Continuing Education Activity

Cholangiocarcinoma is an aggressive malignancy that originates from the biliary epithelium, both inside and outside the liver. Certain preexisting conditions and diseases can increase the risk of developing cholangiocarcinoma. This neoplasm is difficult to diagnose because obtaining a tissue sample for confirmation is not always possible. Unfortunately, cholangiocarcinoma is often locally invasive or metastatic by the time it is detected. While surgery is the only cure, radiation, chemotherapy, and targeted therapy can also be used in conjunction with surgery. This activity explores the diagnosis, evaluation, and treatment of cholangiocarcinoma and its various subtypes, highlighting the importance of an interprofessional team in managing the complicated decision-making process for these patients.

Objectives:

• Identify patients with possible intra- or extrahepatic cholangiocarcinoma based on their clinical presentation.

• Select an appropriate diagnostic strategy for a patient with suspected cholangiocarcinoma.

• Assess and manage the complications of cholangiocarcinoma and its therapeutic modalities.

• Develop and implement effective interprofessional team strategies to facilitate early intervention and improved outcomes for patients with cholangiocarcinoma.

Introduction

Cholangiocarcinoma is an aggressive malignancy of biliary epithelium that may arise anywhere in the biliary tract, from the intrahepatic biliary canaliculi to the terminus where the common bile duct enters the duodenum at the duodenal ampulla. Cholangiocarcinoma is classified by anatomical origin as intrahepatic cholangiocarcinoma (iCCA) or extrahepatic cholangiocarcinoma (eCCA); eCCA is subdivided into perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). More than 95% of cholangiocarcinomas are adenocarcinomas.

Several clinical conditions and premalignant lesions predispose to developing cholangiocarcinoma.[1] The clinical presentation of cholangiocarcinoma will vary with the location and size of the tumor. Diagnosing cholangiocarcinoma can be difficult, particularly for extrahepatic lesions; available biopsy techniques lack diagnostic sensitivity. Surgical intervention is indicated even without a confirmatory tissue diagnosis in the appropriate clinical setting. All patients with suspected or confirmed cholangiocarcinoma should be evaluated for distant metastatic disease; almost 75% of patients have nonresectable or metastatic disease at presentation.

Carbohydrate cell-surface antigen 19-9 (CA 19-9) is a tumor marker excreted by the biliary epithelium that assists with assessing disease severity and surveillance monitoring.[2] The overall prognosis of cholangiocarcinoma is poor, given the aggressive nature of the tumor and the usually advanced stage at presentation. Surgery is the only curative treatment modality; radiation and chemotherapy serve as adjuncts. Recent investigations into the molecular mechanisms underlying cholangiocarcinoma have yielded various targeted therapies that have improved outcomes and will hopefully improve patient care in the future.[3] 

Etiology

Cholangiocarcinoma frequently arises in the absence of genetic predisposition and without a clear etiology. However, certain risk factors that vary with ethnicity and geography predispose to cholangiocarcinoma in some patients.[4] These predisposing risk factors include but are not limited to:

Parasitic infections: Infestation with liver flukes such as Clonorchis and Opisthorchiasis is strongly associated with cholangiocarcinoma. These infestations are endemic to Southeast Asian regions; the highest incidence rates are in northeast Thailand.[5] Liver fluke infestation is due to the consumption of undercooked fish, and parasite-induced chronic biliary inflammation is the primary driver of malignant transformation.[6] 

Primary sclerosing cholangitis: Primary sclerosing cholangitis is a progressive autoimmune cholestatic liver disease. Individuals with primary sclerosing cholangitis have a significantly elevated risk, perhaps as much as 400 times the risk, of developing cholangiocarcinoma compared to the general population, especially with concomitant inflammatory bowel disease.[7] For a comprehensive discussion of this disease process, please see our StatPearls' companion reference, "Primary Sclerosing Cholangitis."

Biliary tree calculi: Hepatolithiasis, cholelithiasis, and choledocholithiasis increase the risk of developing cholangiocarcinoma, especially with larger stones and a more prolonged illness duration. Hepatolithiasis is more common in Asia and may be associated with parasitic infections.[8] 

Cystic biliary lesions: Patients with choledochal cysts, biliary mucinous cystic neoplasms, or intraductal papillary biliary mucinous neoplasms are at a significantly increased risk of developing cholangiocarcinoma.

• Choledochal cysts - All choledochal cysts are associated with an increased risk of cholangiocarcinoma; types I and IV confer the greatest risk. Prompt treatment of choledochal cysts is vital in reducing the risk of cholangiocarcinoma development.[9] Please see StatPearls' companion reference, "Choledochal Cysts," for a thorough discussion of these lesions.
• Biliary mucinous cystic neoplasms - Formerly identified as cystadenomas, biliary mucinous cystic neoplasms (B-MCNs) are predominately intrahepatic cystic lesions that are more common in young women. B-MCNs are frequently asymptomatic incidental findings, but large B-MCNs may cause signs or symptoms of compression or pain secondary to liver capsular distention. B-MCNs are usually septated with thickened internal walls and internal papillary projections, distinguishing them from simple liver cysts during imaging. Complete surgical resection is the preferred treatment for B-MCNs.[10] 
• Intraductal papillary biliary mucinous neoplasms - These mucin-producing lesions, most commonly found in the left lobe of the liver, are analogous to pancreatic intraductal papillary mucinous neoplasms and are frequently asymptomatic. Cross-sectional imaging may reveal an associated solid component, and mucin may be distinguishable with magnetic resonance imaging. Approximately 80% of intraductal papillary biliary mucinous neoplasms harbor a malignancy, and surgical excision is recommended.[11] 

Chronic liver disease: Chronic infection with hepatitis B or C, hemochromatosis, metabolic dysfunction-associated steatotic liver disease (MASLD, formerly nonalcoholic fatty liver disease or NAFLD), and cirrhosis of any etiology are associated with an increased risk of cholangiocarcinoma.[12] 

Lifestyle, environmental, and metabolic factors: Type 2 diabetes, obesity, alcohol consumption, and cigarette smoking increase the risk of developing cholangiocarcinoma. Exposure to Thorotrast, a radioactive thorium dioxide contrast media widely used between 1920 and 1950, increases the risk of cholangiocarcinoma development. Exposure to asbestos and propylene dichloride (1,2-Dichoropropane) also confers an increased risk.[12]

Genetic predisposition: Patients with hereditary nonpolyposis colorectal cancer (Lynch syndrome), BAP1-related tumor predisposition syndrome, multiple biliary papillomatosis, and cystic fibrosis carry an increased risk of cholangiocarcinoma development.

Epidemiology

Cholangiocarcinomas comprise about 3% of gastrointestinal malignancies, are the second most common primary liver tumors, and account for approximately 10% to 15% of all hepatobiliary malignancies.[13] The incidence of intrahepatic cholangiocarcinoma has been rising, possibly due to improved diagnostic and classification techniques, while the incidence of extrahepatic lesions has been falling in recent years. The incidence of cholangiocarcinoma varies markedly according to the geographic area; the incidence rates are up to 50-fold higher in parts of Thailand than in the United States. The incidence of cholangiocarcinoma increases with age, is slightly more common in men, and is most commonly diagnosed between the ages of 50 and 70 years.[14][15] 

Perihilar cholangiocarcinoma is the most commonly encountered subtype, accounting for approximately 50% of cases. Distal (40%) and intrahepatic cholangiocarcinoma (10%) are less common.[1] 

Pathophysiology

Cholangiocarcinoma generally arises in the setting of chronic inflammation, either from precursor lesions or de novo. Mutations in various protooncogenes and tumor suppressor genes mediate carcinogenesis. While the specific molecular carcinogenic pathways have not been identified, cholangiocarcinomas typically harbor mutations RAS, BRAF, TP53, SMAD4, and more.[16][17][18][19] K-ras and TP53 mutations are most commonly seen. However, genetic mutations will vary with the underlying disease etiology, especially for parasite-induced carcinogenesis.

Tumor Location and Morphology

The distinction between intrahepatic, perihilar, and distal cholangiocarcinoma is anatomical. Intrahepatic cholangiocarcinoma arises from the biliary epithelium proximal to the segmental bile ducts. Tumors arising from the left or right hepatic ducts or their confluence are termed perihilar cholangiocarcinoma. Tumors distal to the biliary confluence are distal cholangiocarcinoma. 

Cholangiocarcinoma grows in 3 distinct morphologic forms; the Liver Cancer Study Group of Japan classifies cholangiocarcinoma into mass-forming, periductal infiltrating, and intraductal-growing types (see Table 1. Morphologic Cholangiocarcinoma Classification).[20][21] See Image. Cholangiocarcinoma Tumor Location and Morphology.

Table 1. Morphologic Cholangiocarcinoma Classification

Histopathology

Cholangiocarcinoma arises from bile duct epithelium; 90% to 95% of cholangiocarcinomas are adenocarcinomas.[22] 

Intrahepatic cholangiocarcinoma arises from ducts proximal to the segmental bile ducts, which can be divided into small and large bile ducts. Tumors arising from these ducts differ in their pathologic characteristics and are termed small- and large-duct cholangiocarcinoma. Small-duct cholangiocarcinoma arises in the liver periphery and is lined by cuboidal cholangiocytes. Cuboidal cells often form small tubular glands without mucin production. Positive expression for C-reactive protein (CRP), N-cadherin, and neural cell adhesion molecule (NCAm), with negative S100P expression, is classic. These lesions are more likely to be mass-forming.[22][23]

Large-duct cholangiocarcinoma occurs closer to the liver hilum and arises from biliary glands and columnar cholangiocytes in larger ductules and segmental bile ducts. Large-duct cholangiocarcinoma may develop in the setting of biliary intraepithelial neoplastic lesions (B-MCN, intraductal papillary biliary mucinous neoplasms). In contrast to small-duct carcinoma, mucin production is common, with negative expression for CRP, N-cadherin, and NCAm and overexpression of S100P. These tumors are more likely to be infiltrating or intraductal. Perihilar and distal cholangiocarcinoma are predominantly large-duct types.[22][23][24]

History and Physical

The clinical presentation of cholangiocarcinoma will depend on the location and size of the tumor. Intrahepatic cholangiocarcinoma typically presents with nonspecific symptoms, including abdominal pain, weight loss, and fatigue. Jaundice and cholangitis may occur in the presence of biliary obstruction. Frequently, symptoms occur late in the disease course; tumors can be large at the time of diagnosis.[25] 

Extrahepatic cholangiocarcinomas are symptomatic earlier in their clinical course due to biliary obstruction, leading to jaundice, pruritus, clay-colored stools, and dark-colored urine. There may be a palpable mass and ascites in advanced disease. Uncommonly, patients can present because of signs related to metastatic disease; metastatic disease may be an incidental finding of imaging studies.[26]

The physical examination of a patient with suspected or known cholangiocarcinoma should evaluate nutritional status and liver function and include a focused abdominal exam. Rarely, a palpable mass in the right upper quadrant may be identified secondary to large intrahepatic tumors or with distal cholangiocarcinoma causing a biliary obstruction (Courvoisier sign). Signs of potentially unresectable disease include ascites or features of portal hypertension. 

Evaluation

The presenting symptoms dictate the diagnostic evaluation, including laboratory, imaging, and interventional procedures. Obtaining a tissue diagnosis can be difficult depending on the location of the lesion; this is especially true for perihilar lesions. Modalities for obtaining tissue include brush cytology, fine needle aspiration, or image-guided biopsy. Despite improvement in diagnostic techniques, none of these modalities are sensitive enough to rule out cholangiocarcinoma effectively. In the appropriate clinical setting, surgery is indicated even without tissue confirmation.[27]

Laboratory Studies

It is recommended that all patients undergo a comprehensive medical evaluation that includes a complete blood count (CBC), comprehensive metabolic profile (CMP) including liver function tests (LFTs), and coagulation studies to identify anemia, evidence of portal hypertension and hypersplenism, synthetic liver dysfunction, biliary obstruction, and renal dysfunction. Additionally, elevated transaminases may indicate hepatocyte injury. In tumors that cause biliary obstruction, direct hyperbilirubinemia and elevated alkaline phosphatase are common. Tumor biomarkers, including CA 19-9, carcinoembryonic antigen (CEA), and α-fetoprotein, should be measured. CA 19-9 is typically elevated in cholangiocarcinoma, but the results are unreliable in the presence of biliary obstruction.[2] 

Imaging Studies

Abdominal ultrasonography: often the initial diagnostic tool in patients with suspected cholangiocarcinoma because it is easily performed, noninvasive, cost-effective, and carries no risk of radiation exposure. However, ultrasonography may not yield a conclusive diagnosis. Ultrasonography may reveal a liver mass, signs of intra- or extrahepatic biliary dilation, or gall bladder distention.

Computerized tomography (CT): can identify liver anatomy and evaluate locoregional or metastatic disease. A triple-phase CT with arterial, venous, and portal venous phases is recommended to increase diagnostic accuracy. If the diagnosis is cholangiocarcinoma, a chest CT is recommended to evaluate for metastatic disease.

The CT findings of cholangiocarcinoma will vary with the subtype:

• Intrahepatic-peripheral cholangiocarcinoma usually presents as a mass with irregular margins with or without hepatic capsule retraction and dilatation of the peripheral intrahepatic ducts. The lesion usually demonstrates thin, incomplete rim enhancement during the arterial and portal venous phases.[28]
• Intrahepatic-intraductal disease can cause dilatation of the intrahepatic bile ducts with or without an intraductal polypoid mass or a lobar atrophy-hypertrophy complex. The neoplasm can present as irregular masses with markedly low attenuation, minimal peripheral enhancement, and focal dilatation of intrahepatic ducts around the tumor.[28]
• Perihilar cholangiocarcinoma can present with dilated proximal bile ducts, affecting the liver segments proximal to the lesion. The right and left bile ducts can appear disconnected. A primary mass lesion may not be seen. Often, a biliary stricture is the only finding.[28] 
• Extrahepatic cholangiocarcinomas present as wall thickening of the extrahepatic duct, a mass at the porta hepatis, or proximal biliary dilatation in the periampullary region.

Magnetic resonance imaging (MRI): offers excellent imaging of the liver and, when combined with MR cholangiopancreatography (MRCP), provides the best noninvasive imaging of the biliary tree, allowing the identification of strictures, masses, and cysts. MRI with contrast, which is usually gadolinium-based, enables the visualization of intrahepatic masses and their relationship to hepatic vasculature.[29]

Positron emission tomography (PET): may be used to assess for distant metastatic disease, but the National Comprehensive Cancer Network (NCCN) guidelines do not recommend the routine use of PET in the diagnosis and management of cholangiocarcinoma. 

Interventional Procedures

Endoscopic techniques: endoscopic retrograde cholangiopancreatography (ERCP) is used for biliary decompression and tissue diagnosis. Extrahepatic cholangiocarcinoma may be amenable to ERCP-guided biopsy or cytologic brushing. Unfortunately, the sensitivity of current biopsy techniques is too low to rule out carcinoma effectively, and operative intervention is still recommended in the appropriate clinical scenario, even without a tissue diagnosis. ERCP for biliary drainage may be indicated for severe jaundice or in patients with cholangitis.[30] 

Endoscopic ultrasound (EUS): visualizes the portal structures and the surrounding lymph nodes. In addition, EUS-guided biopsies have a higher sensitivity than ERCP alone but remain inadequate in ruling out cholangiocarcinoma effectively.[31] 

Percutaneous transhepatic cholangiography (PTC): Percutaneous image-guided access to the biliary tree is possible, especially in patients with intrahepatic biliary dilation. PTC allows for decompression of dilated bile ducts without contaminating the biliary tree. In patients undergoing hepatectomy, draining the functional liver remnant (FLR) is essential in improving postoperative liver regeneration and reducing the risk of liver failure.[30] 

Treatment / Management

The management of cholangiocarcinoma is complex and dictated by the site, extent, and relationship of the neoplasm to surrounding structures. Surgery is the only definitive cure, either with resection or liver transplantation. Chemotherapy and radiation are adjunctive treatment modalities. 

Preoperative Considerations

Biliary drainage

Biliary obstruction induces liver atrophy and impairs liver regeneration. Distal cholangiocarcinoma can cause biliary obstruction with dilation of the entire biliary tree. Preoperative biliary drainage, usually via ERCP and biliary stent placement, does not improve outcomes when compared to upfront surgery in patients with resectable disease and increases the risk of postoperative complications.[32] Drainage may be beneficial in patients who undergo neoadjuvant therapy.[33] 

Biliary drainage in perihilar tumors is a more widely debated topic. Perihilar cholangiocarcinoma commonly causes biliary obstruction, with dilation of the ducts proximal to the tumor. Drainage via ERCP results in colonization of the biliary tract with intestinal organisms and has a higher rate of stent misplacement and replacement in more proximal obstruction. PTC has the advantage of biliary drainage without contamination. Routine biliary decompression is not indicated. Selective biliary decompression of the FLR in patients undergoing liver resection, especially in whom the FLR is less than 40%, is indicated, as this minimizes postoperative liver failure. Drainage is also recommended in those undergoing neoadjuvant chemotherapy or portal venous embolization.[30] 

Volumetric analysis

In patients with iCCA and pCCA who require liver resection, the calculation of liver volumes and the FLR is critical to operative planning. Generally, an FLR of greater than 30% in healthy patients and 40% in those with cirrhosis is required. FLR is calculated using CT-guided imaging with software that calculates liver volumes. Patients who have inadequate FLR require interventions to increase liver volumes. Portal venous embolization (PVE) is the most commonly utilized technique and involves preoperative embolization of the portal vein branches to the liver segments to be resected.[34] Embolization results in hypertrophy of the FLR of up to 40%. The rate of hypertrophy, or the kinetic growth rate, is an important marker; a rate greater than 2.66% per week predicts lower postoperative liver failure and mortality.[35] Less common techniques for inducing hypertrophy include liver partition and portal vein ligation for staged hepatectomy and liver venous deprivation. 

Local Therapies

Local therapies are the recommended treatment for intrahepatic cholangiocarcinoma when the tumor is unresectable, or the patient is not fit for surgery. There are various techniques available, but their detailed discussion is beyond the scope of this activity. The techniques are not mutually exclusive and can be used in combination depending on the size and location of the tumor and available expertise.[36] Local therapies for cholangiocarcinoma are extremely important as the majority of patients die from liver failure due to intrahepatic metastases. Delaying the onset of liver failure can significantly improve patient survival and quality of life.[35] For an overview of local therapies for the treatment of cholangiocarcinoma, please see Table 2. Local Therapies for Cholangiocarcinoma.

Transarterial chemoembolization

Transarterial chemoembolization (TACE) employs chemotherapeutic agents directly instilled into the hepatic artery, followed by embolization of the artery, thereby depriving the tumor of its arterial supply. Doxorubicin and platinum agents are most commonly used. The chemotherapeutic agent may be emulsified or incorporated into beads or microspheres and deployed via angiography into the hepatic artery branches that supply the tumor. The procedure is well-tolerated in most patients and can significantly shrink tumors.[37]

Transarterial radioembolization

Transarterial radioembolization (TARE) is a newer technique that installs yttrium 90 (⁹⁰Y) in either resin or glass microspheres via the hepatic artery directly into the tumor, followed by vessel embolization. This results in a high dose of radiation in the immediate vicinity of the tumor and is performed similarly to TACE.[37] 

Ablative techniques

Tumor ablation using radiofrequency or microwave energy is an option for local control in patients with unresectable disease or who are not fit to undergo surgical resection.[38] These techniques can be done using image guidance and are much better tolerated than surgery. Both techniques rely on the application of energy, and the electrode is placed in the center of the tumor. The effectiveness is inversely proportional to size; tumors larger than 3 cm are much less likely to be entirely ablated. These techniques should be used cautiously near larger blood vessels or bile ducts. Ablation can be repeated as often as needed.[39] 

Hepatic artery infusion

Hepatic artery infusion is a technique whereby chemotherapy is instilled directly into the hepatic artery proper via a subcutaneously placed pump. The catheter is threaded into the hepatic artery via the gastroduodenal artery; this requires a surgical procedure to accomplish. Chemotherapy is then infused over the ensuing weeks and can result in significant downstaging of the tumor. When hepatic artery infusion is performed at institutions with extensive experience, the overall results are promising. Hepatic artery infusion is not yet a widely adopted treatment modality.[40][41]

Table 2. Local Therapies for Cholangiocarcinoma

Differential Diagnosis

Since the signs and symptoms of cholangiocarcinoma, including jaundice, abdominal pain, and fatigue, are very nonspecific, the differential diagnosis can be vast. Some possible differential diagnoses include:

• Choledocholithiasis
• Pancreatic cancer
• Primary sclerosing cholangitis
• Primary biliary cirrhosis
• Hepatocellular carcinoma
• Cholangitis
• Cholecystitis

Surgical Oncology

The general principles of liver surgery apply to cholangiocarcinoma. Maintaining an adequate FLR and hepatic inflow and outflow while obtaining microscopically negative margins is critical to good outcomes. Diagnostic laparoscopy should always be performed before laparotomy; as many as 30% of patients may have radiographically occult metastatic disease that would preclude resection.[42] 

Intrahepatic Cholangiocarcinoma

Hepatic resection with microscopically negative margins (R0) is the mainstay of therapy for iCCA. Positive resection margins are associated with higher rates of local recurrence and worse overall survival. Hepatic resection may be anatomic, based on segmental liver anatomy with the removal of entire segments with their surrounding Glissonian sheath, or nonanatomic, with resection of the tumor with negative margins. The extent of resection is dictated by the location and size of the tumor and may include portal vein resection and reconstruction if the vein is involved. A portal lymphadenectomy should be performed routinely.[43][1]

Perihilar Cholangiocarcinoma

Operative decision-making in pCCA is complex, as identifying the extent of the tumor may be difficult. Even with high-quality imaging and endoscopic techniques, the proximal and distal extent of the tumor may not be visualized preoperatively and only be identified intraoperatively. The extrahepatic bile duct and the involved hemiliver are usually resected with a portal lymphadenectomy. Routine resection of the caudate lobe is also recommended, given its proximity to the biliary confluence and its involvement in many tumors. To ensure negative margins, frozen section margins on the bile duct margins should be performed before reconstruction. The Bismuth-Corlette classification is commonly used for perihilar tumors and guides surgical management.[44][45]

• Type I: Tumors distal to the confluence of the left and right hepatic ducts
• Type II: Tumors involving the hepatic duct confluence 
• Type III
  • IIIa: Tumors obstructing the common hepatic duct and the proximal right hepatic duct
  • IIIb: Tumors obstructing the common hepatic duct and the proximal left hepatic duct
• Type IV: Tumors that are multicentric or involve the confluence and both the right or left hepatic duct [46][47][45]

Types I and II  tumors are usually managed with an extrahepatic bile duct resection and resection of adjacent liver parenchyma. Some authors and high-volume centers routinely perform right hepatectomies for these lesions, especially those of the infiltrating type.[48][45][48] 

Type III tumors routinely require an extrahepatic bile duct resection and a right hepatectomy in Type IIIa or left hepatectomy in Type IIIb.[45]

Type IV tumors usually require a liver transplant. The Mayo protocol for these tumors, which involves preoperative chemoradiation followed by liver transplant, has been shown to have a 5-year survival of over 50%.[49] 

Distal Cholangiocarcinoma

These neoplasms are managed with pancreaticoduodenectomy. The proximal bile duct margin should be examined intraoperatively to ensure negative margins. To obtain an R0 resection, much of the extrahepatic bile duct may need to be removed. Rarely, tumors of the mid-duct may be amenable to an extrahepatic bile duct resection alone.[50][51]

Radiation Oncology

Adjuvant Therapy

Radiotherapy (RT) may be used in the adjuvant setting for cholangiocarcinoma.[52] There is typically no role for radiotherapy for patients who undergo a complete resection with microscopically negative margins. RT, usually in combination with chemotherapy, is generally utilized to reduce local recurrence in patients with a microscopically or grossly positive surgical margin. The radiation dose depends on the tumor location, the tolerance of surrounding organs, and underlying liver function. Image-guided techniques, such as three-dimensional conformal and intensity-modulated RT, improve targeting and reduce toxicity. The radiation field should include the operative bed and the regional lymph nodes, including the portal, celiac, para-aortic, superior mesenteric artery, and others. Typical doses range from 40 Gy to 45 Gy to the lymph nodes and 55 Gy to 60 Gy to the tumor site.[49] There is no definitive data to suggest a survival benefit. Patients with node-positive disease may also receive radiotherapy. External beam radiotherapy with a chemosensitizing agent such as capecitabine or gemcitabine is typically used.[53]

Unresectable Disease

RT may be used in unresectable disease to provide local control and symptom relief.[52] Both external beam RT and stereotactic body RT (SBRT) may be used. SBRT allows very high doses of radiation to target lesions with a high degree of accuracy and provides local control rates that appear to be better than conventional fractionated external beam radiotherapy. Radiotherapy is almost always administered with concurrent radiosensitizing chemotherapy. Typical doses in this setting are higher than those in adjuvant therapy. 

Medical Oncology

Adjuvant Therapy

Postoperative therapy should be offered within 8 to 12 weeks and requires preinitiation baseline laboratory tests and imaging. Adjuvant treatment may be delayed in cases where there are significant surgical complications or other patient-related factors decreasing the ability to tolerate chemotherapy. In general, the efficacy of adjuvant therapy decreases as the time to initiation increases.

After resection, adjuvant therapy should be offered to patients with positive surgical margins, positive lymph nodes, or vascular involvement. The role of adjuvant chemotherapy in patients with completely resected specimens with microscopically negative margins is unclear. The benefit of adjuvant therapy is based on 2 trials, including the Biliary Tract Cancer (BILCAP) trial and a randomized trial from Japan employing single-agent adjuvant treatment. In the BILCAP trial, adjuvant capecitabine improved overall survival without chemotherapy, although this trend was not statistically significant.[54] This is currently accepted as a standard of care after resection. Two negative trials have reported no benefit to gemcitabine-based regimens, which are presently discouraged.

The lack of randomized trials plagues trial data on cholangiocarcinoma, which is a rare cancer; most trials combined gallbladder carcinoma with all biliary tract cancers. Some of the benefits of adjuvant chemotherapy may be in the population of patients with gallbladder carcinoma, which has a higher rate of distant metastatic disease.[55][56]

Neoadjuvant setting

Neoadjuvant chemotherapy is currently used in borderline resectable tumors. Some patients may have an adequate response that allows for resection. In addition, neoadjuvant chemotherapy and radiation may be used as part of the Mayo protocol in preparation for liver transplant in patients with hilar cholangiocarcinoma. For patients with upfront resectable disease, there is no currently available data to support the routine use of neoadjuvant chemotherapy.[57]

Locally advanced or metastatic setting

Chemotherapy can significantly extend survival in patients with metastatic disease, and immunotherapy has improved this benefit more recently. Based on the recent TOPAZ-1 trial, the combination of durvalumab with gemcitabine and cisplatin was superior to gemcitabine and cisplatin alone.[58] Pembrolizumab, in combination with gemcitabine and cisplatin, has also been shown to be superior to chemotherapy alone. In general, these regimens are considered the standard of care.[59]

Chemotherapy alone remains the standard of care in several settings where immunotherapy may not be available. Multiple second- and third-line regimens exist for patients with poor performance status, persistent hyperbilirubinemia, or other considerations. With the identification of an increased number of specific tumor mutations and the availability of targeted agents, several targeted agents are now available based on the tumor mutational profile of these cancers.[60]

Prognosis

The overall prognosis for cholangiocarcinoma is poor. Only one-fourth of patients have resectable disease at the time of diagnosis; intrahepatic and perihilar tumors most commonly present at a more advanced stage. The 5-year overall survival rate for intrahepatic cholangiocarcinoma approximates 8%, with a slightly higher but sobering 10% 5-year survival rate for extrahepatic cholangiocarcinoma. Surgery remains the best opportunity to achieve a cure, but surgery is often morbid and can be associated with significant complications.[1]

Complications

Complications from cholangiocarcinoma can be related to the disease itself or due to therapeutic interventions. In patients with advanced cholangiocarcinoma, intrahepatic metastases with eventual liver failure are a significant complication. In addition, biliary obstruction due to mass-like lesions can cause cholangitis, liver atrophy, cirrhosis, and considerable deconditioning. Distant metastatic disease can occur, as can local intraperitoneal spread.

Deterrence and Patient Education

Cholangiocarcinoma is a rare but highly aggressive malignancy of the biliary tract. Symptoms may be vague, especially when the neoplasm begins within the liver, and may include nonspecific symptoms like abdominal pain, weight loss, and fatigue. Extrahepatic tumors may present with jaundice or abdominal pain. Patients with any risk factors for cholangiocarcinoma, such as chronic parasitic infections, biliary cystic disease, or unexplained symptoms such as weight loss, reduced appetite, unexplained fatigue, or unusual yellowing of the skin or urine, should be evaluated by a physician. Diagnosing cholangiocarcinoma may not be straightforward and may require several different imaging techniques or interventional procedures. Approximately one-fourth of patients with cholangiocarcinoma are curable.

Enhancing Healthcare Team Outcomes

Cholangiocarcinoma patients require personalized care that caters to their individual needs. Diagnosing this condition can be challenging and often requires the input of multiple medical specialties. The management of this disease is complex and depends on various factors such as imaging results, patient comorbidities, and the findings of interventions like endoscopy or cholangiography. As a result, a multidisciplinary team must be involved in the patient's care from the time of diagnosis. Moreover, since individualized treatment is crucial for patient-centered care, each case should receive tailored therapy that addresses its unique characteristics. Although cholangiocarcinoma is often not curable, recent advancements in local therapies and the availability of more targeted therapies have improved patient survival rates and quality of life. Therefore, a collaborative, team-based approach is vital for managing this condition effectively.