- TABLE OF CONTENTS
- Hepatocellular Cancer
- Biliary Tract Cancers
- Etiology and Risk Factors
- Signs and Symptoms
- Staging and Prognosis
- Surgery for gallbladder cancer
- Surgery for bile duct cancer
- Adjuvant radiochemotherapy for gallbladder cancer
- Adjuvant chemoradiotherapy for cholangiocarcinoma
- Management of unresectable, locally advanced disease
- Suggested Reading
In the absence of polyps identified ultrasonographically and confirmed by CT during the workup of suspected cholelithiasis, relatively few gallbladder cancers are diagnosed before surgery. Only 1% to 2% of cholecystectomy specimens are found to contain malignancy.
Surgical management of gallbladder carcinoma is based on the local extension of the tumor. Surgery may be curative, but fewer than 30% of patients are potentially resectable at time of diagnosis.
Early-stage disease. Tumors that invade the lamina propria may be treated by cholecystectomy only. This is usually the situation in a gallbladder cancer that is identified by the pathologist following a cholecystectomy for presumed stone disease. Laparoscopic cholecystectomy should not be performed if the diagnosis of gallbladder cancer is suspected preoperatively (eg, gallbladder polyp > 1 cm on preoperative imaging, thickened gallbladder wall without a history of gallstones or cholecystitis). All suspected gallbladder cancers, as well as those documented intraoperatively and those for which the pathology on cholecystectomy identifies disease greater than T1a, should be treated with a formal resection.
The resection should include the gallbladder bed (segments IVb and V) and a portahepatic, paraduodenal, and gastrohepatic ligament lymphadenectomy, as well as a bile duct resection if the disease extends to the cystic duct.
Disease that involves the gallbladder node is particularly curable and should be resected. Nodal disease beyond the pericholedochal (porta hepatis) nodes defines the surgically incurable patient.
The usual pattern of spread is locoregional, although lymphangitic metastasis can be observed for T3 and T4 disease. On the basis of retrospective data, some surgeons will perform radical surgery in T3 and T4 disease with intent to cure.
The rate of resectability is 15% to 20% for high bile duct tumors and up to 70% for distal lesions. Guidelines for surgery include the absence of retropancreatic and paraceliac nodal metastasis, noncontiguous liver metastasis, major vascular invasion, or extrahepatic invasion of adjacent organs. Some surgeons will attempt en bloc resection with vascular reconstruction.
Assessing resectability. High-resolution CT or MRI with biliary reconstruction may be supplemented with hepatic arteriography, portal venography, or duplex imaging preoperatively to assess resectability.
Preoperative treatments. Preoperative stenting for patients with jaundice caused by obstruction is controversial. Many surgeons find that placement of a biliary stent may confound imaging and impede surgery. This must be weighed against the benefit of relieving an obstruction and preventing infection (particularly if the biliary tree has been manipulated in the diagnostic evaluation). Three randomized trials have shown no benefit to preoperative decompression of the biliary tree in patients with obstructive jaundice. Some authors advocate the preoperative placement of biliary stents (non-metal) to facilitate dissection of the hilus. This procedure should be performed close to the planned resection to reduce the risk of cholangitis and maintain the duct at its maximally dilated size.
Proximal tumors. Local excision is often possible for proximal lesions. Hepatic resection is indicated for high bile duct tumors. Resection is not indicated in situations in which a clear surgical margin cannot be obtained.
Mid-ductal and distal tumors. Mid-ductal lesions can often be removed by resection of the bile duct with associated portal lymphadenectomy. Distal or mid-ductal lesions that cannot be locally excised should be removed by pancreaticoduodenectomy.
Reconstruction techniques. Biliary-enteric continuity is usually reconstructed with a Roux-en-Y anastomosis to the hilum for high lesions and in a standard drainage pattern following pancreaticoduodenectomy.
Liver transplant. This procedure has been attempted for unresectable tumors, but early recurrence and poor survival have prevented the widespread application of this approach. Protocols for transplant for patients with localized, unresectable disease who respond to neoadjuvant chemoradiation therapy are ongoing and promising in the highly select population. No comparative studies of patients treated with tranplant compared with best oncologic care (chemotherapy and radiation) are available.
Surgical bypass. For patients found to have unresectable disease at surgical exploration, operative biliary bypass may be performed using a variety of techniques. Bypass results in excellent palliation and obviates the need for further intervention.
Because of the rarity of biliary cancers, there is a paucity of prospective data to guide our practices. In the United States, gallbladder cancer commonly is treated with 5-FU and radiation after resection. A randomized trial performed in Japan showed that treatment with 5-FU and mitomycin(Drug information on mitomycin) produced a survival benefit in patients with resected gallbladder cancers. These data came from a planned subset of a larger trial in which 112 patients with gallbladder cancer were randomized. At 5 years, 26% of chemotherapy-treated patients were alive, compared with 14% of those treated with surgery and observation alone. On the basis of these data, consideration of chemotherapy for these patients is warranted, but definitive conclusions require a larger randomized trial. Two analyses using the SEER database have concluded that adjuvant radiochemotherapy may have a survival benefit for node-positive gallbladder cancer. One of these studies also found a benefit for tumors that were T2+.
For advanced, unresectable gallbladder cancer, palliation of obstructive jaundice and pain should be the goal. Combined-modality chemoradiation therapy may benefit patients with advanced disease. Regarding chemotherapy, many regimens that use oxaliplatin(Drug information on oxaliplatin) (Eloxatin) and gemcitabine(Drug information on gemcitabine) (Gemzar), as well as capecitabine(Drug information on capecitabine) (Xeloda) alone or in combination with cisplatin(Drug information on cisplatin) have been tried. Modest response rates are the norm, and the indolence or aggressiveness of the tumor primarily influences survival.
Delivery of adjuvant chemoradiotherapy is common for patients who have had margin-negative or microscopically positive margin resections, with observational series providing supporting evidence of improved outcomes. Chemoradiotherapy with infusional 5-FU or capecitabine is also given in the setting of positive regional lymph nodes. A meta-analysis by Horgan et al of 20 studies including more than 6,700 patients with either gallbladder or bile duct cancers concluded that adjuvant therapy with chemotherapy or chemoradiotherapy was superior to radiotherapy alone, with the greatest benefit in those with lymph node–positive and R1 disease.
The majority of patients present with unresectable disease, and palliative care is the goal of their management. Most of these patients experience a rapid decline in health. However, several chemotherapy regimens have shown promise for lengthening survival and are detailed in the Chemotherapy section.
There is considerable experience using brachytherapy alone or combined with external-beam radiation therapy for unresectable bile duct tumors. Median survival ranges from 10 to 24 months, and 5-year survival rates are approximately 10% with these approaches. Cholangitis, however, may occur more frequently in patients treated with brachytherapy.
Photodynamic therapy (PDT) in cholangiocarcinoma is an interesting option that may provide a significant survival benefit in addition to treating biliary stenosis and cholestasis and improving quality of life. A randomized trial of stenting alone vs stenting with PDT found a significantly longer median survival and improved quality of life in the PDT group. Although it is unlikely that all of the tumor was treated with PDT, this study did show the importance of local tumor control and its association with quality of life. As previously discussed, another palliative option is use of 90yttrium microspheres.
Biliary tract malignancies are uncommon, and the numbers of clinical trials and of patients in those trials are limited. Generally speaking, responses to chemotherapy are infrequent and brief. However, newer drugs and drug combinations are better tolerated and stand to improve on past results.
5-FU. This drug has historically been the most active single agent, with single-agent response rates in the 10% to 20% range.
Capecitabine. This prodrug of 5-FU (see "Colon, Rectal, and Anal Cancers" chapter) produced responses in 4 of 8 cases of gallbladder cancer but in only 1 of 18 cholangiocarcinomas in a phase II study presented by Hassan et al from the MD Anderson Cancer Center.
Gemcitabine. Multiple studies have documented gemcitabine as an active agent, particularly in gallbladder cancer.
Combination chemotherapy. Combined 5-FU and gemcitabine has modest activity in biliary malignancies. A group in Toronto published results of combination therapy with capecitabine and gemcitabine. The mix of cholangiocarcinoma and gallbladder cancer in the 45 patients studied was nearly 50-50. The overall response rate was 31%, and the median survival was a promising 14 months.
Valle et al followed up on the promising results of their phase II study with a randomized phase III study that compared cisplatin and gemcitabine combined with gemcitabine alone in patients with advanced biliary tract cancer. The median overall survival was 11.7 months in the cisplatin-gemcitabine group and 8.1 months in the gemcitabine-alone group. The median progression-free survival was 8 months in the combination group and 5 months in the gemcitabine-alone group. Adverse events were similar in both arms; however, neutropenia was more common in the cisplatin-gemcitabine group. This study demonstrated that cisplatin-gemcitabine combination therapy resulted in a significant survival advantage without substantial additional toxicity. Gruenberger et al investigated the efficacy and safety of cetuximab(Drug information on cetuximab) in combination with gemcitabine and oxaliplatin (GEMOX) in a phase II study. The overall response rate was 63%, including 10% complete responses and 53% partial responses. Thirty percent of patients were able to undergo secondary curative resection after major response to therapy. The median overall survival was 15.2 months and the median progression-free survival was 8.8 months for all treated patients, including those who underwent secondary resection.
Sidebar: A Japanese phase II study compared gemcitabine plus S-1 (GS), an oral fluoropyrimidine, with S-1 alone in patients with advance biliary tract cancers. The median overall survival was 12.5 months vs 9 months and the median progression-free survival was 7.1 months vs 4.2 months in the GS and S-1 arms, respectively. Grade 3/4 adverse events were infrequent and reversible in both arms of the study. The authors suggest that the GS arm deserves to be compared with gemcitabine plus cisplatin in a phase III study (Morizane C et al: J Clin Oncol 30[4s]:abstract 255, 2012).
Targeted Therapies. There are several studies looking at the use of targeted biologic agents that have shown varying degrees of promise. Biliary tract cancers can overexpress EGFR and VEGF. Therefore, a multicenter phase II study by Lubner et al was done with daily erlotinib and bevacizumab(Drug information on bevacizumab) given every 2 weeks in patients with unresectable cholangiocarcinoma or gallbladder carcinoma. Median overall survival was 9.9 months and time to progression was 4.4 months. Partial response was seen in 12% of the patients and stable disease was seen in 51% of patients. The partial response and stable disease rate of 64% is comparable to that for gemcitabine-based regimens. Molecular analysis showed that KRAS mutants are less likely to respond to erlotinib therapy than are other tumor types. Few grade 3/4 adverse events were seen with this combination of drugs. MEK has been studied as potential target given the important role of the RAS/RAF/MEK cascade in tumor formation. Selumetinib is a potent, oral small-molecule inhibitor of MAPK and MEK1/2. A multicenter phase II study by Bekaii-Saab et al was done with selumetinib in patients with advanced biliary tract cancers. Twelve percent of patients had an objective response. However, 68% of patients experienced stable disease, with 56% having prolonged stable disease for more than 16 weeks. The median progression-free survival was 3.7 months and the median overall survival was 9.8 months. Toxicities were mild, with rash and xerostomia being most common.
Sidebar: A phase II study was conducted using a combination of sorafenib(Drug information on sorafenib) and erlotinib in patients with advanced gallbladder cancer or cholangiocarcinoma. Eligible patients were given continuous sorafenib 400 mg PO twice daily and erlotinib 100 mg PO daily. This was a two-stage study with the primary endpoint being improvement in progression-free survival. Only 7% had a partial response and 27% had stable disease. The median progression-free survival was 2 months and the median overall survival was 6 months. The study failed to meets its primary endpoint and was terminated (El-Khoueiry AB et al: J Clin Oncol 30[s]:abstract 4113, 2012).
Hepatic arterial chemotherapy. There is limited experience with hepatic arterial chemotherapy for biliary tract neoplasms, but there are case reports of responses to floxuridine in the literature.
Treatment recommendations. In the absence of a clinical trial, patients should be offered gemcitabine with cisplatin because of the survival advantage seen with this combination.