level has fallen to normal by percutaneous transhepatic biliary drainage, and laboratory evaluation such as indocyanine green excretion and prothrombin tests) shows almost normal liver function. In the present series, 37 of the 40 patients who underwent extended right hepatectomy had cholestasis. To prevent postoperative hepatic failure, preoperative portal vein embolization is now performed in all patients in whom a major hepatic resection in a cholestatic liver is planned 24±26, although the role of the embolization in reducing the postoperative mortality rate has not yet been fully evaluated. Extensive surgery has been reported to result in long-term survival in selected patients with stage IV gallbladder carcinoma Table 3). In the present series, there were more long-term survivors than in any other report. Survival outcome analysis using two patient groups according to the UICC subgrouping, stage IVA n = 17) and IVB n = 42), did not show a statistically signi cant difference; however, a borderline signi cant difference in survival was noted between two patient groups classi ed simply by whether limited distant metastases were absent or present, stage IV M 0 ) n = 29) and IV M 1 ) n = 30) Fig. 2). The presence of limited distant metastases was associated with worse survival. Thus extensive surgery should be performed in patients with stage III or stage IV M 0 ) gallbladder carcinoma. Based on the present results, radical resection has been abandoned when gallbladder carcinoma is associated with hepatic metastasis, peritoneal seeding and/or para-aortic lymph node metastasis, even if they are con ned to areas near the gallbladder. Radical resection with portal vein resection and/or pancreaticoduodenectomy should be undertaken only when survival for 1 year or more and an improvement in quality of life are possible. To identify limited distant metastases before radical surgery, it may be necessary to utilize more reliable diagnostic procedures such as laparoscopic exploration 27 or routine sampling of para-aortic nodes 6. Acknowledgements The authors are grateful to Dr Jane I. Tsao for her review of this manuscript. 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