The Alliance

Cholangiocarcinoma is a rare cancer that occurs in the bile ducts. Bile is a yellow/green digestive fluid that is constantly made by liver cells. The bile ducts are a network of vessels that drain bile from the liver to the gall bladder, where it is stored, through to the small intestine, where it helps break down fats.¹

^‍Cholangiocarcinoma is the second most common primary liver cancer in the world. It typically affects people over the age of 65 and unfortunately it has a poor prognosis.²In general, the incidence and mortality rates of cholangiocarcinoma appear to be increasing globally and across all age groups, including younger people, but current data show this increase varies between the different subtypes.^1–5

There are three main subtypes of cholangiocarcinoma, which are defined by the location of the tumor. These are classified as below, with the estimated proportion of each type shown¹:

• Intrahepatic cholangiocarcinoma occurs in the smaller bile ducts within the liver before they join into the left or right hepatic ducts, ~10–20%.
• Perihilar/hilar cholangiocarcinoma occurs within the left or right hepatic ducts and the common hepatic duct,~50–60%.
• Distal or extrahepatic cholangiocarcinoma occurs outside the liver in the common bile duct after the cystic duct, ~20–30%.

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Most cases of cholangiocarcinoma happen without any known cause.  General risk factors include age (>65 years old)², obesity, diabetes mellitus, and nonalcoholic fatty liver disease.¹

^‍Some well-defined risk factors for cholangiocarcinoma have one thing in common—they all cause long-term chronic inflammation of the biliary tract. Established risk factors include the following^1,2,6,7:

• Inflammatory diseases, such as primary sclerosing cholangitis (PSC), which causes inflammation of the bile ducts (cholangitis) that leads to the formation of scar tissue (sclerosis).
• Congenital conditions and diseases that result in the bile ducts being wider than usual, such as biliary/choledochal cysts and Caroli disease, disrupt the flow of bile causing stone formation and scarring.
• Bile duct stones or gallstones, which are deposits of bile caused by an infection or slow movement of the bile through the ducts that can irritate the lining of the ducts.
• Viral infections, such as hepatitis B or C, can lead to scaring of the liver (also known as cirrhosis).
• Drugs, chemicals, and toxins, such as asbestos, tobacco, and alcohol can also cause irritation and damage to the liver.
• Parasitic infections with liver flukes (Opisthorchis viverrini and Clonorchis sinensis) occur mainly in Southeast Asia, particularly near the Mekong River. Infection is caused by eating raw fish that has been contaminated with the liver flukes. Once in the liver or bile ducts, the parasites cause inflammation and scarring. In Western countries these types of infection are almost non-existent.

Geographically, the incidence rates of cholangiocarcinoma vary. In Western countries, cholangiocarcinoma affects fewer than six people per 100,000 each year. However, in Southeast Asia, specifically Thailand, South Korea, and China, the incidence of cholangiocarcinoma is higher, affecting more than six people per 100,000 each year.² This variation may be based on the exposure to the risk factors listed above, such as the high prevalence of carcinogenic liver flukes in Southeast Asia.^1,8

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It is crucial to diagnose cholangiocarcinoma as early as possible in order to optimize survival rates. Currently, the survival rate 5 years after diagnosis is between 7% and 20% globally.¹ The symptoms described above are general and can be associated with more common, less serious, conditions; therefore, cholangiocarcinoma can be difficult to diagnose. Diagnosis often occurs at an advanced stage of disease and many cases (20–25% for intrahepatic cholangiocarcinoma) are detected incidentally when investigations and scans are conducted for other reasons.^1,2,9

Given that cholangiocarcinoma is difficult to diagnose, a combination of methods is required to accurately confirm a diagnosis. The methods used vary across different regions of the world and may include the following^{1,3,9,10–13}:

• Observation of symptoms, with details of past medical history, and a physical examination to check for pain in the abdomen and enlargement of the liver or other organs.
• Blood tests to assess liver function as well as proteins associated with some cancers such as cancer antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA). The blood may also be tested for a protein known as IgG4 to rule out autoimmune cholangitis.
• General imaging of the bile ducts and surrounding organs using various methods, such as:

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Treatment options vary across different regions of the world depending on what is available and approved in each country. Currently, the only potentially curative treatment is surgery; however, this is only an option in approximately 25% of patients.¹ Surgery can be performed to remove the cancer or to relieve the symptoms the patient is experiencing. The location of the tumor can affect the surgical treatment, so it is critical that the patient is properly evaluated by a specialist to determine if surgery is an option.^1,3,4,9

Surgical treatment options include the following^11–13:

• Removal of the affected bile ducts. This is usually only performed in early stages of the disease when only the bile ducts are affected. The remaining healthy ducts are reconnected to the small intestine.
• Partial liver resection (removal) can be carried out at earlier stages if the cancer has only spread to certain parts of the liver and is removed with the affected bile ducts.
• The Whipple procedure involves removal of the bile ducts, part of the stomach, part of the small intestine, the pancreas, gall bladder, and the surrounding lymph nodes, if affected.
• Bypass of the blocked bile ducts to allow the flow of bile to the small intestine and relieve the symptoms of jaundice. This is usually carried out where removal of the tumor is not possible.
• Stent insertion, where a tube is placed into the bile ducts to hold them open and prevent blockages.

For patients where surgery is not an option, chemotherapy with the anticancer drugs gemcitabine and cisplatin is the first treatment option. Second-line treatment for those in which the first-line treatments have not worked or the cancer has come back and is advanced or metastatic, include a combination of folinic acid, fluorouracil, and oxaliplatin (often referred to as FOLFOX).^1,13

These chemotherapeutic drugs are given intravenously and work together to destroy fast growing cells, such as cancer cells, by interfering with the process of cell replication. However, because other cells in the body also divide quickly, they can cause several side effects, including easy bruising/bleeding, anemia, fatigue, susceptibility to infections, sickness, diarrhea, mouth ulcers, suppressed appetite, changes in taste, hair loss, and changes to the skin and nails. Damage to the kidneys and liver may occur as the body tries to excrete these toxic agents.^11–13

Radiation therapy may be given to lower the risk of the cancer coming back after surgery or to relieve symptoms. It utilizes high-energy X-rays, gamma rays, or protons to kill cancer cells. The two main types of radiation therapy are:

• Stereotactic body radiation therapy (SBRT) that directs radiation beams from many different positions around the body, which results in the cancer receiving high doses of radiation, but the surrounding tissues receiving only a low dose, thus lowering the risk of side effects.¹¹
• Selective internal radiation therapy (SIRT), which uses small pellets of radioactive material that are inserted next to or into the tumor to minimize the risk of radiation to other organs and tissues. (Note: this is type of therapy is not approved in the UK).¹⁵

The side effects of radiation therapy are similar to chemotherapy and may also result in skin changes such as redness, blistering, and peeling, but usually only occur in the area being treated.¹⁵

More personalized/targeted therapies for patients with specific gene mutations are currently under investigation in clinical trials. One targeted therapy that has already been approved in the US, UK, and Europe is pemigatinib, which can be used for patients who have an FGFR2 fusion.^16–18

Please find patient information sheets available here.

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Genetic and molecular profiling is a fast expanding area of interest across all cancers. Molecular profiling looks at the mutations present within a patient’s cancerous cells. Currently, in cholangiocarcinoma, several genetic mutations/abnormalities have been identified, including^1,3,19:

• IDH1/2
• BRCA1/2  
• BAP1  
• ARID1A/B and ARID2  
• ELF3  
• PBRM1  
• PRKACA/B  
• CDKN2A/B  
• CCND1  
• FGFR1/2/3  
• MCL1  
• PD-L1  
• PBRM1  
• TP53  
• MYC  
• SMAD4  
• ERBB2

However, the mutations that cause cholangiocarcinoma vary from one person to the next. These mutations may also vary from one cancer cell to another within the same person. This represents a limitation to current therapies, as one treatment may not work for all patients with cholangiocarcinoma and may not work on all the cholangiocarcinoma cells, leading to treatment failure or the disease returning. The future of cholangiocarcinoma treatment relies on research into the genetic causes to allow for personalized targeted therapies and clinical trials that compare combinations of different therapies to maximize destruction of the cancer cells.¹

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When developing a new drug or treatment approach, it is important to prove that it is safe and effective in the patients who will be treated. Clinical trials aim to develop new treatments to improve survival rates or the quality of life for patients.  

New treatments for cholangiocarcinoma that are currently being tested in clinical trials include liver transplantation, targeted therapies for patients with specific types of mutations, and immunotherapies, which are treatments that help the immune system find and attack cancer cells better.

Liver transplants may be beneficial for certain types of cholangiocarcinoma. Clinical trials have been undertaken in patients with perihilar cholangiocarcinoma that can and cannot be surgically removed. In these studies, patients were treated with a combination of chemotherapy and radiation therapy, followed by a liver transplant. These studies showed a benefit in some patients as they were free from disease after 5 years, however in some patients the cancer returned. Potential obstacles to this strategy include the limited availability of livers for transplantation and the need for life-long medication to suppress the immune system. Therefore, identifying factors that affect whether treatment will work well is vital to improving treatment options.¹

^‍Targeted therapies require molecular testing to be carried out first to see if the cancer has a particular mutation/s that make it more likely to respond to specific agents. Agents that may be of benefit include^10,13:

• Entrectinib or larotrectinib for those with NTRK gene fusions
• Pemigatinib and infigratinib for those with FGFR2 fusions/rearrangements
• Erdafitinib and futibatinib for those with FGFR mutations  
• Ivosidenib for those with IDH1 mutations
• Dabrafenib and trametinib for those with BRAFV600E mutations
• Zanidatamab for those with HER2 mutations

Immunotherapies such as pembrolizumab and nivolumab are being tested in clinical trials in combination with other agents. Pembrolizumab and nivolumab work by blocking a protein called PD 1, which is present on the surface of a type of immune cell known as the T cell. This blockade allows the T cells to remain active and destroy cancer cells.^1,10,13

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It is recommended that patients with cholangiocarcinoma are seen in dedicated centers with multidisciplinary treatment teams, where diagnosis and management can be personalized. At-risk populations (such as those in areas where liver flukes are present) should also be identified, educated about the risk of eating raw fish, and followed up so that diagnosis occurs as early as possible.²

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