Abstract. A 69-year-old man diagnosed as having gallbladder cancer with liver invasion and metastasis to Couinaud's hepatic segment 8 (S8) was referred to ...
J Hepatobiliary Pancreat Surg (2008) 15:655–658 DOI 10.1007/s00534-007-1311-9
Resection of gallbladder cancer with hepatic metastasis after chemotherapy with gemcitabine HARUKI MORIMOTO1, TETSUO AJIKI1, SHIRO TAKASE2, TSUNENORI FUJITA1, TAKU MATSUMOTO1, YOSHIYASU MITA1, IPPEI MATSUMOTO1, YASUHIRO FUJINO2, YASUYUKI SUZUKI3, YOSHIKAZU KURODA2, and YONSON KU1 1
Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medical Sciences, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan Department of Gastrointestinal Surgery, Kobe University Graduate School of Medical Sciences, Kobe, Japan 3 Department of Gastroenterological Surgery, Kagawa University School of Medicine, Kagawa, Japan 2
Abstract A 69-year-old man diagnosed as having gallbladder cancer with liver invasion and metastasis to Couinaud’s hepatic segment 8 (S8) was referred to our hospital. Because of the presence of liver metastasis, gemcitabine administration was chosen. Although gemcitabine was effective for the liver metastasis, his serum carcinoembryonic antigen (CEA) level had gradually increased after 12 cycles of gemcitabine administration. There was no distant metastasis other than the liver metastasis (manageable with gemcitabine) on detailed radiological examination. Therefore, we performed surgery for the primary lesion, after obtaining informed consent. Pathological examination demonstrated viable cancer cells with necrosis and fibrosis in the gallbladder, and fibrosis without viable cancer cells in the induration in liver S8. Gemcitabine was re-administered as postoperative adjuvant chemotherapy. Twenty months after the surgery, there was no sign of recurrence. In selected patients, gemcitabine treatment may be effective against gallbladder cancer with metastasis. Key words Gallbladder Chemotherapy
cancer
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Gemcitabine
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Introduction Surgery is the most effective and potentially curative treatment for gallbladder cancer. However, the majority of patients present with advanced disease, due to the lack of early symptoms, and the prognosis for patients with inoperable tumors remains dismal. In patients with metastatic biliary cancer who received palliative therapy, the median survival time was about 6 months.1,2 Therefore, there is a clear need for effective chemotherapeutic methods in the management of gallbladder cancer. Recently, gemcitabine was approved as the treatment Offprint requests to: T. Ajiki Received: June 28, 2007 / Accepted: October 9, 2007
for biliary tract cancers in Japan. We encountered a patient who underwent resection of gallbladder cancer after the successful management of liver metastasis by gemcitabine administration.
Case report A 69-year-old man presented to a local hospital because of abdominal pain and icterus, and was diagnosed as having advanced gallbladder cancer. He was referred to our hospital for further investigation and therapy in January 2005. Laboratory data on admission showed slight elevations of serum total bilirubin (T-bil, 1.2 mg/ dl), γ-glutamyltranspeptidase (γ-GTP; 87 IU/l), and carcinoembryonic antigen (CEA; 9.6 ng/ml). Carbohydrate antigen (CA) 19-9 was not elevated. The patient’s clinical course and changes in CEA are shown in Fig. 1. Abdominal computed tomography (CT) scans on the first admission showed gallbladder wall thickening, an unclear border between the gallbladder and liver bed, and a ring-like enhanced mass (15 mm) in Couinaud’s hepatic segment 8 (S8; Fig. 2a). Concerning the evaluation of the liver metastasis, angiography and magnetic resonance imaging scan (MRI) showed similar findings. The diagnosis was advanced gallbladder cancer with direct invasion and metastasis to the liver, and we evaluated the patient as inoperable because of the presence of liver metastasis. With the patient’s informed consent, chemotherapy with gemcitabine was started, at a dose of 1000 mg/m2 weekly for 3 weeks, followed by a 1-week rest. Because of transient grade 3 neutropenia (according to the National Cancer Institute common toxicity criteria3), the gemcitabine regimen was soon changed to weekly for 2 weeks followed by a 1-week rest, and he continued to receive this treatment as an outpatient. His serum CEA level gradually decreased, and a follow-up CT scan performed 8 cycles later, in May 2005, showed
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H. Morimoto et al.: Resected GB cancer after gemcitabine 1
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Fig. 1. Clinical course and changes in serum carcinoembryonic antigen (CEA). The points marked a, b, and c correspond to the timing of the computed tomography (CT) examinations shown in Fig. 2a, b, c. GEM, gemcitabine
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Fig. 2. a–c Changes on CT images showing gallbladder cancer and liver metastasis (arrows). d Pathological examination demonstrated poorly differentiated adenocarcinoma with fibrosis and necrosis; e the induration (arrows) in Couinaud’s
hepatic segment 8 (S8) consisted almost entirely of fibrosis and there was no evidence of viable cancer cells. d H&E, ×100; e H&E, ×40
thinning of the gallbladder wall and downsizing of the liver metastasis (Fig. 2b). However, 12 cycles later, in October 2005, his serum CEA levels had gradually increased again, and he was admitted to our hospital for investigation and therapy in January 2006. CT scan obtained in January 2006 after 16 cycles showed irregular thickening of the gallbladder wall, the liver metastasis in S8 had almost disappeared, and there
were no other liver metastatic lesions (Fig. 2c). MRI also showed only a single low-intensity area measuring 5 mm in S8. Fluorine 18 fluorodeoxyglucose-positron emission tomography (FDG-PET) showed significant FDG uptake in the primary lesion, but there was no significant increase in uptake in the liver or other organs. To summarize, the gemcitabine chemotherapy had resulted in regression of the liver metastasis in S8 and
H. Morimoto et al.: Resected GB cancer after gemcitabine
there was no new metastatic lesion, but there remained an uncontrollable primary gallbladder lesion, which was probably causing the increase in CEA. In order to control the primary lesion, we performed surgery, after obtaining informed consent. Macroscopically, peritoneal dissemination was not found, and the gallbladder cancer with liver invasion showed strong adhesion to the duodenum and transverse colon. There was no evidence of liver metastasis on intraoperative ultrasonography. We performed cholecystectomy, with resection of the liver bed and D2 lymph node dissection, partial resection of the duodenum and transverse colon, and excision of the induration in S8 that was compatible with the radiological metastatic site. Pathological examination demonstrated viable cancer cells (poorly differentiated adenocarcinoma) with necrosis and fibrosis in the primary lesion (Fig. 2d), and direct invasion to the liver bed, duodenum, and transverse colon. No lymph node metastasis was observed. Histologically, the induration in S8 showed fibrosis without viable cancer cells, a finding which was histologically compatible with a chemotherapeutic response (Fig. 2e). The patient had an uneventful postoperative course and gemcitabine administration was started again. Twenty-five cycles later, in December 2006, his serum CEA level had decreased to 4.5 ng/ml. In September 2007, 31 months after the gemcitabine administration was started, the patient is well and has no signs of recurrence.
Discussion Gemcitabine is an active agent commonly used to treat pancreatic cancer4,5 and non-small cell lung carcinoma. Recently, gemcitabine has been reported to be an effective chemotherapeutic drug for biliary tract carcinoma. In an experimental setting, we have reported the efficacy of gemcitabine in orthotopically inoculated gallbladder cancer in nude mice.6 Clinically, several phase II studies of single-agent gemcitabine have been reported; in a Japanese phase II study, Okusaka et al.7 reported a response rate of 17.5% and median survival time of 7.6 months, and they concluded that chemotherapy with single-agent gemcitabine was feasible and appeared to show efficacy in advanced or metastatic biliary tract cancer. Although a large randomized phase III study needs to be performed to confirm its efficacy against biliary tract carcinoma, gemcitabine appears to provide a more favorable prognosis in patients with this disease compared to other agents or best supportive care. Our patient showed a good response to gemcitabine for the metastatic liver lesion, but the agent was not so effective in the primary lesion. Sugita et al.8 reported
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that combined chemotherapy with irinotecan and lowdose cisplatin may have effective antitumor activity against liver metastasis of bile duct cancer and against liver and lymph node metastasis of gallbladder cancer. To our knowledge, there has been no report about the efficacy of gemcitabine in different disease sites. In gastric cancer, Takahashi et al.9 reported that the antitumor activity of S-1 was different in different disease sites; the response rates were 45.4% for primary tumors, 54.5% for lymph nodes, and 37.5% for liver metastases. Further study is required to examine the efficacy of gemcitabine against primary and metastatic gallbladder cancers. There was no evidence in the present patient of whether or not the effect of gemcitabine pretreatment before surgery was significant. Moreover, this present result of good prognosis might just be incidental. However, surgery after preoperative, neoadjuvant chemotherapy for biliary tract cancers has seldom been reported to date. Aretxabala et al.10 developed a prospective randomized trial to evaluate the effect of neoadjuvant chemoradiation (5-fluorouracil [FU] + radiation) in patients with gallbladder cancer, and concluded that in this series of patients, neoadjuvant chemoradiation had no positive effect on survival. In contrast, McMasters et al.11 reported that preoperative chemoradiation (5-FU + radiation) for patients with extrahepatic cholangiocarcinoma resulted in a high rate of pathological complete response and may have improved the ability to achieve a tumorfree resection margin. Our search of MEDLINE and the database of the Japan Medical Abstracts Society did not find any report of resection following preoperative gemcitabine treatment for gallbladder cancers. We performed surgery after 16 cycles of gemcitabine treatment after obtaining informed consent. Because there was no apparent metastatic lesion on various radiological examinations, the aim of the surgery was control of the primary lesion. Fortunately, there has not been any evidence of recurrence in this patient 20 months after the surgery, but further careful follow-up is required. References 1. Glimelius B, Hoffman K, Sjödén PO, Jacobsson G, Sellström H, Enander LK, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996;7:593–600. 2. Ishikawa T, Horimi T, Shima Y, Okabayashi T, Nishioka Y, Hamada M, et al. Evaluation of aggressive surgical treatment for advanced carcinoma of the gallbladder. J Hepatobiliary Pancreat Surg 2003;10:233–8. 3. National Cancer Institute. Common toxicity criteria (version 2). Bethesda: Division of Cancer Treatment and Diagnosis, National Cancer Institute, 1999.
658 4. Glimelius B. Chemotherapy in the treatment of cancer of the pancreas. J Hepatobiliary Pancreat Surg 1998;5:235–41. 5. Fung MC, Sakata T. What’s new in pancreatic cancer treatment? J Hepatobiliary Pancreat Surg 2002;9:61–75. 6. Mita Y, Ajiki T, Kamigaki T, Okazaki T, Hori H, Horiuchi H, et al. Antitumor effect of gemcitabine on orthotopically inoculated human gallbladder cancer cells in nude mice. Ann Surg Oncol 2007;14:1374–80. 7. Okusaka T, Ishii H, Funakoshi A, Yamao K, Ohkawa S, Saito S, et al. Phase II study of single-agent gemcitabine in patients with advanced biliary tract cancer. Cancer Chemother Pharmacol 2006;57:647–53. 8. Sugita H, Hirota M, Ichihara A, Furuhashi S, Kihara S, Shimada S. Combined chemotherapy of irinotecan and low-dose
H. Morimoto et al.: Resected GB cancer after gemcitabine cisplatin (I/low-P) against metastatic biliary tract cancer. J Hepatobiliary Pancreat Surg 2006;13:463–7. 9. Takahashi I, Kakeji Y, Emi Y, Sakurai M, Yonemura Y, Kimura Y, et al. S-1 in the treatment of advanced and recurrent gastric cancer: current state and future prospects. Gastric Cancer 2003;6:28–33. 10. Aretxabala X, Roa I, Berrios M, Hepp J, Gallardo J, Cordova A, et al. Chemoradiotherapy in gallbladder cancer. J Surg Oncol 2006;93:699–704. 11. McMasters KM, Tuttle TM, Leach SD, Rich T, Cleary KR, Evans DB, et al. Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. Am J Surg 1997;174:605–9.
