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

Dr. Kozuch and coauthors have written a comprehensive review of gallbladder and biliary tract carcinoma. We would like to update several issues related to this topic, with particular emphasis on new chemotherapy strategies and drug combinations for improving outcomes.

Fluorouracil, Gemcitabine(Drug information on gemcitabine), and Capecitabine(Drug information on capecitabine)
First-line treatment with fluorouracil(Drug information on fluorouracil) (5-FU) has been used in this setting for 30 years. Response rates range from 0% to 24%. Gemcitabine (Gemzar) monotherapy has also been studied and produces an overall response rate of up to 60%. With highdose gemcitabine (2,200 mg/m² every 2 weeks), the partial response rate was 22% and median overall survival was 11.5 months. Lozano et al[1] studied single-agent capecitabine (Xeloda), an orally administered prodrug of 5-FU. At 2,000 mg/m²/d, capecitabine produced a 50% response rate and up to a 70% 1-year overall survival rate in hepatobiliary cancer patients.

A phase II trial of gemcitabine and capecitabine in patients with unresectable or metastatic cholangiocarcinoma is being conducted by the Southwest Oncology Group (SWOG).[2] The starting dose of capecitabine is 650 mg/m² bid, which is subsequently reduced to 162 mg/m², based on toxicity and renal function. The starting dose of gemcitabine is 1,000 mg/m², which is reduced to 250 mg/m². The results of this trial will help us to understand the effectiveness and toxicity profile of capecitabine in combination with gemcitabine in patients with unresectable cholangiocarcinoma.

Epidermal Growth Factor Receptor Inhibitors
Overexpression of the epidermal growth factor receptor (EGFR) in hepatobiliary cancer has been reported.[ 3] The EGFR pathway appears to be an important regulator of cell growth in hepatobiliary cell lines. Activation of EGFR and its ligand, transforming growth factor (TGF)-alpha, initiates a series of signal transduction cascades that include mitogen-activated protein kinase (MAPK), Akt, and other enzymes. EGFR expression by tumor cells has been linked with aggressive tumor growth, disease progression, poor survival, and poor response to therapy.

Because there is no standard therapy set up for unresectable metastatic biliary cholangiocarcinoma and the prognosis remains dismal, agents that inhibit the EGFR pathway represent a potentially promising strategy for the treatment of hepatobiliary cancer. Philip et al evaluated the EGFR inhibitor erlotinib (OSI-774, Tarceva) in advanced biliary carcinoma, and Ramanathan et al examined the ability of GW572016 to inhibit EGFR overexpression in hepatobiliary cancer patients.

GW572016 has been shown to inhibit extracellular signal-regulated kinases 1 and 2 (ERK1/2 ) and Akt phosphorylation in both EGFR- and erbB2-expressing cell lines.[4] The ability of GW572016 to inhibit Akt phosphorylation is associated with a 23-fold increase in cell control. Treatment with GW572016 has resulted in the inhibition of cell proliferation and apoptosis. Tumor types in which GW572016 has produced an objective response or stable disease include breast, colon, colorectal, ovary, lung, and head and neck carcinomas. Cardiac dysfunction has been seen among patients receiving GW572016; therefore, only patients with normal leftventricular ejection function (LVEF) are eligible for investigations of this agent, and patients undergo LVEF monitoring during such trials.

In a phase I study with GW572016, hepatic toxicity was mild and not doselimiting- an important consideration in patients with hepatobiliary cancer. Hematologic toxicity including thrombocytopenia was also mild, thus offering significant advantages. The starting dose of GW572016 in the current trial is 1,500 mg/d, with dose reduction to 750 mg per day. This protocol is currently open for accrual.

3-AP
Recently, 3-AP (Triapine)-a small molecule that inhibits ribonucleotide reductase-combined with gemcitabine (Gemzar) showed promising results in a clinical phase II study in gallbladder cancer and cholangiocarcinoma patients, conducted by Scott Wadler and the California Cancer Consortium for the Cancer Therapy Evaluation Program of the National Cancer Institute. The 3-AP dose was 105 mg/m² given as a 4-hour IV infusion on days 1, 8, and 15; the gemcitabine dose was 1,000 mg/m² given as a 30-minute IV infusion 1 hour after completion of 3-AP on days 1, 8, and 15; and each cycle lasted 28 days.

In addition to regulating DNA synthesis, ribonucleotide reductase is strongly correlated with the malignant potentials of the cells and acts as an oncogene. Overexpression of the ribonucleotide reductase M2 subunit leads to cell transformation and growth with overexpression of ornithine decarboxylase, myc, V-src, and raf oncogene. Overexpression of the M2 subunit also results in increased raf-1 membrane-associated protein and mitogene-activated kinase activities.

3-AP has been shown to have extremely potent antitumor effects both in vitro and in vivo. A phase I study conducted at the City of Hope identified the maximum tolerated dose to be 105 mg/m². Dose-limiting toxicities included neutropenia, thrombocytopenia, dyspnea, and reversible hypertension. 3-AP has been shown to enhance the cellular uptake and DNA incorporation of gemcitabine in kappaB-expressing tumor cell lines. In the phase I study, 3-AP in combination with gemcitabine produced a complete response in one patient diagnosed with an unknown primary metastatic to the head of the pancreas and liver (presumably cholangiocarcinoma). A phase II trial is being conducted in patients with unresectable gallbladder, bile duct, and ampulla carcinoma to test the efficacy of this combination.

Other Emerging New Agents
Given the absence of standard therapeutic guidelines for the disease, cholangiocarcinoma remains one of the most challenging of all human cancers. Potential future therapies may emerge from research with new agents such as bevacizumab(Drug information on bevacizumab) (Avastin), which, in combination with IV 5-FU- based chemotherapy, was recently approved by the US Food and Drug Administration for the first-line treatment of patients with metastatic colorectal cancer. Bevacizumab inhibits vascular endothelial growth factor (VEGF) and other promoters of angiogenesis and may significantly improve response rates or inhibit tumor growth. Cholangiocarcinoma has been known to increase activation of cyclooxygenase (COX)-2 and receptor tyrosine kinase, both of which play a role in the angiogenesis pathway. Gefitinib(Drug information on gefitinib) (Iressa), an inhibitor of intracellular tyrosine kinase that is thought to significantly block the EGFR pathway of tumor growth, regardless of EGFR receptor bindings. Gefitinib has already been approved for use in non-small-cell lung cancer, and possible use of the agent in cholangiocarcinoma seems rational.

Cetuximab (Erbitux) was recently approved for colorectal cancer and can also be considered as a potential agent in cholangiocarcinoma. Cetuximab(Drug information on cetuximab) targets EGFR on the surface of cancer cells, interfering with tumor growth. In colorectal cancer patients who received cetuximab alone, the tumor response rate was 10.8%. About 3% of patients experienced a severe infusion reaction characterized by rapid onset of airway obstruction, skin rashes, and hypotension. These agents appear to play a promising role in the treatment of cholangiocarcinoma in combination with either chemotherapy or radiation.

Surgical Considerations
The successful surgical treatment of gallbladder cancer is dependent on the preoperative diagnosis of the disease. Given the large number of cholecystectomies performed each year for symptomatic gallbladder disease, a major contribution toward curing these rare carcinomas can be made by surgeons and radiologists. Although the disease is especially rare in patients with asymptomatic gallbladder lesions, they should also be scrutinized for the presence of gallbladder cancer.

Notes from the radiologist that a solitary mass greater than 1 cm presumed to be a nonmobile, noncalcified single stone may well be a gallbladder tumor will set in motion an approach to differential diagnosis for the surgeon. First, a confirmatory computed tomography (CT) scan can be scheduled and reviewed before any surgical intervention is planned. As the plans for removal are considered, the surgeon can assess his or her ability to perform the appropriate resection of the gallbladder and liver bed with a portal node dissection. At the time of exploration, examination of the gallbladder and the surrounding liver bed can avoid an untoward laparoscopic resection. If the gallbladder has severe inflammatory changes, thickening, retraction, or a tumor-like appearance (hard, sclerotic), an open resection should be employed. These findings are particularly worrisome if the clinical appearance suggests a con condition very different from the clinical symptoms. This sequence of steps will avoid the unfortunate scenario of a laparoscopic cholecystectomy that contaminates the surgical field and abdomen. Finally, the patient can be informed of the possibility that the same-day laparoscopic surgery may be replaced by a more complex, higher-risk open operation.

For bile duct tumors, careful assessment of the extent of disease is critical. The major difficulties with curative resection are related to multiplicity of lesions and extent of the disease within the porta hepatitis. As the disease progresses, it often does so by infiltrating throughout the surrounding tissue, creating a sclerotic reaction and extensions of tumor. The tumor reaction is often difficult to differentiate from the cellular inflammatory reaction of the previously placed biliary stent. Intraoperative assessment of infiltration is a challenge and requires a skilled surgeon and pathologist to select patients for extensive resections with an expectation of negative margins. As the tumor grows into the liver from the bifurcation of the bile ducts, the ductal size becomes smaller and the number larger, reflecting the arborized level of the biliary system. Although still a "doable" operation, the morbidity of the reconstitution of the biliary drainage is increased and likelihood of a negative margin is reduced.

In summary, the surgical treatment of these tumors requires a meticulous preoperative analysis, technical expertise to perform the intraoperative assessment, and advanced surgical skills to perform the extirpation.