Liver, Gallbladder, and Biliary Tract Cancers

April 17, 2009

Hepatocellular carcinoma is one of the most common malignancies in the world, with approximately 1 million new cases recorded annually.

HEPATOCELLULAR CANCER

Hepatocellular carcinoma is one of the most common malignancies in the world, with approximately 1 million new cases recorded annually.

Epidemiology

Gender Hepatocellular carcinoma is the most common tumor in males worldwide, with a male-to-female ratio of 5:1 in Asia and 2:1 in the United States.

Geography Tumor incidence varies significantly, depending on geographic location. In the United States, hepatocellular carcinoma represents < 2% of all tumors, whereas in the Far East and sub-Saharan Africa, this neoplasm occurs at an incidence of 150 per 100,000 population and comprises almost 50% of all diagnosed tumors. A study analyzing SEER (Surveillance, Epidemiology, and End Results) data has shown that the incidence of hepatocellular carcinoma is rising in both white and black populations in the United States, with a current incidence of about 3.4 cases per 100,000 in whites and 5.6 per 100,000 in blacks. Modeling of the spread of hepatitis C virus (HCV) suggests that this number may continue to increase dramatically.

Age The incidence of hepatocellular cancer increases with age. The mean age at diagnosis is 53 years in Asia and 67 years in the United States.

Race The incidence of hepatocellular tumors is higher in Asian immigrants and blacks than in whites.

Survival In patients who undergo curative resection, the 5-year survival rate is approximately 20%–90% depending on initial stage and functional liver status. Recurrence is common, with metastases arising in the remaining liver, lungs, bone, kidneys, and heart. Most patients present with unresectable disease. Patients with unimpaired liver function who can undergo resection may experience significantly longer survival than those whose disease is not resected.

Etiology and risk factors

Hepatitis B The close geographic relationship between hepatitis B incidence and hepatocellular carcinoma rates is well recognized. In endemic areas of hepatitis B, approximately 90% of all patients with hepatocellular carcinoma are positive for hepatitis B surface antigen (HBsAg). The presence of the hepatitis B “e” antigen has been found to increase risk ninefold. The most compelling epidemiologic evidence of a causal relationship between hepatitis B infection and hepatocellular carcinoma is the observation of a significant decline in the incidence of childhood hepatocellular carcinoma after the introduction of a national immunization program in Taiwan. The hepatitis B “x” gene, which can interact with p53, has been a focus of study on the pathogenesis of hepatocellular carcinoma.

Hepatitis C has also been implicated in hepatocellular carcinoma development. The molecular mechanisms of HCV infection and carcinogenesis are poorly understood. Unlike patients with hepatitis B infection, patients with hepatocellular carcinoma infected with hepatitis C usually have cirrhotic livers at diagnosis; this finding suggests an extended period of infection (or hepatic damage) before malignancy develops.

Alcohol Patients with alcoholic cirrhosis are at risk for hepatocellular carcinoma, but the addition of HCV infection increases that risk dramatically.

Other possible etiologies include aflatoxin, hemochromatosis, hepatic venous obstruction, thorotrast (a contrast agent no longer used for radiologic procedures), androgens, estrogens, and α1-antitrypsin deficiency.

Prevention A large 5-year randomized study performed in China has confirmed that treatment of chronic hepatitis B infection with the antiviral lamivudine not only decreases the risk of progression to cirrhosis of the liver but also decreases the rate of progression to hepatocellular cancer. Treated patients had a 3.9% risk of hepatocellular cancer over 5 years, compared with 7.4% for those in the placebo group (hazard ratio: 0.49; P = 0.047.

Signs and symptoms

Nonspecific symptoms Patients usually present with abdominal pain and other vague symptoms, including malaise, fever, chills, anorexia, weight loss, and jaundice.

Physical findings An abdominal mass is noted on physical examination in one-third of patients. Less common findings include splenomegaly, ascites, abdominal tenderness, muscle wasting, and spider nevi. Up to 10% of patients may present with an acute abdomen due to a ruptured tumor.

Screening and diagnosis

Presently, no organization recommends routine screening of average-risk, asymptomatic adults for liver, gallbladder, and biliary tract cancers.

α-Fetoprotein is produced by 70% of hepatocellular carcinomas. The normal range for this serum marker is 0–20 ng/mL, and a level > 200 ng/mL is essentially diagnostic for hepatocellular cancer in the absence of chronic, active hepatitis B infection. In the presence of active hepatitis B infection, the diagnostic cutoff is considered to be at least 1,000 ng/mL. In the setting of hepatitis C infection, the cutoff for diagnosis of hepatocellular carcinoma has not been well studied. In hepatitis C, values > 200 ng/mL appear to be highly predictive of hepatocellular carcinoma. False-positive results may be due to acute or chronic hepatitis, germ-cell tumors, or pregnancy. In its guidelines for diagnosis of hepatic masses suspicious for hepatocellular carcinomas, the National Comprehensive Cancer Network (NCCN) does not recommend biopsy for patients with an α-fetoprotein level > 400 ng/mL, except in the presence of HBsAg positivity. In that situation, a cutoff value of 4,000 ng/mL is recommended for biopsy.

Hepatitis B and C Given the association between hepatitis B and C and hepatocellular cancer, blood should be sent for hepatitis B and C antigen and antibody determinations.

Imaging The initial diagnostic test in the symptomatic patient may be ultrasonography, as it is noninvasive and can detect lesions as small as 1 cm. Ultrasound findings should be followed up with more specific imaging.

Triple-phase, high-resolution CT and contrast-enhanced MRI are the primary imaging modalities used to diagnose and stage hepatocellular carcinoma. Recent reports have documented a high number of false-positive results with CT angioportography (CTAP) and CT hepatic angiography (CTHA). CT scan predicts resectability in only 40%–50% of cases and does not accurately determine the functional extent of cirrhosis. Major difficulties arise when the liver parenchyma is not homogeneous and the lesions are smaller than 1 cm.

Laparoscopy is useful for the evaluation of small tumors, the extent of cirrhosis, peritoneal seeding, and the volume of noninvolved liver and therefore may be used prior to open laparotomy for resection. Laparoscopic or intraoperative ultrasonography should be used to confirm preoperative imaging tests. The laparoscopic results may change surgical management in up to one-third of selected patients.

High-risk patients should be screened for hepatocellular carcinoma using ultrasonography and serum α-fetoprotein levels. At present, however, there is no standard screening interval, and screening has not been shown to affect survival. Data suggest that, for screened patients, there is an increase in the proportion of cancers that are resectable. A study comparing 6-month and 12-month survival intervals in a cohort of HCV-infected patients with hemophilia showed no substantial benefit to more frequent screening.

Pathology

Three morphologic patterns of hepatocellular carcinoma have been described: nodular, diffuse, and massive. Diffuse and massive types account for > 90% of cases. The nodular type usually has multiple lesions in both lobes.

Histologic arrangements Several histologic arrangements have been identified: trabecular, compact, pseudoglandular or acinar, clear cell, and a fibrolamellar variant, which is associated with a relatively favorable prognosis.

Staging and prognosis

The staging system for hepatocellular cancer is based on the number and size of lesions and the presence or absence of vascular invasion (Table 1). The Okuda staging system accounts for the degree of liver dysfunction and may better predict prognosis than the TNM stage. However, the Okuda staging system does not adequately predictresectability. Because of the limited value of standard staging, the most important factors determining survival are technical resectability of lesions and degree of dysfunction of the normal liver. Groups in Spain, Italy, and China have created prognostic indices that may prove useful for making treatment decisions.

Of the 5%–30% of patients who can undergo resection, factors associated with improved survival include curative resection, small tumor size, well-differentiated tumors, and normal performance status. Cirrhosis, nodal metastases, and an elevated prothrombin time are indicative of a poor prognosis, as are male sex, age > 50 years, poor performance status, duration of symptoms < 3 months, tumor rupture, aneuploidy, high DNA synthesis rate, hypocalcemia, vascular invasion, and a high serum α-fetoprotein level.

Treatment

SURGERY

Surgery is the form of treatment that offers the greatest potential for cure, even though only a small minority of patients will actually be cured. Unfortunately, many patients whose disease is thought to be resectable are clinically understaged preoperatively.

Only stage I or II tumors have a significant likelihood of being resectable for cure. However, a large tumor may still be potentially resectable for cure. Moreover, contiguous involvement of large vessels (including the portal vein and inferior vena cava) or bile ducts does not automatically mitigate against a resection, especially in patients with a fibrolamellar histology, although such resections are considerably more difficult.

Bilobar disease may be addressed with formal resection, tumor ablation techniques (eg, cryoablation, radiofrequency ablation, and ethanol injection ablation), or a combination of the two modalities.

Contraindications to resection include imminent clinical hepatic failure (jaundice in the absence of biliary obstruction), hypoalbuminemia, ascites, renal insufficiency, hypoglycemia, prolongation of the prothrombin and partial thromboplastin times, main portal vein involvement, extrahepatic metastatic disease, or other comorbid diseases that would preclude surgery of any kind.

Noncirrhotic vs cirrhotic patients Resection should be performed in all noncirrhotic patients when feasible. Resection of hepatocellular carcinoma in the presence of cirrhosis is more controversial due to its increased morbidity in this setting. Cirrhosis has been a major deterrent to resection in western nations. Resectability rates vary from 0%–43% for cirrhotic patients, whereas up to 60% of patients without cirrhosis undergo resection. Use of the modified Child-Pugh classification of liver reserve may guide the surgeon in preoperative assessment of liver function status and may aid in the selection
of operable patients.

When resection is performed in the presence of cirrhosis, Child class A patients fare better than Child class B or C patients. Survival rates at 5 years following resection range from 4% to 36%, with noncirrhotic patients living longer than cirrhotic patients.

Transplantation Owing to the risk of hepatic failure following resection in cirrhotic patients, transplantation has become an option for patients with hepatocellular cancer and cirrhosis. In a

study of 181 patients with hepatocellular carcinoma, Starzl and Iwatsuki found similar overall 5-year survival rates in patients treated with transplantation vs resection (36% vs 33%). Survival rates were similar in the two groups when tumors were compared for TNM stage. However, survival was significantly improved in patients with concomitant cirrhosis if they were treated with transplantation. Tumor recurrence rates for stages II and III tumors were significantly lower after transplantation than after resection, but no differences were seen for stage IV tumors.

Patients with cirrhosis and single tumors < 5 cm or multiple tumors (up to 3 with none > 3 cm) can be considered for transplantation. Larger tumors may be treated with resection when feasible. Chemoembolization followed by transplantation may be considered in selected patients. The use of transplantation is significantly limited by the scarcity and lack of immediate availability of donor organs. Recently, changes in the organ allocation system have decreased waiting times for patients with documented hepatocellular cancer.

NON-RESECTIONAL THERAPIES

Given the high risk of recurrence after resection, the multifocal nature of hepatocellular carcinoma, and its association with chronic liver disease, nonresectional therapies can play an important role in management. A number of prognostic factors have been identified for patients with unresectable hepatocellular carcinoma. These factors, taken alone, can have a great effect on survival rates, making cross-treatment comparisons more difficult because considerable selection bias may be present in any nonrandomized trial. Additionally, comparisons are difficult, as there are few randomized trials among the large number of non-resectional, liver-directed therapies currently available.

Radiation therapy

Adjuvant treatment Intrahepatic recurrence has been observed in up to two-thirds of patients treated with partial hepatectomy for hepatocellular carcinoma. Such a recurrence may represent growth at the resected edge, metastatic disease, or a new primary tumor. There is no evidence, however, that adjuvant radiation therapy can reduce this risk.

Unresectable disease Whole-liver radiation therapy can provide palliation in patients with unresectable tumors but is limited to a total dose of ≤ 30 Gy due to the risk of radiation-induced liver disease. Whole-liver irradiation has been combined with chemotherapy and transcatheter arterial chemoembolization, with objective response rates of approximately 40%–50% and median survival rates of about 18 months. Patients with tumor regrowth after chemoembolization may respond to radiotherapy.

Radiation therapy has also been delivered using yttrium-90 microspheres infused via the hepatic artery. This approach has encouraging response rates and a low toxicity profile and may be complementary with other forms of therapy.

Three-dimensional conformal radiation therapy treatment planning can allow patients with nondiffuse disease to be safely irradiated to doses well above the whole-liver tolerance dose, with doses up to 90 Gy given safely to selected patients and a response rate of 40%, with a median survival of 15 months.

Multiple institutions have reported response rates as high as 90% with acceptable toxicity when conformal radiation therapy was combined with transcatheter arterial chemoembolization (TACE). Good response and local control rates have also been reported for proton, carbon ion, and stereotactic radiotherapy.

Hepatic TACE

Normal hepatocytes receive most of their blood supply from the portal vein, whereas tumors create new blood vessels from branches of the hepatic arterial system. This target is exploited by

embolization of the hepatic artery with any number of substances, resulting in radiographic response rates in about 50% of patients and evidence of tumor liquefaction in over two-thirds of patients. Embolization is accomplished by advancing a catheter within the tumor-feeding branch of the hepatic artery. Materials injected have included Gelfoam powder, polyvinyl alcohol, iodized oil (Lipiodol), collagen, and autologous blood clot. Chemoembolization should be reserved for symptomatic tumors, reducing tumor size for resection or ablation, or as a bridge while awaiting transplant.

The effect of TACE on survival remains controversial, with randomized studies returning mixed results. A randomized, controlled trial in Spain was stopped early due to a survival benefit. Meta-analysis of studies does indicate a positive impact on overall survival.

Intratumoral ethanol injection

The direct injection of 95% ethanol into a neoplastic lesion causes cellular dehydration and coagulation necrosis. Intratumoral ethanol ablation is employed via a percutaneous route under ultrasonographic guidance. Percutaneous intratumoral ethanol injection is best suited for use in patients with few lesions, each < 5 cm, although larger lesions may be injected multiple times.

Although intratumoral ethanol injection appears to be an effective palliative modality in certain patients, its effect on patient survival is unclear.

CRYOTHERAPY AND RADIOFREQUENCY ABLATION

Similar to ethanol ablation, cryotherapy and radiofrequency ablation (RFA) techniques are suitable for treatment of localized disease. Cryotherapy has been used intraoperatively to ablate small solitary tumors outside a planned resection (ie, in patients with bilobar disease). Cryotherapy must be performed using laparotomy, which limits its use in the palliative setting. RFA can be performed either via laparotomy or percutaneously and has limitations similar to those of ethanol ablation. As with ethanol ablation, there are no data about a survival advantage with these therapies, which may prove to be most useful for temporary tumor control in patients awaiting liver transplants. A randomized trial comparing RFA with ethanol injection found a significant benefit to RFA for local recurrence-free survival (96% vs 62% at 2 years) but not for overall survival (98% vs 88%).

A cautionary note regarding percutaneous RFA has been raised by publication of a report from Barcelona, citing 4 of 32 patients in a series who developed needle-track tumor seeding relating to subcapsular tumor location and poorly differentiated tumors.

Chemotherapy

Systemically administered chemotherapy has, for the most part, been disappointing in patients with hepatocellular carcinoma. This fact relates to both low rates of response to available agents and to difficulty with toxicity for modestly active agents because of liver dysfunction. Agents with partial response rates near or above 10% include doxorubicin, fluorouracil (5-FU), and cisplatin. Two newer agents, oxaliplatin (Eloxatin) and gemcitabine (Gemzar), which do not require liver metabolism or excretion, have garnered some interest. Both agents appear to be more active when partnered with a second agent, but results from phase II combination studies are mixed.

Hepatic arterial infusion (HAI) Use of HAI, principally floxuridine (fluorodeoxyuridine [FUDR]), has good biologic rationale but is hampered by high rates of biliary complications and the requirement for surgical pump placement in patients who are generally poor surgical candidates. A meta-analysis concluded that HAI after curative liver resection improved survival significantly at both 2 (23% benefit) and 3 (28% benefit) years.

Biologic therapy Interferon-alpha (IFN-α) has been shown to have potential beneficial effects in prevention of hepatocellular carcinoma; however, recent randomized studies have failed to show a benefit in patients with preexisting cirrhosis and advanced cancers. Adjuvant interferon, however, was associated with a reduction in recurrence in two small randomized trials. This finding needs to be confirmed in a much larger trial. Moderate-to-high doses of interferon are poorly tolerated by patients with frankly cirrhotic livers.

Biochemotherapy Results of combination biochemotherapy in a study of 154 patients by Leung et al were encouraging. Using a combination of cisplatin, interferon-α-2a (Roferon-A), doxorubicin, and 5-FU for 4 days out of 28 days, resulted in a response rate of around 20%. Moreover, 10% of patients whose tumors were initially thought to be unresectable subsequently underwent complete resection. Eight of these patients had documented pathologic complete remissions. A phase III study of PIAF (cisplatin [Platinol]/interferon-α-2b/doxorubicin[Adriamycin]/5-FU) versus single-agent doxorubicin has confirmed a higher response rate for PIAF, but survival was not significantly better than with doxorubicin. Of note, all patients in this series had hepatitis B-associated hepatocellular carcinoma. Patt et al have studied a less-toxic regimen of continuous 5-FU with interferon-α-2b, demonstrating a median survival of 15.5 months.

Targeted therapies

A group led by Philip at Karmanos Cancer Institute has reported results of a phase II trial of the epidermal growth factor receptor (EGFR)-targeting agent erlotinib (Tarceva) in HCC and biliary tumors. Erlotinib was administered orally, 150 mg daily, to 35 patients with HCC. The response rate was only 9%, but OS for the group was an encouraging 13 months.

Sorafenib (Nexavar), an inhibitor of RAF and VEGF kinases, was recently demonstrated to be the first systemic agent to convinicingly improve survival in a placebo-controlled randomized study. This now represents standard of care for patients with advanced disease that is not amenable to locoregional therapy such as embolization. Studies in conjunction with embolization are already underway. The drug is the first approved for this indication by the FDA.

BILIARY TRACT CANCERS

Gallbladder carcinoma is diagnosed approximately 5,000 times a year in the United States, making it the most common biliary tract tumor and the fifth most common GI tract cancer. Approximately 4,500 cases of bile duct tumors occur each year in the United States.

Epidemiology

GALLBLADDER CANCER

Gender Women are more commonly afflicted with gallbladder cancer than are men, with a female-to-male ratio of 1.7:1.

Age The median age at presentation of gallbladder cancer is 73 years.

Race An incidence five to six times that of the general population is seen in southwestern Native Americans, Hispanics, and Alaskans.

BILE DUCT CANCER

Gender Bile duct tumors are found in an equal number of men and women.

Age Extrahepatic bile duct tumors occur primarily in older individuals; the median age at diagnosis is 70 years.

Etiology and risk factors

GALLBLADDER CANCER

The risk of developing gallbladder cancer is higher in patients with cholelithiasis or calcified gallbladders and in typhoid carriers.

BILE DUCT CANCER

Ulcerative colitis is a clear risk factor for bile duct tumors. Patients with ulcerative colitis have an incidence of bile duct cancer that is 9-21 times higher than that of the general population. This risk does not decline after total colectomy for ulcerative colitis.

Other risk factors Primary sclerosing cholangitis, congenital anomalies of the pancreaticobiliary tree, and parasitic infections are also associated with bile duct tumors. No association of bile duct cancer with calculi, infection, or chronic obstruction has been found.

Signs and symptoms

GALLBLADDER CANCER

Early disease In the early stages, gallbladder cancer is usually asymptomatic.

Late disease Later, symptoms similar to those of benign gallbladder disease arise; they include right upper quadrant pain, nausea, vomiting, fatty food intolerance, anorexia, jaundice, and weight loss. This nonspecificity of symptoms delays presentation for medical attention and contributes to the low curability of gallbladder cancer.

Physical findings may include tenderness, an abdominal mass, hepatomegaly, jaundice, fever, and ascites.

BILE DUCT CANCER

Jaundice is the most frequent symptom found in patients with high bile duct tumors; it is present in up to 98% of such patients.

Nonspecific signs and symptoms Patients who do not present with jaundice have vague complaints, including abdominal pain, weight loss, pruritus, fever, and an abdominal mass.

Diagnosis

GALLBLADDER CANCER

Gallbladder carcinomas are often diagnosed at an advanced stage, such that by the time symptoms have developed, most tumors are unresectable.

Laboratory values in patients with gallbladder carcinoma are nonspecific but may include anemia, leukocytosis, and an elevated bilirubin level.

Ultrasonography is useful for defining a thickened gallbladder wall and may show tumor extension into the liver.

CT is more helpful than ultrasonography in assessing adenopathy and spread of disease into the liver, porta hepatis, or adjacent structures. MRI may be used to evaluate intrahepatic spread.

Endoscopic retrograde cholangiopancreatography (ERCP) or transhepatic cholangiography (THC) may be useful in the presence of jaundice to determine the location of biliary obstruction and involvement of the liver.


 

BILE DUCT CANCER

Cholangiocarcinoma may present earlier than gallbladder cancer by virtue of the development of biliary obstruction with jaundice, which may be painless. Tissue confirmation of suspected bile duct cancer can be difficult. The goals of the diagnostic evaluation include the determination of the level and extent of obstruction, the extent of local invasion of disease, and the identification of metastases.

Many patients with cholangiocarcinoma are thought to have metastatic adenocarcinoma of an unknown primary, although occasionally the metastatic lesion may produce biliary dilatation without the primary lesion itself being radiographically visualized.

Ultrasonography It is generally accepted that ultrasonography should be the first imaging procedure in the evaluation of the jaundiced patient.

CT is a complementary test to ultrasonography, but both tests are accurate for staging in only 50% of patients and for determining resectability in < 45% of patients.

Cholangiography is essential to determine the location and nature of the obstruction. Percutaneous THC is used for proximal lesions, and ERCP is used for distal lesions. Magnetic resonance cholangiopancreatography (MRCP) may replace invasive studies in the near future. Histologic confirmation of tumor can be made in 45%–85% of patients with the use of exfoliative or brush cytology during cholangiography.

Pathology

GALLBLADDER CANCER

Histologic types Over 85% of gallbladder neoplasms are adenocarcinomas and the remaining 15% are squamous cell or mixed tumors.

Route of spread The initial route of spread of gallbladder cancer is locoregional rather than distant. For patients undergoing resection for presumed high-risk gallbladder masses or preoperatively defined disease limited to the gallbladder, 25% of patients will have lymphatic involvement and 70% will have direct extension of disease into the liver defined at operation.

BILE DUCT CANCER

Adenocarcinoma Morphologically, more than 90% of bile duct tumors are adenocarcinomas. Three macroscopic appearances have been identified: The papillary and nodular types occur more frequently in the distal bile duct, whereas the sclerosing type is found in the proximal bile duct. Patients with papillary lesions have the best prognosis.

Other histologic types Unusual malignant diseases of the biliary tract include adenosquamous carcinoma, leiomyosarcoma, and mucoepidermoid carcinoma.

Route of spread Most bile duct tumors grow slowly, spreading frequently by local extension and rarely by the hematogenous route. Nodal metastases are found in up to one-third of patients.

Staging and prognosis

GALLBLADDER CANCER

Gallbladder cancer is staged primarily at the time of surgery, and staging is determined by lymphatic involvement and extension of disease into adjacent structures (Table 2). 

Stage Survival of gallbladder carcinoma is directly related to disease stage. The 5-year survival rate is 83% for tumors that are confined to the gallbladder mucosa; this rate decreases to 33% if the tumor extends through the gallbladder. For patients who have involvement of the lymph nodes or metastatic disease, 5-year survival rates range from 0%–15%.

Type of therapy Median survival is also improved in patients who have undergone curative resection, as compared with those who have had palliative procedures or no surgery (17 months vs 6 and 3 months, respectively).

BILE DUCT CANCER

Over 70% of patients with cholangiocarcinoma present with local extension, lymph node involvement, or distant spread of disease. The AJCC (American Joint Committee on Cancer) staging system for extrahepatic tumors is shown in Table 3.

Stage Survival for these patients is poor and is directly related to disease stage. Median survival is 12–20 months for patients with disease limited to the bile ducts and ≤ 8 months when the disease has spread.

Tumor location Survival is also related to tumor location, with patients with distal lesions doing better than those with mid or proximal tumors.

Success of therapy Curative resection and negative margins result in improved survival.

Treatment

In the absence of polyps identified ultrasonographically and confirmed by CT during the work-up of suspected cholelithiasas, relatively few patients with gallbladder cancer are diagnosed prior

to surgery. Only 1%–2% of cholecystectomy specimens are found to contain malignancy.

SURGERY FOR GALLBLADDER CANCER

Surgical management of gallbladder carcinoma is based on the local extension of the tumor.

Early-stage disease Tumors that invade the mucosa, those that do not penetrate the muscularis, and those that penetrate full thickness but do not abut the liver or muscularis require cholecystectomy alone. Laparoscopic cholecystectomy may be adequate for T1 tumors. If there is direct extension of disease to or through the serosa, the resection should include the gallbladder bed (segments IVb and V) and a porta hepatis lymphadenectomy. 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.

SURGERY FOR BILE DUCT CANCER

The rate of resectability is 15%–20% for high bile duct tumors and up to 70% for distal lesions.

Assessing resectability Higher resolution CT or MRI with biliary reconstruction may be supplemented with hepatic arteriography, portal venography, or duplex imaging preoperatively to assess resectability.

Preoperative treatments 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 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 transplantation has been attempted for unresectable tumors, but early recurrence and poor survival have prevented the widespread application of this approach.

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.

ADJUVANT RADIATION THERAPY FOR BILIARY TRACT CANCER

A review of the patterns of initial disease recurrence after resection of gallbladder cancer (80 patients, in whom disease recurred in 53) and hilar cholangiocarcinoma (76 patients, in whom disease recurred in 52) found a distinct difference with regard to total locoregional failure versus total distant failure. Hilar cholangiocarcinomas were much more likely to include locoregional failure alone or as a component (65% of all failures), compared with gallbladder cancer (28% of all failures). Distant failure was found alone or as a component in 72% of all recurrences of gallbladder cancer but only in 36% of hilar cholangiocarcinomas.

ADJUVANT CHEMOTHERAPY

A randomized trial performed in Japan showed that treatment with 5-FU and mitomycin (Mutamycin) 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. Based on these data, consideration of chemotherapy for these patients is warranted, but definitive conclusions would require a larger randomized trial.

TREATMENT OF UNRESECTABLE DISEASE

Like pancreatic adenocarcinoma, unresectable biliary tract carcinoma has a poor prognosis.

Stenting

Many patients with unresectable disease, particularly those with pain, nausea, or pruritus, will benefit from nonsurgical percutaneous or endoscopic stenting.

Radiation therapy

There are few data on radiation therapy for unresectable gallbladder cancer, other than reports of intraoperative radiation therapy. External-beam radiation therapy would be anticipated to provide a palliative benefit.

There is considerable experience using brachytherapy alone or combined with external-beam radiation therapy for unresectable bile duct tumors. Median survival ranges from 10–24 months, and 5-year survival rates are approximately 10% with these approaches. Cholangitis, however, may occur more frequently in people treated with brachytherapy. A randomized trial of stenting alone versus with photodynamic therapy (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 control and its association with quality of life. Radiation therapy may also ultimately play a role in the promotion of viral replication for gene therapy.

Chemotherapy

Because biliary tract malignancies are uncommon cancers, the number of clinical trials and the number 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 has historically been the most active single agent, with single-agent response rates in the 10%–20% range.

Capecitabine (Xeloda), a prodrug of 5-FU (see chapter 16), produced responses in 4 of 8 gallbladder cancers but in only 1 of 18 cholangiocarcinomas in a phase II study presented by Hassan et al from M. D. Anderson Cancer Center.

Gemcitabine Multiple studies have documented gemcitabine as an active agent, particularly in gallbladder cancer. Cisplatin and gemcitabine may be a synergistic doublet, with reported response rates for gallbladder cancer in the range of 30%–50%.

Combination chemotherapy with both 5-FU and gemcitabine (Gemzar) have modest activity in biliary malignancies. A group in Toronto published results of combination therapy with capecitabine (Xeloda) 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. This regimen is a reasonable alternative to gemcitabine and cisplatin for biliary tract neoplasms.

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 and/or 5-FU (or capecitabine), with or without leucovorin. Other agents, such as doxorubicin or cisplatin, may be added, but, as noted, there is no unequivocal evidence that combination chemotherapy produces any substantial benefits in improving quality of life or survival.

SUGGESTED READING

ON HEPATOCELLULAR CARCINOMA

Ben-Josef E, Normolle D, Ensminger WD, et al: Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol 23:8739–8747, 2005.

Gupta S, Bent S, Kohlwes J: Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C: A systematic review and critical analysis. Ann Intern Med 139:46–50, 2003.

Hashimoto T, Tokuuye K, Fukumitsu N, et al: Repeated proton beam therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 65:196–202, 2006.

Llovet J, Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 37:429–442, 2003.

Mathurin P, Raynard B, Dharancy S, et al: Meta-analysis: Evaluation of adjuvant therapy after curative liver resection for hepatocellular carcinoma. Aliment Pharmacol Ther 17:1247–1261, 2003.

Mok TS, Yeo W, Yu S, et al: An intensive surveillance program detected a high incidence of hepatocellular carcinoma among hepatitis B virus carriers with abnormal alpha-fetoprotein levels or abdominal ultrasonography results. J Clin Oncol 23:8041–8047, 2005.

Yao FY, Bass NM, Ascher NL, et al: Liver transplantation for hepatocellular carcinoma: Lessons from the first year under the Model of End-Stage Liver Disease (MELD) organ allocation policy. Liver Transpl 10:621–630, 2004.

Yeo W, Mok TS, Zee B, et al: A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable heaptocellular carcinoma. J Natl Cancer Inst 97:1532–1538, 2005.

ON GALLBLADDER TUMORS

Doval DC, Sekhon JS, Gupta SK, et al: A phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer. Br J Cancer 90:1516–1520, 2004.

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ON BILE DUCT TUMORS

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