This article summarizes the current literature in treatment of unresectable biliary tract and primary liver tumors. Locoregional therapies including radiofrequency ablation, percutaneous ethanol injection, cryoablation, microwave ablation, transarterial chemoembolization, hepatic artery infusion, radioembolization ( 90 Y), and bland embolization are discussed and clinical trials compared. Palliative strategies including surgical, percutaneous, and endoscopic techniques to decompress the biliary system and improve symptoms are also summarized. Systemic chemotherapy and sorafenib used in conjunction with locoregional therapies or as sole therapeutic options are discussed.
Key points
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Hepatocellular carcinoma and cholangiocarcinoma are frequently unresectable because of advanced local disease.
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Patients with unresectable tumors may be amenable to ablation techniques administered through multiple routes and techniques of administration.
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Palliation should also include restoring biliary drainage, pain management, improving nutritional status and fat absorption, and improving pruritus.
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Systemic chemotherapy and sorafenib are palliative options used in conjunction with locoregional therapies or as sole therapeutic options.
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) account for nearly all primary liver tumors. Resection is the most effective therapy for both tumors but is frequently not possible, often because of advanced local disease. Patients with unresectable tumors have a poor prognosis, with median survival often 3 to 6 months. Although several treatment options exist, these are not curative approaches and rather palliative.
HCC is the most common primary liver tumor, representing 90% of primary liver cancers. Cirrhosis is associated with HCC in almost 90% of the cases. Chronic hepatitis B virus and hepatitis C virus contribute to HCC development in approximately 80% of cases. The mean annual incidence of HCC in cirrhotic patients is 3% to 4%, and this figure increases proportionally with liver function impairment. Less than 20% of these tumors are amenable to definitive surgical management, because of advanced intrahepatic disease or other medical conditions that prohibit major surgery. Locoregional therapies have been recommended in patients with HCC as a form of palliation. Locoregional therapies include radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), cryoablation, microwave ablation, transarterial chemoembolization (TACE), hepatic artery infusion (HAI), radioembolization ( 90 Y), and bland embolization.
CCA is the second most common primary liver cancer after HCC and comprises 10% of primary liver cancers. CCA can be subdivided into cancers affecting the intrahepatic, perihilar, and extrahepatic biliary tree. At presentation, most CCAs are perihilar (50%–60%), 20% are intrahepatic, 20% are distal extrahepatic, and 5% are multifocal. Most patients with CCA have no known risk factors; however, there seems to be an association with chronic inflammation of the biliary epithelium and diseases such as primary sclerosing cholangitis, chronic infection with liver flukes, hepatolithiasis, and viral hepatitis. Surgical resection offers the approach for long-term survival, but few patients are operative candidates. Palliative strategies include surgical, percutaneous, and endoscopic techniques to decompress the biliary system and locoregional palliative therapies.
Strategy
The selection of the best treatment is dependent on the status of the underlying liver and the tumor stage. Although HCC is rare in a noncirrhotic liver, these patients are the most likely candidates for liver resection. In most cases in which cirrhosis underlies HCC, the degree of functional impairment often precludes safe surgery. CCA develops in the background of cirrhosis in only 10% of patients; however, most CCA cases are deemed unresectable at presentation.
Most patients are not candidates for resection because of advanced tumors, tumor location near major intrahepatic vessels precluding a negative-margin resection, multifocal tumors, or poor hepatic functional reserve. Liver function is assessed through the Child-Turcotte-Pugh classification, and this is combined with a detailed evaluation of tumor extent. There are multiple staging systems for liver cancer, such as the TNM (Tumor, Node, Metastases), Okuda, CLIP (Cancer of the Liver Italian Program), and BCLC (Barcelona Clinic Liver Cancer) staging. These assessments examine the liver for characteristics such as multifocality, vascular invasion, and extrahepatic disease. In addition, the general condition and performance status of the patient is assessed. Patients with high-risk tumors, multiple comorbid conditions and poor performance status may be candidates for palliative treatment alone.
Even in centers with extensive experience in hepatic resection, the resection rate for HCC is in the range of 10% to 37%. In patients with unresectable HCC disease, liver transplantation should always be considered. Select patients may also be amenable to ablation techniques administered through multiple routes and techniques of administration. These options are reported to offer potential long-term benefit. TACE and sorafenib administration are palliative approaches that have been shown to have a positive impact on survival.
Treatment protocols for intrahepatic CCAs (ICCs) are not as common as those for HCC. Nevertheless, there is a clear role for hepatic resection when feasible, and chemoembolization has been used successfully in unresectable patients. CCA is diagnosed at late stages in most patients and resection is possible in only 15% to 20% of cases. If the disease is deemed unresectable, palliation should include restoring biliary drainage to reduce risk of cholangitis, pain management, improving nutritional status and fat absorption, and improving pruritus.
Strategy
The selection of the best treatment is dependent on the status of the underlying liver and the tumor stage. Although HCC is rare in a noncirrhotic liver, these patients are the most likely candidates for liver resection. In most cases in which cirrhosis underlies HCC, the degree of functional impairment often precludes safe surgery. CCA develops in the background of cirrhosis in only 10% of patients; however, most CCA cases are deemed unresectable at presentation.
Most patients are not candidates for resection because of advanced tumors, tumor location near major intrahepatic vessels precluding a negative-margin resection, multifocal tumors, or poor hepatic functional reserve. Liver function is assessed through the Child-Turcotte-Pugh classification, and this is combined with a detailed evaluation of tumor extent. There are multiple staging systems for liver cancer, such as the TNM (Tumor, Node, Metastases), Okuda, CLIP (Cancer of the Liver Italian Program), and BCLC (Barcelona Clinic Liver Cancer) staging. These assessments examine the liver for characteristics such as multifocality, vascular invasion, and extrahepatic disease. In addition, the general condition and performance status of the patient is assessed. Patients with high-risk tumors, multiple comorbid conditions and poor performance status may be candidates for palliative treatment alone.
Even in centers with extensive experience in hepatic resection, the resection rate for HCC is in the range of 10% to 37%. In patients with unresectable HCC disease, liver transplantation should always be considered. Select patients may also be amenable to ablation techniques administered through multiple routes and techniques of administration. These options are reported to offer potential long-term benefit. TACE and sorafenib administration are palliative approaches that have been shown to have a positive impact on survival.
Treatment protocols for intrahepatic CCAs (ICCs) are not as common as those for HCC. Nevertheless, there is a clear role for hepatic resection when feasible, and chemoembolization has been used successfully in unresectable patients. CCA is diagnosed at late stages in most patients and resection is possible in only 15% to 20% of cases. If the disease is deemed unresectable, palliation should include restoring biliary drainage to reduce risk of cholangitis, pain management, improving nutritional status and fat absorption, and improving pruritus.
Treatments
Locoregional Therapy
RFA
If patients are not candidates for surgery, they are offered percutaneous ablation if focally confined disease exists. RFA uses the energy of radiowaves for hyperthermic ablation of liver tumors. Several studies have reported complete tumor necrosis in 80% to 90% of HCCs smaller than 3 to 5 cm after a single session of RFA confirmed by contrast computed tomography. The complete ablation rate for larger tumors is less favorable: a study of RFA for 126 HCCs 3.1 to 9.5 cm reported a complete necrosis rate of 48%. The best results of ablation are achieved in solitary tumors smaller than 2 cm, in which these techniques may achieve complete necrosis, and recurrence rates are similar to resection in 90% of cases. RFA is a safe procedure for treatment of HCC in carefully selected patients with cirrhosis. Because of the versatility of probe designs that allows quick ablation of large tumors and the safety reported, RFA has largely replaced cryoablation of liver tumors.
Use of ablation for ICC management is increasing. In a study of 13 patients with ICC treated with RFA, local control was successful in 88% at a median follow-up of 19.5 months. The treatment failures occurred in the tumors more than 5 cm in diameter. The median overall survival after RFA was 38.5 months. RFA may result in successful local tumor control in patients with intermediate (3–5 cm) or small (<3 cm) ICC. Tumor size more than 5 cm, tumor geometry, proximity to large intrahepatic vessels, or subcapsular location may result in insufficient ablations and are associated with poorer clinical outcomes.
PEI
PEI can be used in the presence of contraindications for ablation such as tumor in a subcapsular location or in the vicinity of the gallbladder or heart. PEI induces tumor necrosis by cellular dehydration, protein denaturation, and thrombosis of small vessels. HCC is softer than the surrounding cirrhotic liver and is often encapsulated, thus allowing selective diffusion of ethanol within the tumor mass. Histopathologic studies have shown that PEI can induce complete tumor necrosis in about 70% of patients with HCCs smaller than 3 cm. The extent of necrosis is closely related to the tumor size, with an almost 100% rate of complete necrosis in HCCs smaller than 2 cm. PEI has been shown to be more cost effective than hepatic resection in patients with a single HCC smaller than 3 cm.
Compared with PEI, necrosis induced by ablation is more predictable, and treatment by a single session is sufficient in most patients with small HCCs. A prospective nonrandomized study comparing ablation in 42 patients and PEI in 44 patients with HCCs 3 cm or smaller showed that ablation achieved a higher complete necrosis rate (90% vs 80%) with fewer treatment sessions (mean 1.2 vs 4.8 sessions) but was associated with a higher complication rate (12% vs 0%).
Cryoablation
Cryoablation has been used for the treatment of liver tumors since the 1980s. Rapid freezing to subzero temperature leads to ice formation in the extracellular space and drawing of water from the cells, causing cellular damage by dehydration and destruction of the normal cellular architecture. Although larger tumors can be treated, cryoablation is most effective for tumors smaller than 5 cm. The largest series of cryoablation for HCC was performed by Zhou and Tang in China and reported a 5-year survival rate of 37.9% among 191 patients with HCC and a 5-year survival of 53.1% in a subgroup of 56 patients with tumors smaller than 5 cm. Like other ablation techniques, complete necrosis of highly vascular tumors or tumors adjacent to large vessels may be impeded by the effects of blood flow.
RFA was compared with cryoablation in a meta-analysis involving 433 patients with HCC. The study showed that RFA resulted in fewer complications (odds ratio [OR]: 2.80, 95% confidence interval [CI]: 1.54–5.09) and less local recurrence (OR: 1.96; 95% CI: 1.12–3.42). There was no significant difference in mortality (OR: 2.21; 95% CI: 0.45–10.8). Overall, current data suggest that cryoablation is an effective local ablative therapy for unresectable HCC.
Microwave ablation
Microwave ablation therapy is a form of thermoablative treatment in which tissue necrosis is induced by the heating effect of microwaves emitted from a needle electrode inserted into the tumor. The microwaves act mainly on the watery component of tissues, producing dielectric heat and tissue coagulation. Irreversible cellular damage from protein coagulation occurs at temperatures higher than 50°C. Compared with PEI, microwave ablation creates a more predictable and reproducible area of tissue necrosis, and it can ablate the tumor capsule as well as surrounding extracapsular invasion. The percutaneous approach has the advantages of applicability to high-risk patients and repeatability, but it is most effective in HCC cases smaller than 3 cm. Ohmoto and colleagues studied the results of percutaneous microwave ablation in 17 tumor nodules and found complete ablation in 80% of tumors 2 cm or smaller, whereas 71% of tumors larger than 2 cm developed local recurrence. With a favorable safety profile and tumor ablation rate, microwave ablation seems to be a promising therapy for patients with unresectable HCC, especially those with small tumors associated with poor liver function.
Regional Chemotherapy
HAI
HAI therapy represents another liver-directed treatment option. Primary liver malignancies are predominately dependent on the hepatic artery for blood supply, whereas normal liver tissues are perfused primarily by the portal vein. HAI therapy allows delivery of increased local concentration of cytotoxic agents to hepatic malignancies not achievable by systemic administration, especially for drugs with high systemic clearance. The regional advantage of an agent given by HAI over an intravenous infusion is proportional to the systemic clearance and hepatic extraction of the drug. Fluorodeoxyuridine is an attractive agent for HAI therapy because of its high first-pass clearance and low toxicity. Gemcitabine is also reported to be a potential agent, with a favorable toxicity profile and proven effectiveness in primary liver cancers. Unlike other locoregional therapies, HAI chemotherapy is not limited by tumor size, number, or proximity to major vasculatures, all of which are common contraindications to resection or ablation. A recently completed phase II study of HAI for patients with unresectable primary liver cancers reported positive findings. Sixteen of 34 evaluable patients (47%) had a partial response (15 of 26 with CCA and 2 of 8 with HCC). The median time to progression was 7.4 months, and overall survival was 29.5 months.
Chemoembolization
TACE is a regional therapy widely used for unresectable HCC. Patients with more advanced disease (large or multifocal HCC) are candidates for TACE if liver function is preserved and performance status acceptable. Response to this locoregional approach is associated with improved survival, and it has a significant impact on outcome at this stage of the disease. During the procedure, iodized poppyseed oil (lipiodol) and chemotherapeutic agents (doxorubicin, cisplatin, or mitomycin C) are administered through the feeding artery of the tumor, followed by arterial embolization. Other regimens are also used and the method of TACE is often institutional specific. Because the blood supply to HCCs is predominantly derived from the hepatic artery, transarterial embolization can induce tumor necrosis in HCCs. In a study of 100 patients with HCCs smaller than 4 cm treated by transarterial embolization alone, a complete necrosis rate of 64% and a 5-year survival rate of 53% were reported. The combined use of a lipiodol-cytotoxic drug emulsion and embolization has some theoretic advantages over chemotherapy or embolization alone. The oil-based chemotherapy slurry is selectively retained in the tumor for weeks and therefore helps to concentrate the cytotoxic agents into the tumor. In addition, the necrotizing effect of the lipiodol-drug emulsion is further enhanced by an arterial embolization. In a prospective trial, the 1-year survival rate after TACE was significantly better than survival after transarterial chemotherapy with a lipiodol-drug emulsion alone (86.3% vs 65.9%).
A recent study comparing TACE with transcatheter arterial embolization (TAE) without chemotherapy and transcatheter arterial infusion (TAI) in HCC reported that TACE and TAE were more effective in reduction of tumor size than TAI, and although they were associated with more acute liver function damage, it was reversible. However, another study by Sumie and colleagues comparing HAI chemotherapy using low-dose cisplatin and 5-fluorouracil with TACE found that HAI had a better antitumor effect than that of TACE, whereas the cumulative survival rates were comparable between the 2 treatment groups. A randomized phase III trial comparing TACE with TAI using zinostatin stimalamar (SMANCS) showed that adding embolization did not increase survival over TAI in patients with HCC. The ideal chemotherapeutic agent and whether embolization is necessary remain a point of debate.
The use of TACE for treating HCC is well established, with robust survival benefit outcomes. Its use for CCA is less established. A recent study randomized patients with unresectable ICC to TACE (n = 72) or best supportive therapy alone (n = 83), and a strong survival benefit was observed. Those who underwent TACE survived a median of 12.2 months, and those who received supportive therapy, only 3.3 months. A study by Gusani and colleagues showed that TACE with gemcitabine in combination therapy (with oxaliplatin or cisplatin) offered better overall survival than gemcitabine alone in unresectable CCA (13.8 vs 6.3 months). Kuhlman and colleagues recently published promising data on the use of TACE using irinotecan-eluting beads (iDEB-TACE). Three independent trials were conducted, and 26 patients with ICC were treated with iDEB-TACE (200 mg irinotecan), 10 patients were treated with conventional TACE using 15 mg mitomycin C mixed with ionized oil (lipiodol) followed by gel foam embolization; and 31 patients were treated with systemic gemcitabine and oxaliplatin. Patients in the iDEB-TACE group had 6 months improved overall survival over the conventional TACE group.
Radioembolization
Transarterial internal radiotherapy for HCC is a targeted therapy, with a radioactive isotope carried in an agent that is selectively retained by the tumor. Intra-arterial iodine 131 injected with lipiodol produced a tumor response rate ranging from 40% to 52% in various studies, and it seems to be well tolerated. Complete tumor necrosis has been shown with super selective high-dose therapy in patients with HCCs smaller than 5 cm. A recent prospective randomized trial comparing transarterial iodine 131 (n = 65) and TACE (n = 64) showed no significant difference in tumor response rate (24% vs 25%) or 1-year survival rate (38% vs 42%), but the former treatment was better tolerated.
Yttrium 90 delivered in glass microspheres is another form of transarterial radiotherapy that is approved by the US Food and Drug Administration under humanitarian use exemption. It has a higher radiation dose and thus a greater cytotoxic effect than iodine 131. In a study of 71 patients with unresectable HCC treated with transarterial yttrium 90 microspheres, an overall response rate of 89% was reported and the median survival was 9.4 months. It remains unclear whether yttrium 90 has any advantage over iodine 131 treatment, because no comparable study has been reported.
Radioembolization is an established treatment of HCC but has not been commonly reported in the management of CCA. Radioembolization using yttrium 90 microspheres was assessed in 33 patients with unresectable ICC and appeared safe. Median overall survival was 22 months and time to progression was 9.8 months. Yttrium 90 radioembolization has been shown to have a minimal embolic effect and an acceptable safety profile in ICC as well.
External-beam radiotherapy
The application of locoregional therapies is limited because of the size and number of tumors, liver function, portal hypertension, and the distribution or vascular supply of the tumor. Stereotactic body radiosurgery (SBRT) has been shown to be effective by allowing the delivery of large doses of radiation to a precise location and sparing the surrounding normal tissues. The use of SBRT for the treatment of primary liver tumors is emerging; however, one of the challenges is the low tolerance of the liver to irradiation. This factor is especially important when treating HCC, in which cirrhosis is frequently present, because radiation-induced liver disease occurs more frequently in patients with poor baseline liver function.
A study by Ibarra and colleagues was able to show comparable rates of freedom from local progression (FFLP) in patients treated with SBRT compared with other locoregional therapies. In this study, 21 patients with HCC and 11 patients with ICC were treated, and overall FFLP for advanced HCC was 63% at a median follow-up of 12.9 months. The median time to local progression was 6.3 months. The 1-year and 2-year overall survival rates were 87% and 55%, respectively. Patients with ICC had an overall FFLP of 55.5% at a median follow-up of 7.8 months. The median time to local progression was 4.2 months and the 6-month and 1-year overall survival rates were 75% and 45%, respectively. This finding compares favorably with other locoregional therapies. SBRT is a safe and effective option for the treatment of primary liver tumors. Small and nonmetastatic tumors have been shown to be associated with better responses and better long-term control.
SBRT for advanced CCA has had promising results as well. A study by Barney and colleagues had 10 patients with unresectable primary or recurrent CCA lesions who underwent abdominal SBRT. The median follow-up was 14 months. Local control, defined as freedom from progression within the SBRT field, was 100%, but 4 patients with treatment to intrahepatic sites experienced progression elsewhere in the liver. Estimates for freedom from distant progression at 6 and 12 months were 73% and 31%, respectively. Overall survival estimates for the cohort at 6 and 12 months were 83% and 73%, respectively. This study suggests that SBRT may affect patient survival in addition to local control in patients with CCA.
Endoscopic and percutaneous palliation
The primary aim of palliation in a patient with unresectable CCA is to relieve the obstructive cholestasis and its associated morbidities, such as pruritus, cholangitis, and pain. Palliation of obstructive jaundice can be achieved successfully through 3 major routes: surgically, by the creation of a choledochojejunostomy, choledochoduodenostomy, or hepaticojejunostomy; percutaneously, via percutaneous transhepatic cholangiography (PTC) and stent placement; and endoscopically, via endoscopic retrograde cholangiopancreatography and stent placement. Photodynamic therapy (PDT) and intraluminal brachytherapy (ILBT) delivered by either the percutaneous or endoscopic route may be used in addition to stent placement. In addition, a PTC may be the initial access to the biliary tree, which is then stented endoscopically (rendezvous procedure), or stents may be deployed via the PTC track.
Endoscopic therapy is the least invasive modality for achieving adequate symptom relief and perhaps may provide a survival benefit in these patients. Endoscopic stent placement has been shown to be as successful at restoring biliary flow and relieving obstructive jaundice as surgical hepaticojejunostomy or choledochojejunostomy. A randomized trial of patients with low common bile duct obstruction compared surgical biliary bypass with endoscopic stent insertion, and 92% of patients in both groups achieved decompression, but there was a lower procedure-related mortality (3% vs 14%), major complication rate (11% vs 29%), and length of hospital stay (20 days vs 26 days) in the endoscopic group. The decreased morbidity and mortality of endoscopic intervention to establish biliary drainage has significantly reduced the number of surgical interventions performed for biliary obstruction in malignancy.
Single or multiple biliary stents can be placed depending on the extent of the stricture. Single stents are adequate for strictures of the main bile duct below the confluence. However, for hilar strictures, debate exists as to whether single or double stents should be inserted. It is known that only 25% to 30% of the liver needs to be drained to achieve adequate palliation of obstructive jaundice. Several studies have shown that a single stent achieves adequate drainage in 75% to 80% of cases; however, the necessity for 2 or more stents may be critical in the remaining 20% to 25%. A prospective randomized controlled trial comparing unilateral versus bilateral stents found that unilateral stents achieved a higher success rate (81% vs 73%), with a lower early complication rate (19% vs 27%). There was no difference with respect to procedure-related mortality, late complications, or survival, suggesting that a unilateral stent is likely to suffice in most cases.
A decision between metal versus plastic stents needs to be made with consideration to the long-term need of the stent. In patients surviving more than 6 months, metal stents, compared with plastic stents, are associated with fewer interventions, reduced hospital inpatient stay, and fewer overall complications than plastic stents. Patency rates are higher with metal stents because of both larger diameter (10 mm when deployed) and material strength. Metal stents can also be revised with the placement of additional internal stents, allowing for long-term patency. Raju and colleagues reported that metal stents for inoperable hilar CCA had a median patency time of 5.6 months, compared with 1.9 months for plastic stents, and were more cost effective, given the reduced need for salvage PTC and restenting. Plastic stents should therefore be reserved for temporary preoperative drainage in patients considered for curative resection. In those with advanced disease, in which palliation is necessary, plastic stents have limited use, because of their shorter and less predictable patency rates. Thus, metal stents are the treatment of choice in these situations.
PDT has emerged as a promising new modality of treatment of patients who do not undergo resection. PDT involves the administration of a photosensitizing agent known to preferentially accumulate in tumor cells followed by the exposure of the target tissue to a light of the appropriate photoactivating wavelength. This process initiates a photochemical reaction with the generation of cytotoxic reactive oxygen species, resulting in apoptosis and necrosis of tumors cells. In a prospective study, 39 patients with CCA were randomized to treatment with biliary stenting plus PDT or stenting alone. The PDT group had higher median survival (493 days vs 98 days), less cholestasis, better quality-of-life scores, and better stabilization of performance status than did the stenting group. In a large retrospective study looking at patients with hilar CCAs treated with surgery, stenting alone or stenting with PDT, PDT and stenting resulted in longer median survival (12 months vs 6.4 months), lower serum bilirubin levels, and higher performance status compared with stenting alone.
ILBT can be performed endoscopically or percutaneously. Iridium 192 seeds mounted on a catheter are placed directly across the stricture in the bile ducts. Several studies have evaluated ILBT for palliation of unresectable CCA. Some studies have shown improved survival, whereas other studies have shown no benefit or an increased incidence of complications caused by cholangitis.
Among patients with advanced HCC, jaundice occurs in 5% to 44% of patients. Prognosis is worse in patients with unresectable HCC and obstructive jaundice. TACE is not recommended in patients with a serum bilirubin level of more than 3 mg/dL, and systemic chemotherapy and radiotherapy are usually not well tolerated in patients with significant hyperbilirubinemia. In patients who are not candidates for surgery, endoscopic and percutaneous biliary drainage are the 2 main nonsurgical treatment options, and they can provide palliation and allow for further adjuvant therapies. Endoscopy is usually the first-line treatment because of its low hemorrhagic risk and successful drainage rates. Mean stent patency time and mean survival range from 1 to 15.9 months and 2.8 to 12.3 months, respectively. Choi and colleagues compared endoscopic versus percutaneous biliary drainage in HCC and concluded that endoscopy had longer duration of drainage and higher rates of successful drainage. PDT can also be an effective treatment option for HCC with bile duct invasion. PDT has been shown to prolong survival in conjunction with biliary drainage in HCC.
Related posts:
Endoscopic and Percutaneous Approaches to the Treatment of Biliary Tract and Primary Liver Tumors
Intrahepatic Cholangiocarcinoma
Distal Cholangiocarcinoma
Hilar Cholangiocarcinoma
An Emerging Role for Radiation Therapy in the Treatment of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma
Systemic and Targeted Therapy for Biliary Tract Tumors and Primary Liver Tumors
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