This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of gallbladder cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

General Information About Gallbladder Cancer

Cellular Classification of Gallbladder Cancer

Some histologic types of gallbladder cancer have a better prognosis than others; papillary carcinomas have the best prognosis. The histologic types of gallbladder cancer include the following:[1]

• Carcinoma in situ.
• Biliary intraepithelial neoplasia, high grade.
• Intracystic papillary neoplasm with high-grade intraepithelial neoplasia.
• Mucinous cystic neoplasm with high-grade intraepithelial neoplasia.
• Adenocarcinoma.
• Adenocarcinoma, biliary type.
• Adenocarcinoma, intestinal type.
• Adenocarcinoma, gastric foveolar type.
• Mucinous adenocarcinoma.
• Clear cell adenocarcinoma.
• Signet-ring cell carcinoma.
• Squamous cell carcinoma.
• Adenosquamous carcinoma.
• Undifferentiated carcinoma.
• High-grade neuroendocrine carcinoma.
• Small cell neuroendocrine carcinoma.
• Mixed adenoneuroendocrine carcinoma.
• Intraductal papillary neoplasm with an associated invasive carcinoma.
• Mucinous cystic neoplasm with an associated invasive carcinoma.

Stage Information for Gallbladder Cancer

Localized and Locally Advanced Gallbladder Cancer Treatment

One study reported on patterns of lymph node spread from gallbladder cancer and outcomes of patients with metastases to lymph nodes in 111 consecutive surgical patients in a single institution from 1981 to 1995.[1][Level of evidence: 3iiiA] The standard surgical procedure was removal of the gallbladder, a wedge resection of the liver, resection of the extrahepatic bile duct, and resection of the regional (N1 and N2) lymph nodes. Kaplan-Meier estimates of the 5-year survival for node-negative tumors pathologically staged as T2 to T4 were 42.5% ± 6.5% and for similar node-positive tumors, 31% ± 6.2%.

Standard treatment options for localized and locally advanced gallbladder cancer

Standard treatment options for localized and locally advanced gallbladder cancer include the following:

1. Surgery: In previously unsuspected gallbladder cancer that is discovered in the surgical specimen after a routine gallbladder operation and confined to mucosa (T1), the majority of patients are cured.[2,3] During laparoscopic removal of an unsuspected cancer, there is potential for implantation of carcinoma at all port sites (including the camera site).[4] All port sites are typically excised completely, even for stage I cancers.
   The need for re-exploration for more extended resection in incidentally discovered T1b disease is controversial. A multicenter retrospective review identified lymph node metastases in 12% of patients who underwent re-resection after cholecystectomy, but there are no prospective data regarding relative outcome with a second surgery in these patients.[5][Level of evidence: 3iiiD]
   Patients with T2 or T3 disease have higher rates of unsuspected invasive disease at the time of diagnosis. A multicenter retrospective review was performed on patients who underwent re-resection after carcinoma was discovered incidentally. Residual disease was present in 57% of patients with T2 disease (including 31% with lymph node involvement and 10% with liver involvement) and in 77% of patients with T3 disease (including 46% with lymph node metastases and 36% with liver involvement).[5] On the basis of these observations, eligible patients may undergo re-exploration to resect liver tissue near the gallbladder bed, portal lymph nodes, and lymphatic tissue in the hepatoduodenal ligament. Retrospective analyses suggest delayed recurrences and potentially improved survival with extended re-resection.[6-8][Level of evidence: 3iiiD]
   For patients with locoregional lymph node involvement (at the cystic duct, common bile duct, hepatic artery, and portal vein), long-term disease-free survival can occasionally be achieved with radical resection. In jaundiced patients (stage III or stage IV), there should be consideration of preoperative percutaneous transhepatic biliary drainage for relief of biliary obstruction.
   Surgery with curative intent is not considered possible in patients with metastatic spread beyond the locoregional lymph nodes or to distant organs.
2. External-beam radiation therapy (EBRT): The use of EBRT with or without chemotherapy as a primary treatment has been reported in small groups of patients to produce short-term control. Similar benefits have been reported for radiation therapy with or without chemotherapy administered following resection.[9,10]
   There are no phase III studies to support the use of adjuvant radiation therapy, even for patients with high-risk localized disease.

Treatment options under clinical evaluation for localized and locally advanced gallbladder cancer

Treatment options under clinical evaluation for localized and locally advanced gallbladder cancer include the following:

• Clinical trials are exploring ways of improving local control with radiation therapy combined with radiosensitizer drugs. When possible, such patients are appropriately considered candidates for these studies.

Unresectable, Metastatic, or Recurrent Gallbladder Cancer Treatment

Treatment options for unresectable, metastatic, or recurrent gallbladder cancer

Treatment options for unresectable, metastatic, or recurrent gallbladder cancer include the following:

1. Relief of biliary obstruction is warranted when symptoms such as pruritus and hepatic dysfunction outweigh other symptoms of the cancer. The preferred approach is percutaneous transhepatic drainage or endoscopically placed stents;[1] surgical bypass may be appropriate when these approaches are infeasible.
   Palliative radiation therapy after biliary drainage may be beneficial, and patients may be candidates for inclusion in clinical trials that explore ways to improve the effects of radiation therapy with various radiation sensitizers such as hyperthermia, radiosensitizer drugs, or cytotoxic chemotherapeutic agents.
2. Systemic chemotherapy is appropriate for selected patients with adequate performance status and intact organ function. Fluoropyrimidines, gemcitabine, platinum agents, and docetaxel have been reported to produce transient partial remissions in a minority of patients. The incidence of gallbladder cancer is low, and clinical trials often enroll patients with all subsites of biliary tract cancers. Therefore, data must be interpreted with caution when applied specifically to patients with gallbladder cancer. (Refer to the PDQ summary on Bile Duct Cancer [Cholangiocarcinoma] Treatment for more information.)
   In a phase III study, 410 patients with unresectable, metastatic, or recurrent biliary tract cancer were randomly assigned to receive of up to 6 months of gemcitabine versus gemcitabine and cisplatin.[2]

   • With a median follow-up of 8.2 months, the median overall survival (OS) was superior for patients treated with combination chemotherapy (11.7 months vs. 8.1 months; hazard ratio, 0.64; [95% confidence interval, 0.52–0.80]; P < .001).[2][Level of evidence: 1iiA]
   • A similar median OS benefit was demonstrated in all subgroups, including 149 patients with gallbladder cancer.
   • Grade 3 and 4 toxicities occurred with similar frequency in both study arms, with the exception of increased hematologic toxic effects in patients randomly assigned to gemcitabine-cisplatin and increased hepatotoxicity in patients randomly assigned to single-agent gemcitabine.
   A three-arm randomized phase III study of patients with unresectable gallbladder cancer compared best supportive care (n = 27), fluorouracil plus folinic acid (FUFA) weekly for 30 weeks (n = 28), and modified gemcitabine plus oxaliplatin (mGEMOX) for up to six 21-day cycles.[3][Level of evidence: 1iiA]

   • With a median follow-up of 9 months, OS was 4.5 months for best supportive care (95% CI, 0.2−8.8 months), 4.6 months for FUFA (95% CI, 3−6.2 months), and 9.5 months for mGEMOX (95% CI, 5−14 months; P = .039).
   • The only significant difference in grade 3/4 toxicities between the chemotherapy arms was transaminitis, which was more prevalent in the mGEMOX arm (P = .04).
   A phase III noninferiority study (NCT01470443) enrolled 114 patients with metastatic biliary tract cancers, including 30 (26%) with primary gallbladder cancer. Patients were randomly assigned to receive capecitabine plus oxaliplatin (XELOX) or gemcitabine plus oxaliplatin (GEMOX).[4][Level of evidence: 1iiD]

   • OS was not significantly different, with 10.4 months (95% CI, 8.0−12.6 months) in the GEMOX group compared with 10.6 months (95% CI, 7.3−15.5 months) in the XELOX group (P = .131).
   • The primary endpoint of 6-month progression-free-survival (PFS) was 44.6% for the GEMOX group and 46.7% for the XELOX group (95% confidence interval of difference in 6-month PFS rate, -12%−16%, meeting criteria for noninferiority).
   • A predefined subgroup analysis based on the primary site of disease did not reveal a difference in objective response rate between the two arms in patients with gallbladder cancer (P = .598).

Pending further clinical trials, cisplatin plus gemcitabine is considered the reference standard for patients with unresectable, metastatic, or recurrent gallbladder cancer. Potential alternatives include gemcitabine plus capecitabine, GEMOX, and XELOX. Clinical trials should be considered for all patients.

All patients with unresectable, metastatic, or recurrent disease should have molecular testing for deficient mismatch repair (dMMR) or microsatellite instability (MSI-H). Extrapolating from a subgroup of patients with gastrointestinal and hepatopancreatobiliary tumors in the I-PREDICT (NCT02534675) and KEYNOTE-158 (NCT02628067) studies, patients with either dMMR or MSI-H tumors can be considered for treatment with pembrolizumab.[5,6][Level of evidence: 3iiiDiv]

Additional testing for IDH1 mutation and FGFR2 fusion may provide potential targets in clinical trials.

Changes to This Summary (01/26/2022)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Gallbladder Cancer

Updated statistics with estimated new cases and deaths for 2022 (cited American Cancer Society as reference 1).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary