Gallbladder and Biliary Tract Carcinoma: A Comprehensive Update, Part 2

Cancers of the gallbladder and bile ducts are uncommon, aggressive malignancies that present both a diagnostic and therapeutic challenge. With an annual incidence of 7,200 cases in the United States, and the difficulty in diagnosing biliary tract tumors, there is a paucity of data supporting therapeutic options. This comprehensive update by Daines et al demonstrates the advances in diagnostic and staging techniques, which have led to appropriate surgical resection. Despite these advances, the prognosis of gallbladder and cholangiocarcinoma remains bleak, without significant improvement in survival, contrary to the author's optimistic introduction. There is a lack of active chemotherapy and clinical trials exploring adjuvant and palliative therapy. Guidelines such as those advocated by the National Comprehensive Cancer Network (NCCN) help to establish standards for the evaluation and treatment of these uncommon tumors and provide a framework for the development of clinical trials.[1]

Diagnosis and Staging
The occurrence of gallbladder cancer demonstrates a marked geographic variation, which may relate to the incidence of gallstones and obesity among other risk factors. Over the past few decades, the incidence and mortality of gallbladder cancer has decreased, possibly as a result of the widespread use of cholecysectomy for benign disease. Gallbladder cancer may be discovered at the time of surgery, on pathologic review, or during evaluation for symptoms such as an abdominal mass or jaundice. Ultrasound is the most common radiographic study used to assess gallbladder disease. Findings that suggest gallbladder cancer should be followed by an evaluation for resectability. The sixth edition of the American Joint Committee on Cancer (AJCC) Staging Manual has been updated to better identify resectable, and therefore, potentially curable gallbladder cancer.[2]

A T3 lesion is one that invades one adjacent organ, still allowing for surgical resection, whereas a T4 lesion invades the portal vein, hepatic artery, or multiple organs precluding resectability. The group staging reinforces this distinction, identifying stage II disease as resectable (IIa, T3, N0 and IIb, T1-3, N1) and stage III tumors as unresectable (T4, N0-1). For tumors suspected prior to surgical exploration, the diagnostic procedures for staging gallbladder cancer are presented in this paper.

Endoscopic ultrasound is not yet incorporated into the NCCN guidelines as a diagnostic and staging tool. This technology can be invaluable in determining extent of disease and identifying lesions to biopsy. Identification of distant lymph node involvement, such as those in the body or tail region of the pancreas, are consistent with metastatic disease and can be readily and safely identified by endoscopic ultrasound with fine-needle aspiration.

Surgical Resection
The appropriate surgical resection for gallbladder cancer involves an extended cholecystectomy including lymphadenectomy and consideration of a partial hepatic resection and bile duct excision. For gallbladder cancer found at the time of surgical exploration, this surgery would provide the appropriate staging and therapy. Gallbladder cancer found incidentally in the pathology specimen to be invading the muscle layer of the gallbladder (T1b), or beyond, should be treated with excision of the port sites in the case of a laproscopic cholecystectomy in addition to the extended resection.

The benefit of adjuvant therapy is based on small phase II studies compared to historic controls. As recommended in the NCCN guidelines, fluorouracil(Drug information on fluorouracil) with radiation to the tumor bed has suggested improved survival, although randomized prospective studies are lacking. Chemotherapeutic agents are being explored that may offer a greater benefit in eradicating micrometastatic disease in the peritoneum or the liver. As of yet, no agent has demonstrated sufficient activity to be pursued as adjuvant therapy.

Cholangiocarcinoma
Only a minority of cholangiocarcinomas are diagnosed at a stage at which surgical resection is possible. Cholangiocarcinoma that arises in the setting of primary sclerosing cholangitis may be technically resectable; however, the diseased liver usually precludes resection. Most patients with cholangiocarcinoma present with advanced disease and concurrent liver compromise. Percutaneous and endoscopic biliary drainage procedures have made it possible to relieve biliary obstruction without surgical intervention so that therapy can proceed.

Cholangiocarcinomas may arise from the intrahepatic small-duct radicals, or more commonly the extrahepatic bile ducts, and are staged and approached differently. Intrahepatic bile duct cancer is staged according to AJCC staging with primary hepatocellular cancer. Surgically resectable tumors are either solitary without vascular invasion (stage I) or multiple but all less than 5 cm (stage II), assuming liver function is adequate to tolerate an anatomic resection.[1] After complete resection, there is no role for adjuvant therapy outside of a clinical trial. If complete resection is not possible, ablative therapy with radiofrequency ablation or cryotherapy can be considered, although there are no studies demonstrating a survival advantage.

Extrahepatic Bile Duct Cancer
Extrahepatic bile duct cancer includes those of either the right or left hepatic duct, the confluence of the right and left hepatic duct (hilar), the common hepatic duct, and the common bile duct including the intrapancreatic portion of the common bile duct. Tumor that by radiographic evaluation involves the main portal vein, the bilateral branches of the portal vein, the common hepatic artery, or organs other then the liver, pancreas, or gallbladder are considered T4 and unresectable by standard surgical procedures. As with gallbladder cancer, endoscopic ultrasound can provide valuable information in regard to lymph node staging.

Hilar carcinomas are the most common, with only a small percentage amenable to complete surgical resection. Attempts to improve the rate of resection have included preoperative chemotherapy and irradiation (external- beam or brachytherapy), and more radical surgical procedures such as liver transplant, especially in the setting of primary sclerosing cholangitis. Liver transplantation for cholangiocarcinoma is highly controversial, given the limited availability of organs and the high rate of recurrence. The addition of adjuvant therapy after complete surgical resection or in the setting of a liver transplant remains a subject of clinical trials.

Systemic Therapy
Systemic therapy for gallbladder and biliary tract cancers is an ongoing pursuit. As summarized by Daines et al, multiple phase II studies have demonstrated response rates ranging from 10% to 30%, but median overall survival remains approximately 6 to 9 months. New agents are being explored for the treatment of advanced disease, and as emphasized in the NCCN guidelines, clinical trial participation is encouraged.