Gallbladder Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

	Purpose of This PDQ Summary
	General Information
	Cellular Classification
	Stage Information
	Localized Gallbladder Cancer
	Unresectable Gallbladder Cancer
	Recurrent Gallbladder Cancer
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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of gallbladder cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Signs and symptoms.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

Note: Estimated new cases and deaths from gallbladder (and other biliary) cancer in the United States in 2009:[1]

• New cases: 9,760.
• Deaths: 3,370.

Cancer that arises in the gallbladder is uncommon. The most common symptoms caused by gallbladder cancer are jaundice, pain, and fever.

In patients whose superficial cancer (T1 or confined to the mucosa) is discovered on pathological examination of tissue after gallbladder removal for other reasons, the disease is often cured without further therapy. In patients who present with symptoms, the tumor is rarely diagnosed preoperatively.[2] In such cases, the tumor often cannot be removed completely by surgery and the patient cannot be cured, though palliative measures may be beneficial. For patients with T2 or greater disease, extended resection with partial hepatectomy and portal node dissection may be an option.[3,4]

Cholelithiasis is an associated finding in the majority of cases, but less than 1% of patients with cholelithiasis develop this cancer.

References:

1. American Cancer Society.: Cancer Facts and Figures 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed June 16, 2009.
2. Chao TC, Greager JA: Primary carcinoma of the gallbladder. J Surg Oncol 46 (4): 215-21, 1991.
3. Shoup M, Fong Y: Surgical indications and extent of resection in gallbladder cancer. Surg Oncol Clin N Am 11 (4): 985-94, 2002.
4. Sasson AR, Hoffman JP, Ross E, et al.: Trimodality therapy for advanced gallbladder cancer. Am Surg 67 (3): 277-83; discussion 284, 2001.

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

• Carcinoma in situ.
• Adenocarcinoma, not otherwise specified (NOS).
• Papillary carcinoma.
• Adenocarcinoma, intestinal type.
• Mucinous carcinoma.
• Clear cell adenocarcinoma.
• Signet-ring cell carcinoma.
• Adenosquamous carcinoma.
• Squamous cell carcinoma.
• Small cell (oat cell) carcinoma.*
• Undifferentiated carcinoma.*
• Carcinoma, NOS.
• Carcinosarcoma.

*Grade 4 by definition.

References:

1. Gallbladder. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 139-44.

The American Joint Committee on Cancer (AJCC) has designated staging by the TNM classification as follows:[1]

TNM Definitions

Primary tumor (T)

• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• Tis: Carcinoma in situ
• T1: Tumor invades lamina propria or muscle layer
  • T1a: Tumor invades lamina propria
  • T1b: Tumor invades the muscle layer
• T2: Tumor invades the perimuscular connective tissue; no extension beyond the serosa or into the liver
• T3: Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, or pancreas, omentum or extrahepatic bile ducts
• T4: Tumor invades main portal vein or hepatic artery or invades multiple extrahepatic organs or structures

Regional lymph nodes (N)

• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Regional lymph node metastasis

Distant metastasis (M)

• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

AJCC Stage Groupings

Stage 0

• Tis, N0, M0

Stage IA

• T1, N0, M0

Stage IB

• T2, N0, M0

Stage IIA

• T3, N0, M0

Stage IIB

• T1, N1, M0
• T2, N1, M0
• T3, N1, M0

Stage III

• T4, any N, M0

Stage IV

• Any T, any N, M1

LOCALIZED (STAGE I)

These types of patients have cancer confined to the gallbladder wall that can be completely resected. They represent a minority of cases of gallbladder cancer. Patients with cancers confined to the mucosa have 5-year survival rates of nearly 100%.[2] Patients with muscular invasion or beyond have a survival of less than 15%. Regional lymphatics and lymph nodes should be removed along with the gallbladder in such patients.

UNRESECTABLE (STAGE II-IV)

With the exception of some patients with focal stage IIA disease, these types of patients have cancer that cannot be completely resected. They represent the majority of cases of gallbladder cancer. Often the cancer invades directly into adjacent liver or biliary lymph nodes or has disseminated throughout the peritoneal cavity. Spread to distant parts of the body is not uncommon. At this stage, standard therapy is directed at palliation. Because of its rarity, no specific clinical trials exist; however, such patients can be included in trials aimed at improving local control by combining radiation therapy with radiosensitizer drugs.

References:

1. Gallbladder. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 139-44.
2. Shirai Y, Yoshida K, Tsukada K, et al.: Inapparent carcinoma of the gallbladder. An appraisal of a radical second operation after simple cholecystectomy. Ann Surg 215 (4): 326-31, 1992.

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Localized gallbladder cancer is defined by the following TNM classification:

• Tis, T1a or b, selected T2, rare T3; N0; M0

When gallbladder cancer is previously unsuspected and is discovered in the mucosa of the gallbladder at pathologic examination, it is curable in more than 80% of cases. Gallbladder cancer suspected before surgery because of symptoms, however, usually penetrates the muscularis and serosa and is curable in fewer than 5% of patients.

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:

1. Surgery: In previously unsuspected gallbladder cancer, discovered in the surgical specimen following a routine gallbladder operation and confined to mucosa or muscle layer (T1), the majority of patients are cured and require no further surgical intervention.[2,3] Re-exploration to resect liver tissue near the gallbladder bed or extended or formal hepatectomy and lymphadenectomy including N1 and N2 lymph node basins may be associated with delayed recurrences or extended survival in patients with stage I or II gallbladder cancer.[4,5] Apparently localized cancers that are suspected before or during the operation can be surgically removed with a wedge of liver and lymph nodes and lymphatic tissue in the hepatoduodenal ligament. Long-term disease-free survival will occasionally be achieved. In jaundiced patients (stage III or stage IV), there should be consideration of preoperative percutaneous transhepatic biliary drainage for relief of biliary obstruction.

   Implantation of the carcinoma at all port sites (including the camera site) after laparoscopic removal of an unsuspected cancer is a problem. Even for stage I cancers, the port sites must be excised completely.[6]

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.[7,8]

TREATMENT OPTIONS UNDER CLINICAL EVALUATION:

• 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.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with localized gallbladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Tsukada K, Kurosaki I, Uchida K, et al.: Lymph node spread from carcinoma of the gallbladder. Cancer 80 (4): 661-7, 1997.
2. Fong Y, Brennan MF, Turnbull A, et al.: Gallbladder cancer discovered during laparoscopic surgery. Potential for iatrogenic tumor dissemination. Arch Surg 128 (9): 1054-6, 1993.
3. Chijiiwa K, Tanaka M: Carcinoma of the gallbladder: an appraisal of surgical resection. Surgery 115 (6): 751-6, 1994.
4. Shirai Y, Yoshida K, Tsukada K, et al.: Inapparent carcinoma of the gallbladder. An appraisal of a radical second operation after simple cholecystectomy. Ann Surg 215 (4): 326-31, 1992.
5. Yamaguchi K, Chijiiwa K, Saiki S, et al.: Retrospective analysis of 70 operations for gallbladder carcinoma. Br J Surg 84 (2): 200-4, 1997.
6. Wibbenmeyer LA, Wade TP, Chen RC, et al.: Laparoscopic cholecystectomy can disseminate in situ carcinoma of the gallbladder. J Am Coll Surg 181 (6): 504-10, 1995.
7. Smoron GL: Radiation therapy of carcinoma of gallbladder and biliary tract. Cancer 40 (4): 1422-4, 1977.
8. Hejna M, Pruckmayer M, Raderer M: The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature. Eur J Cancer 34 (7): 977-86, 1998.

Unresectable gallbladder cancer is defined by the following TNM classification:

• Any T, N1, M0
• Any T, N0 or N1, M1
• Most T3, N0, M0
• T4, N0, M0

These patients are not curable. Significant symptomatic benefit can often be achieved with relief of biliary obstruction. A few patients have very slow-growing tumors and may live several years.

STANDARD TREATMENT OPTIONS:

Palliative treatment options may include the following:

1. The preferred approach to biliary obstruction is percutaneous transhepatic radiologic catheter bypass or endoscopically placed stents.[1]
2. Standard external-beam radiation therapy can, on occasion, alleviate biliary obstruction in some patients and may supplement bypass procedures.
3. Palliative surgery may relieve bile duct obstruction and is warranted when symptoms produced by biliary blockade (pruritus, hepatic dysfunction, and cholangitis) outweigh other symptoms from the cancer.
4. Standard chemotherapy is usually not effective, though occasional patients may be palliated. Clinical trials should be considered as a first option for most patients.[2,3]

TREATMENT OPTIONS UNDER CLINICAL EVALUATION:

• Clinical trials are in progress to improve local control rates by radiation therapy using brachytherapy and/or radiosensitizer drugs or to discover more effective forms of chemotherapy. When possible, patients should be considered for these clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with unresectable gallbladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001.
2. Bartlett DL, Ramanathan RK, Deutsch M: Cancer of the biliary tree. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1009-31.
3. Hejna M, Pruckmayer M, Raderer M: The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature. Eur J Cancer 34 (7): 977-86, 1998.

The prognosis for any treated cancer patient with progressing or recurrent gallbladder cancer is poor. The question and selection of further treatment depends on many factors: tumor burden, prior treatment, site of recurrence, and individual patient considerations. Patients may have portal hypertension caused by portal vein compression by the tumor. Transperitoneal and intrahepatic metastases are not uncommon. Clinical trials are appropriate and should be considered when possible.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent gallbladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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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

Updated statistics with estimated new cases and deaths for 2009 (cited American Cancer Society as reference 1).

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Date Last Modified: 2009-07-02