The prognosis of patients with carcinoma of the gallbladder remains poor, as most patients present at an advanced tumor stage.1 Surgical resection with tumor-free margins provides the only hope for long-term survival. However, the low resection rate ranging from 22% to 38%2,3 poses many challenges for surgeons. The extent of tumor invasion in the gallbladder wall and the presence or absence of nodal involvement influences the survival after resection. When the tumor is confined to the gallbladder wall, the 5-year survival rate ranges from 10% to 30%.4 When the tumor invades the gallbladder serosa, local lymph nodes, or adjacent liver, the 5-year survival rate decreases to 5%.4,5 In patients undergoing resection with curative intent, loco-regional failure is commonly seen as a major cause of death. Adjuvant therapy is a rational treatment despite the paucity of evidence that provides an advantage in survival of patients with this tumor.5,6
The incidence of carcinoma of the gallbladder is varied around the world. The tumor is very common in native American and South American populations as well as in people from Poland and Northern India,1 but its incidence in the Chinese population is low. For patients with gallbladder cancer in the Chinese population, the 3-year survival rate was 55% after curative surgery and 0 after palliative treatment.7 At first this study aimed to identify specific prognostic factors (i.e., epidemiological, therapeutic, and histopathological factors) for predicting the survival of Chinese patients with this tumor treated at a single institution. Secondly, it was to assess the value of adjuvant therapy in these patients.
From April 1980 to December 2005, 164 patients (83 males, 81 females) underwent surgery for gallbladder carcinoma at the Department of General Surgical Oncology, Cancer Hospital of the Chinese Academy of Medical Sciences (CAMS). In this retrospective study, data were collected from medical records and regular follow-up visits until December 2007. Fourteen of these patients were lost to follow-up, resulting in a study population of 150. Data on demographic characteristics, symptoms on presentation, operative procedure, tumor pathology, adjuvant therapy, and stages of the tumor were analyzed. The preoperative diagnosis of gallbladder cancer was based on the features on ultrasonography and computed tomography (CT). The extent of biliary obstruction was assessed by cholangiogram using endoscopic retrograde cholangiopancreatography or percutaneous cholangiography in jaundiced patients. The presence of intra- and extra-hepatic metastases was investigated by chest X-ray, CT scan, or magnetic resonance imaging. For patients without distant metastasis, curative resection was carried out unless the patients were medically unfit or refused surgery. Curative resection was defined as a microscopically negative resection with no gross evidence of residual disease, that is, RO resection. Resection carried out with curative intent was ultimately defined as a palliative intervention if the margin status was microscopically (R1) or macroscopically (R2) positive. Types of curative resections included simple cholecystectomy or radical cholecystectomy with or without hepatectomy. Stages of the tumor were classified according to the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system,8 which was based on radiological and operative findings. All patients with curative resections were followed up at our center every 3 months after surgery. Regular abdominal ultrasonography or CT scan was carried out to detect the tumor at the previous operative site.
The demographic and clinicopathologic data were retrospectively reviewed. Continuous variables expressed as median and range were compared using the Mann-Whitney U test. Categorical variables were compared using the Chi-square test with Yates’ correction for continuity or the Fisher's exact test where appropriate. The survival rate was estimated with the Kaplan-Meier method and compared with the log-rank test. Hospital deaths were included in the overall survival analysis. Multivariate analysis was made using the Cox proportional hazards model to identify independent prognostic factors. All statistical analyses were made using statistical software (SPSS 11.0 for Windows, SPSS, Inc, Chicago, IL, USA). A P value less than 0.05 was considered statistically significant.
The median age of the 150 patients with carcinoma of the gallbladder was 59 years (range, 30–80 years). The female to male ratio was 1:1 (75 females:75 males). Six patients had other malignancies (2 patients with hepatocellular carcinoma, 1 patient with lung cancer, 1 patient with renal carcinoma, 1 patient with gastric carcinoma, and 1 patient with esophageal carcinoma). Exactly 93.3% of the patients presented with abdominal pain and 21.3% with jaundice. Only 10 patients (6.7%) were totally asymptomatic at the initial presentation, and their tumors were diagnosed incidentally on routine physical examination. Radiological studies revealed gallstones in 43 patients (28.7%).
Operative strategy for gallbladder carcinoma was strongly influenced by tumor stage (Table 1). Simple cholecystectomy was performed as a potentially curative procedure when a carcinoma was observed incidentally or as a palliative intervention when symptomatic gallstones were associated with the incurability of the tumor. Tumor localization significantly determined the extent of surgery necessary for macroscopically complete resection. Sixty patients (40%) underwent radical R0 resection of tumors (Table 2). In 15 patients, surgical procedures included hepatic wedge resection of segments IVb and V and dissection of lymph nodes in the hepatoduodenal ligament and the posterosuperior pancreaticoduodenal nodes. In 5 patients, extended radical surgery (including partial gastrectomy or colectomy) was performed because of tumor adherence to or invasion into these organs. Moreover, two pancreaticoduodenectomies were undertaken to address the extent of pancreatic and duodenal involvement. The major bile duct was resected in three patients. None of the patients who underwent radical cholecystectomy or simple cholecystectomy had grossly positive resection margins. This low rate of curative surgery was due to tumor infiltration in lymph nodes at a rate of 59% and distant metastasis at a rate of 19%, determined peri-operatively. Palliative procedures were given to 57 patients (38%): 44 accepted simple cholecystectomy and 13 accepted cholecystectomy and hepatic wedge resection of segments IVb and V. The remaining 33 patients (22%) underwent biopsy alone or had a biliary bypass or drainage.
Postoperative morbidity and mortality
The hospital mortality rate after surgery was 2.0% (3 patients): one died on postoperative day 13 of pulmonary failure after pancreaticoduodenectomy; one died on postoperative day 7 of a pulmonary embolis after laparotomy and biopsy for unresectable cancer; one died on postoperative day 29 of cardiac failure after surgical exploration of the abdomen for unresectable cancer. The postoperative 30-day morbidity was 6%. Surgery-related complications included wound infection (n=5), bile duct fistulas (n=2), pancreatic fistulas (n=1), and pneumonia (n=1). Morbidity rates were dependent on the surgical procedure, and patients undergoing cholecystectomy with proximal bile duct resection had the highest complication rate (12%).
In 141 patients with histologically proven gallbladder cancer (curative resection, 60; palliative resection, 57; and tumor biopsy only, 24), 112 had adenocarcinomas, 15 had papillary adenocarcinomas, 5 had mucinous adenocarcinomas, 2 had squamous cell carcinomas, 5 had adenosquamous cell carcinomas, and 2 had poorly differentiated carcinomas. Tumor grading in the 141 patients was as follows: grade 1, 24%; grade 2, 33%; grade 3, 42%; and grade 4, 1%. Prognosis was significantly better when tumors were grade 1, with a median survival time of 40.8 months, than grade 2 and grade 3/4 (poorly differentiated), with median survival time of 9.7 months (P=0.000 vs grade 1) and 7.0 months (P=0.025 vs grade 2), respectively.
Pathologic staging was performed according to the 2002 AJCC staging system. Overall stage distribution was as follows: stage 0, 2 patients (1.3%); stage IA, 3 (2%); stage IB, 17 (11.3%); stage IIA, 31 (20.7%); stage IIB, 40 (26.7%); stage III, 28 (18.7%); and stage IV, 29 (19.3%). Pathologic stages classified by surgical procedures are shown in Table 1.
Positive regional lymph nodes were found in 7/24 (29.2%) T2 tumors, in 47/80 (58.8%) T3, and in 35/41 (85.4%) T4; none of the 2 Tis and 3 T1 tumor patients had any evidence of involved lymph nodes. The median survival time of patients with positive regional lymph nodes was significantly shorter than that of those without involved nodes (91.3 vs 7.5 months, P=0.000) (Figure 1).
Adjuvant therapy was administered to 62 of the 150 patients: radiotherapy (range 12–66 Gy; mean 51.07 Gy) in 29 (including 10 who also received chemotherapy (5-fluorouracil, leucovorin, adriamycin, doxorubicinol, mitomycin-C, and cisplatin)), and chemotherapy only in 33. Among the 43 patients who received chemotherapy, 23 were treated by intra-arterial infusion of 5-fluorouracil, cisplatin, and mitomycin. Table 3 shows the outcomes of these patients stratified by respectability of the tumor and AJCC stage.
Survival and prognostic factors
The mean period of follow-up was 21 months. The overall 1-, 3-, and 5-year survival rates were 50.5%,29.5%, and 26.2%, respectively, with a median survival time of 12.3 months. Curative therapy was associated with longer survival than palliative resection or only laparotomy. The 5-year survival rate and the median survival time were 60.3% and 97.3 months for patients receiving curative resection, 5.9% and 8.3 months for patients receiving palliative surgery, and 0 and 3.7 months for patients receiving laparotomy (P=0.000).
The effect of AJCC stage, type of surgical treatment (curative vs palliative vs laparotomy), gender, age, presence of gallstones, tumor grade, adjuvant therapy, jaundice at presentation, depth of tumor invasion (T stage), lymph node involvement (N stage), distant metastasis (M), and carcinoembryonic antigen (CEA) level on survival was evaluated using univariate analysis (Table 4). These variables except age and gender were correlated significantly with the patient survival (P <0.05). The Cox proportional hazards method was used for multivariate analysis to determine which of the factors (found to be significant in univariate analysis) were correlated to the patient survival. AJCC stage (P=0.000) (Figure 2), type of surgical treatment (P=0.000) (Figure 3), and adjuvant therapy (P=0.01) (Figure 4) were significantly related to patient outcomes (Table 5).
Gallbladder cancer is a rare but often lethal malignancy. Even with advances in diagnosis and treatment of gallbladder cancer, long-term survival remains dismal. Only a minority of patients are candidates for resection at the time of diagnosis. Nonetheless, our results showed that selected patients have a favorable outcome after curative surgery. The 5-year survival rate in 40% of the patients who were able to undergo complete resection was 60.3%.
Gallbladder cancer affects women more commonly than men in all populations, with some series reporting the prevalence three to five times higher for females.1,9 The highest frequency occurs in women of over 65 years with a long history of gallstones. In this series, the female-to-male ratio was 1:1, and the median age was 59 years, which was younger than the previously reported.
The clinicopathological course of gallbladder carcinoma is influenced by type of resection or surgery, the depth of tumor invasion, the presence or absence of lymph node metastasis, and the histological type and TNM stage of the cancer.2,3,10–16 The pre-eminence of depth of invasion (T stage), lymph node metastasis (N stage), the histological type TNM stage and surgical margin status over other prognostic factors of surgical outcome in gallbladder carcinoma cases is widely accepted. In our study, multivariate analysis demonstrated that tumor-free margin is one of the most important predictors of survival.
In previously reported series of patients with gallbladder cancer, the resection rates range from 17% to 47%, and the 5-year survival rates after complete resection vary from 18% to 58%.2,3,8–14 Gallbladder cancer warrants extended resection only if potentially curative (RO) resection is feasible. In patients treated with curative intent, the success of complete resection depended on T-stage, which is in accordance with other reports.2,3,10,15
For Tis and T1a tumors (mucosa), it is generally agreed that simple cholecystectomy is an adequate treatment,1–7,16,17 while for Tlb tumors, a more aggressive surgical approach is required. Tlb tumors are associated with lymph node metastases in 15% of cases, whereas T1a tumors are associated with lymph node metastases in only 2.5% of cases. In this series, lymph node metastasis was absent and the 5-year survival rate was 100% in the 5 patients who had Tis or T1 tumors. Radical resection is certainly warranted and recommended in patients with T2 tumors. The reported incidence of lymph node metastasis in T2 tumor cases is 17.4%—61.9%.7,18 In this series, the incidence of lymph node metastasis was 29.2%. The median survival time of 18 T2 patients with negative surgical margins and curative lymph node dissection was 103.5 months, whereas that of 7 T2 patients with positive surgical margins or noncurative lymph node dissection who died from this disease was within 2 years. The outcome of surgery for patients with T3 and T4 is poorly independent of the high rate of lymph node metastasis and non-curative surgery.1,2,19 Recently, extended resection or pancreaticoduodenectomy has been advocated for advanced gallbladder carcinoma and, in some series, has increased the 5-year survival rate to 15%-63% (T3) and 7%-25% (T4).1,17 In our study, pancreatoduodenectomy was performed in 2 patients with direct involvement of the head of the pancreas, but the outcomes were disappointing: one died 13 days postoperatively from pulmonary failure and the other died 6 months postoperatively from liver metastasis. Lymph node metastasis is common,18 and in our surgical series the rate of lymph node metastasis was 58.8% in T3 tumor cases and 85.4% in T4 tumor cases. In our patients with T3 or T4 gallbladder carcinomas, the survival was significantly better after curative resection than after resection for other reasons.
The role of chemotherapy alone or in combination with radiotherapy in gallbladder carcinoma remains controversial.1,5,6 Mitomycin-C and 5-FU are the most active single agents, and 5-FU is frequently combined with radiotherapy because of its potential radiosensitizing effect. A prospective, randomized phase-III trial comparing surgery with surgery plus adjuvant chemotherapy (5-FU and mitomycin C) in 508 patients diagnosed with resectable pancreaticobiliary carcinoma, 112 of whom also had gallbladder cancer, found improvement in the 5-year survival rate for patients in the adjuvant treatment group (26% compared with 14.4% in the control group; P=0.0367); however, the improvement appeared to be limited to the subgroup of patients who underwent non-curative resections.20 Similarly, adjuvant radiotherapy has been shown to have a survival benefit, especially in patients with microscopic positive margins or residual disease after resection.21 Our results showed that adjuvant therapy was an independent factor affecting survival in multivariate analysis, but after stratification, our analysis showed that adjuvant therapy benefited only patients receiving palliative surgery. Adjuvant therapy prolonged the median survival of patients with T3 tumors from 7.2 months to 12.4 months (P=0.015). In the series reported by Mojica et al,22 the median survival of patients who received adjuvant radiotherapy (17% of 3187 cases) was higher (14 months vs 8 months for those not treated with adjuvant radiotherapy; P <0.001). The benefit was most striking in patients who had regional disease (16 months vs 5 months for those not treated with adjuvant radiotherapy).
In conclusion, the limitation of this study included retrospective data analysis and some patients followed up for less than 5 years. However, gallbladder carcinoma is an aggressive disease with a poor prognosis. Our study suggests that AJCC stage and type of surgery are strong predictors of survival. To increase the possibility of long-term survival, aggressive resection should be pursued in all patients. Complete or RO resection (negative margins and nodal dissection one level past microscopically involved lymph nodes) clearly improves the survival. Adjuvant therapy use is clearly associated with improved survival in patients with loco-regional disease, especially in patients surgically treated with non-curative intent. So more effective adjuvant therapies and new drugs are needed to improve the overall survival.
1. Misra S, Chaturvedi A, Misra NC, Sharma ID. Carcinoma of the gallbladder. Lancet Oncol 2003; 4: 167-176.
2. Puhalla H, Wild T, Bareck E, Pokorny H, Ploner M, Soliman T, et al. Long-term follow-up of surgically treated gallbladder cancer patients. Eur J Surg Oncol 2002; 28: 857-863.
3. Ito H, Matros E, Brooks DC, Osteen RT, Zinner MJ, Swanson RS, et al. Treatment outcomes associated with surgery for gallbladder cancer: A 20-year experience. J Gastrointest Surg 2004; 8: 183-190.
4. Yee K, Sheppard BC, Domreis J, Blanke CD. Cancers of the gallbladder and biliary ducts. Oncology 2002; 16: 939-949.
5. Czito BG, Hurwitz HI, Clough RW, Tyler DS, Morse MA, Clary BM, et al. Adjuvant external-beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: a 23-year experience. Int J Radiat Oncol Biol Phys 2005; 62: 1030-1034.
6. de 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.
7. Chan SY, Poon RT, Lo CM, Ng KK, Fan ST. Management of carcinoma of the gallbladder: A single-institution experience in 16 years. J Surg Oncol 2008; 97: 156-164.
8. AJCC Cancer Staging Manual: American Joint Committee on Cancer Gallbladder. 6th edition. Philadelphia: Lippincott-Raven Publishers; 2002: 139-144.
9. Lazcano-Ponce EC, Miquel JF, Munoz N, Herrero R, Ferrecio C, Wistuba II, et al. Epidemiology and molecular pathology of GBC. CA Cancer J Clin 2001; 51: 349-364.
10. Bartlett DL, Fong Y, Fortner JG, Brennan MF, Blumgart LH. Long-term results after resection for gallbladder cancer. Implications for staging and management. Ann Surg 1996; 224: 639-646.
11. Benoist S, Panis Y, Fagniez PL. Long-term results after curative resection for carcinoma of the gallbladder. French University Association for Surgical Research. Am J Surg 1998; 175: 118-122.
12. North JH Jr, Pack MS, Hong C, Rivera DE. Prognostic factors for adenocarcinoma of the gallbladder: An analysis of 162 cases. Am Surg 1998; 64: 437-440.
13. Rückert JC, Rückert RI, Gellert K, Hecker K, Müller JM. Surgery for carcinoma of the gallbladder. Hepato-gastroenterology 1996; 43: 527-533.
14. Schauer RJ, Meyer G, Baretton G, Schildberg FW, Rau HG. Prognostic factors and long-term results after surgery for gallbladder carcinoma: A retrospective study of 127 patients. Langenbecks Arch Surg 2001; 386: 110-117.
15. Todoroki T, Kawamato T, Takahashi H. Treatment of gallbladder carcinoma by radical resection. Br J Surg 1999; 86: 622-627.
16. Taner CB, Nagorney DM, Donohue JH. Surgical treatment of gallbladder cancer. J Gastrointest Surg 2004; 8: 83-89.
17. Mekeel KL, Hemming AW. Combined resection of the liver and the inferior vena cava for hydatid disease. J Gastrointest Surg 2007; 11: 1741-1743.
18. Endo I, Shimada H, Tanabe M, Fujii Y, Takeda K, Morioka D, et al. Prognostic significance of the number of positive lymph nodes in gallbladder cancer. J Gastrointest Surg 2006; 10: 999-1007.
19. Noshiro H, Chijiiwa K, Yamaguchi K, Shimizu S, Sugitani A, Tanaka M. Factors affecting surgical outcome for gallbladder carcinoma. Hepatogastroenterology 2003; 50: 939-944.
20. Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, et al. Study Group of Surgical Adjuvant Therapy
for Carcinomas of the Pancreas and Biliary Tract. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 2002; 95: 1685-1695.
21. Houry S, Barrier A, Huguier M. Irradiation therapy for gallbladder carcinoma: recent advances. J Hepatobiliary Pancreat Surg 2001; 8: 518-524.
22. Mojica P, Smith D, Ellenhorn J. Adjuvant radiation therapy is associated with improved survival for gallbladder carcinoma with regional metastatic disease. J Surg Oncol 2007; 96: 8-13.