Bile Duct Cancer or Cholangiocarcinoma Treatment

What are the types of bile duct cancer (cholangiocarcinoma)?​​

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There are two types of bile duct cancer:

1. Intrahepatic bile duct cancer (or intrahepatic cholangiocarcinoma): this type forms in the bile ducts inside the liver. Only a small number of bile duct cancers are intrahepatic.

2. Extrahepatic bile duct cancer: this type forms in the bile ducts outside the liver. The two subtypes of extrahepatic bile duct cancer are perihilar bile duct cancer and distal bile duct cancer:

• Perihilar bile duct cancer (or perihilar cholangiocarcinoma): this type is found in the area where the right and left bile ducts exit the liver and join to form the common hepatic duct. It is also called a Klatskin tumor.

• Distal bile duct cancer (or distal cholangiocarcinoma): this type is found in the area where the ducts from the liver and gallbladder join to form the common bile duct. 

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What are the signs and sympotms of bile duct cancer (cholangiocarcinoma)?

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Bile duct cancer can be difficult to diagnose, as it often does not cause many specific symptoms in the early stages. Symptoms may include:

• loss of appetite

• unintentional loss of weight

• feeling or being sick

• pain in the abdomen

• Yellow skin or eyes (jaundice) and itchy skin

• dark urine

• clay coloured stool

  

What causes bile duct cancer (cholangiocarcinoma)? 

  

Cholangiocarcinomas usually occur in people older than 60 years of age, though it can occur at any age. At the moment we do not know the exact causes of bile duct cancers. However, we know certain conditions that increase the risk for bile duct cancer, such as chronic liver disease, primary sclerosing cholangitis (a disease in which bile ducts get narrow and blocked by inflammation and scarring), ulcerative colitis (an inflammatory bowel disease), cysts in the bile ducts, smoking and infections from certain parasites​ (more common in Asia).

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How is bile duct cancer (cholangiocarcinoma) diagnosed? ​

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The purpose of the diagnostic workup is to establish the diagnosis of bile duct cancer and see how mcuh it has spread in order to form the best management plan for each patient. For this purpose a combination of tests may be required in addition to history and physical examination. 

• Boold tests: full blood count, clotting, bilirubin levels and liver and kidney function tests.

• Tumour markers: specifically CA19-9 and CEA which may be increased in bile duct cancers.

• Ultrasound scan: this is usually the first examination for patients presenting with jaundice. The test can detect dilatation of the bile ducts system, which may be a radiological sign of blockage caused by bile duct cancer. It is a very good test to detect gallstones, however not so good for accurate diagnosis of bile duct cancer and therefore further tests are required.

• CT scan: 3-dimensional x-ray imaging investigation of the liver and bile ducts that may show a mass (tumour) or signs of it, such as dilatation of the bile duct system down to a point of narrowing or mass. It is also very useful to detect any involvement of vascular structures byt the cancer or metastases if the cancer has spread to other organs. 

• MRI and MRCP: 3-dimension imaging investigation using magnetic waves. It is better than CT in detecting smaller lesions in the liver and provides a more detailed mapping of the bile duct system.

• Percutaneous transhepatic cholangiography (PTC): this proceduce is usually performed under local anaesthetic. Under ultrasoud or x-ray guidance a small needle is inserted from the skin into the liver and the bile ducts. Then a small catheter is positioned and secured in place. X-ray pictures can be taken after inserting contrast dye in the bile duct system via the catheter. Tissue from the area of the cancer can also be obtained in order to establish a histopathological diagnosis (confirmation of cancer after reviewing the sampled tissue under the microscope by a pathologist). PTC has also a therapeutic aspect, as the catheter can also be used to drain the bile into a bag and relieve the jaundice caused by the cancer or in order to insert a stent to open up the blocked ducts. 

• ​Endoscopic retrograde cholangiopancreatography (ERCP): this procedure is usually performed under sedation. During the first part a camera is used to enter through the mouth into the stomach and the duodenum. The ampulla (opening of the common bile duct into the duodenum) is identifed and a small catheter is inserted. X-ray pictures can be taken after inserting contrast dye in the bile duct via the catheter. Tissue from the area of the cancer can also be obtained in order to establish a histopathological diagnosis (confirmation of cancer after reviewing the sampled tissue under the microscope by a pathologist). ERCP has also a therapeutic aspect, as a stent can be inserted to open up the blocked duct and relieve the jaundice. 

• ​Endoscopic ultrasound (EUS): this is also usually performed under sedation. During the first part a camera is used to enter through the mouth into the stomach and the duodenum. The end of the camera has an ultrasound probe, which can take pictures of the liver and bile ducts from cloe proximity. Also, with the use of a fine needle, tissue from the area of the cancer can also be obtained in order to establish a histopathological diagnosis (confirmation of cancer after reviewing the sampled tissue under the microscope by a pathologist).​​​

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What are the bile duct cancer (cholangiocarcinoma) stages? ​

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Intrahepatic bile duct cancer (intrahepatic cholangiocarcinoma)

• Stage 0 or carcinoma in situ: abnormal cells are found in the innermost layer of the lining of the bile ducts in the liver. These abnormal cells are not actually cancer, but may turn into cancer in the future.

• Stage I:

  • stage IA: the cancer is 5 cm or smaller. 

  • stage IB: the cancer is larger than 5 cm.

• Stage II: the cancer has spread through the wall of an intrahepatic bile duct and into a blood vessel or more than one tumor has formed in the intrahepatic bile duct and may have spread into a blood vessel.​

• Stage III:

  • stage IIIA: the cancer has spread through the capsule (outer lining) of the liver. 

  • stage IIIB: the cancer has spread to organs or tissues near the liver, such as the duodenum, colon, stomach, diaphragm or the part of the inferior vena cava (big vein that brings the blood from the lower body into the heart) behind the liver or the cancer has spread to nearby lymph nodes.

• Stage IV: the cancer has spread to other parts of the body, such as lungs, bones, distant lymph nodes or other organs in the abdomen.

Perihilar bile duct cancer (perihilar cholangiocarcinoma)

• Stage 0 (or carcinoma in situ): abnormal cells are found in the innermost layer of the lining of the bile ducts in the liver. These abnormal cells are not actually cancer, but may turn into cancer in the future.

•  Stage I: cancer has formed in the innermost layer of the bile duct and has spread into the muscle layer or fibrous tissue layer of the bile duct wall.

•  Stage II: the cancer has spread through the wall of the bile duct to nearby fatty tissue or nearby liver tissue. 

• Stage III: 

  • Stage IIIA: the cancer is involving branches on one side of the hepatic artery or of the portal vein. 

  •  Stage IIIB: the cancer has spread to one or more of the following nearby structures: 

    • the main part of the portal vein or its branches on both sides

    • the common hepatic artery

    • the right hepatic duct and the left branch of the hepatic artery or of the portal vein

    • the left hepatic duct and the right branch of the hepatic artery or of the portal vein

  •  Stage IIIC: the cancer has spread to 1-3 nearby lymph nodes.

• Stage IV: 

  • Stage IVA: the cancer has spread to 4 or more nearby lymph nodes.

  • Stage IVB: the cancer has spread to other parts of the body, such as lungs, bones, distant lymph nodes or other organs in the abdomen.

Distal bile duct cancer (distal cholangiocarcinoma)

• Stage 0 (or carcinoma in situ): abnormal cells are found in the innermost layer of the lining of the bile ducts in the liver. These abnormal cells are not actually cancer, but may turn into cancer in the future. 

• Stage I: the cancer has formed and spread fewer than mm into the wall of the distal bile duct.

• Stage II: 

  • Stage IIA: the cancer has spread fewer than 5 mm into the wall of the distal bile duct and has spread to 1-3 nearby lymph nodes or the cancer has spread 5 -12 mm into the wall of the distal bile duct.

  • Stage IIB: the cancer has spread 5 mm or more into the wall of the distal bile duct and may have spread to 1-3 nearby lymph nodes.

• Stage III: 

  • Stage IIIA: the cancer has spread into the wall of the distal bile duct and to 4 or more nearby lymph nodes.

  • Stage IIIB: the cancer has spread into the large blood vessels and may have spread to 1 or more nearby lymph nodes.

• Stage IV: the cancer has spread to other parts of the body, such as lungs, bones, distant lymph nodes or other organs in the abdomen.

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What are the treatment options for bile duct cancer (cholangiocarcinoma)?

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The optimal treatment of bile duct cancer depends on the stage of the disease and the patient's fitness and wishes. If the disease is localised and has not spread to distant lymph nodes or organs, surgery to remove the tumour is the most aggressive option that also confers the best longer term outcomes, especially if it is combined with adjuvant systemic treatment (chemotherapy and/or immunotherapy). Surgery should be considered for all stages of localised bile duct cancer. The earlier the stage the more likely is that surgery is possible.

If the cancer has spread forming metastases in distant lymph nodes or organs, then the intent of treatment is palliative. This means the treatment goals are to extend life as much as possible and control the symptoms of the disease. In this setting systemic treatment with chemotherapy nad/or immunotherapy plays the main role and in some cases radiotherapy may also be useful.

All cases of bile duct cancer should be discussed in an MDT, which is a meeting of cancer specialist doctors of various specialties, including surgery, radiology and oncology, as well as other healthcare professionals, such as specialist nurses, dieticians etc. The MDT goes through each case and suggests an individualised plan.

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Can I ask for a second opinion?

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All cases of bile duct cancer should be discussed in an MDT and a personalised plan should be produced for each patient. Patients may ask for a second opinion as suggested treatment pathways may vary depending on availability of the various treatments and the experience of the MDT teams and specialist centres.

 

What is the role of surgery for bile duct cancer (cholangiocarcinoma)?

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Surgery is the most aggressive treatment option for bile duct cancers. It is also the one that may confer the best oncological outcomes and even a chance for cure (ie the cancer successfully removed and not coming back). Surgery should be considered as a treatment option for all cases of localised bile duct cancer (cancers that have not spread to far away organs creating metastasis). The earlier the stage the more likely is that surgery is possible. The best results are expected when surgery is followed by systemic treatment (adjuvant treatment) with chemotherapy and/or immunotherapy. 

The type of operation depends on the location of the tumour in the biliary system. For intrahepatic cholangiocarcinomas, a liver resection is required. For perihilar tumours, a liver resection combined with resection of the extrahepatic bile duct is nedeed. For distal cholangiocarcinomas a pancreeaticoduodenectomy (or Whipples) operation is required. In all these operations the local lymph nodes are removed together with the tumour. All these are major operations with substantial perioperative risks, including risk of mortality and therefore the patient's fitness and appropriate consenting is paramount. Very rarely, if the cancer is extensive throughout the biliary tree outside the liver (from the perihilar area down to the ampulla) a combined liver resection and pancreaticoduodenectomy may be performed (hepatopancreatectomy). 

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When a bile duct cancer (cholangiocarcinoma) is called inoperable?

 

Inoperable means that a cancer cannot be removed by surgery. There are two main reasons for a cancer to be called inoperable.

Firstly, if the cancer has spread to distant lymph nodes and organs forming metastases. In these cases, even if the main cancer (primary tumour) can be removed with surgery, the patient's life expectancy (survival) is no better than not having an operation. Therefore, surgery is not indicated. Exception to this may be very rare cases of oligometastatic disease (defined generally as less than 3 metastases) that remain stable on systemic treatment for a prolonged period of time. In these cases, some surgical times may offer an operation after thoroughly explaining to the patient that this is outside the usual practice. 

The second and more ambiguous scenario though, includes tumours that have not spread to distant organs, but involved vital vascular structures, such as the arteries and veins that feed the liver. Sometimes, these tumours are also called inoperable by surgical teams that have no experience in complex surgical resections. However, a substantial number of these tumours can be removed with surgery after utilising specialised surgical techniques, including vein resection and reconstruction, arterial divestment or arterial resection and reconstruction. These are even more complex operations and best carried out by surgeons with substantial experience in performing complex oncological resections of the liver and pancreas.  

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Why selecting your surgeon is important for a good outcome?

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Management of bile duct cancer (cholangiocarcinoma) is complex and therefore better delivered by specialist multidisciplinary teams. With regards to surgery for cholangiocarcinoma, publised evidence and studies in the literature support that outcomes are better if the operation is performed in a high volume centre. This is why this kind of surgery has been centralised in the UK for many years now. Even so, not all apsects of surgical treatment are offered everywhere. Within specialist centres and surgical teams, expertise and experience varies. These variations become more important in cases of tumours that involve major vessels, when experience in operating after neoadjuvant chemotherapy and on major vessels is crucial for a successful outcome. Techniques to remove and replace or separate from the tumour large veins and arteries during these operations are usually required and are not widely practiced. Therefore, identifying and selecting a surgeon with substantial experience is highly recommended.

Complex oncological surgery was the focus of Mr Chatzizacharias' fellowship training in the USA. Mr Chatzizacharias has brought these expertise back to the UK, where he has been delivering excellent outcomes in major complex resections for his patients.​

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Am I fit to have an operation?

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Due to the substantial risks of bile duct cancer operations, any patient that can have an operation should go through an assessment of fitness. This starts with the clinical teams, oncology and surgical teams, and continues with a pre-assessment appointment. In that appointment the patient will be reviewed by an anaesthetic doctor. Various tests, such as heart and lung tests or an exercise tolerance test, may be required to help with the assessment of fitness and final decision. With all the information in hand, the patient will be informed about specific risks and/or concerns; and after all questions are answered a decision is made. If a patient is not deemed fit for an operation or if he/she does not want to proceed with the operation, then they can be considered for other treatments.

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Am I too old to have an operation?

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Old age is not on its own precluding surgery. However, old age is related to frailty and medical conditions, such as heart and lung problems. Therefore, a careful assessment as described above and an open discussion with the patient about expectations and possible outcomes, including changes in every day life and its quality after an operation, are absolutely necessary.

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What is the role of chemotherapy for bile duct cancer (cholangiocarcinoma)?

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Chemotherapy can be delivered for bile duct cancer after an operation (adjuvant), before an operation (neoadjuvant) or if the cancer is inoperable (palliative). The purpose of adjuvant chemotherapy is to kill any cancer cells that are still circulating in the body after an operation. Adjuvant chemotherapy improves oncological outcomes after an operation. In cases of tumours that are locally extensive but not spread to distant lymph nodes or organs, chemotherapy may be delivered before an operation (neoadjuvant), with the purpose to shrink the tumour (downstaging). In cases of inoperable cholangiocarcinomas, either due of extensive local disease or due to distant metastasis, chemotherapy is delivered to control any symptoms and extend the patient's life as much as possible (palliative). 

There are various chemotherapy agents and combinations used for cholangiocarcinoma. The most common ones are: gemcitabine and cisplatin; folinic acid, fluorouracil (5FU) and oxaliplatin (FOLFOX); capecitabine and oxaliplatin (XELOX); gemcitabine and oxaliplatin (GEMOX) and gemcitabine and capecitabine. 

For any type of chemotherapy to be possible, jaundice has to be treated. This is achieved by placement of a stent in the bile duct either via a PTC or an ERCP. Chemotherapy can cause side effects and every patient may be affected in different ways. Side effects may include being sick, extreme tiredness and low blood cell levels. How patients tolerate chemotherapy and how the adverse effects are managed are important parameters for their management.

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What is the role of immunotherapy for bile duct cancer (cholangiocarcinoma)?

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Immunotherapy, also called biological therapy, biotherapy or biological response modifying therapy (BRM therapy), is a set of treatment techniques that boost the body’s natural defences to fight bile duct cancer. Some immunotherapy treatments boost the immune system overall, while others try to teach it to attack specific types of cells found in tumours. Treatments may include the administration of vaccines, tablets or monoclonal antibodies (these are a type of protein that can attach to cancer cells in the body). Durvalumab and pembrolizumab are two immunotherapy drugs that are used around the world to treat bile duct cancer. 

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What is the role of radiotherapy for bile duct cancer (cholangiocarcinoma)?

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Radiotherapy is an option for cancers that remain localised in the bile duct (have not metastasised) and also for treating metastatic sites. It can be delivered alone or in combination with chemotherapy (chemoradiotherapy). The purpose of radiotherapy is to control the cancer as much as possible and provide some relief from symptoms, such as pain or jaundice. However, it cannot kill the cancer completely.​

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Is liver transplantation possible for bile duct cancer (cholangiocarcinoma)?

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Liver transplantation has been performed around the world over the last few years for intrahepatic or perihilar cholangiocarcinomas. In the UK, there are plans for liver trasnplantation to be offered as a treatment option for specific cases of bile duct cancers, however this is not yet approved by the national regulating body. 

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What affects bile duct cancer (cholangiocarcinoma) prognosis?

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Once the diagnosis of bile duct cancer has been established, the prognosis depends on the extent of the disease and the treatment options. More specifically:

• the location of the cancer in the bile duct system

• the stage of the cancer and if it has spread to lymph nodes, nearby vessels or distant orgnas.

• any underlying conditions, such as chronic liver disease or primary sclerosing cholangitis

• CA19-9 levels

• whether the cancer can be completely removed by surgery

• whether the cancer will respond to any non-surgical treatments​​

In general, the prognosis for patients with cholangiocarcinoma is usually poor. The five-year survival rate for cholangiocarcinoma that hasn’t spread outside of the bile ducts ranges from 18-23%. That number drops to 2-3% for cancer that’s spread beyond bile ducts.

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Are there any clinical trials for bile duct cancer (cholangiocarcinoma)?

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Clinical trials are medical research studies that are trying to find better or new treatments for vbile duct cancer. There are pros and cons to taking part in a trial. For example, a trial may be an opportunity to receive a new treatment, however, there is no guarantee that every patient will receive it. Interested patients should speak to their cancer specialist about the existing trials and whether any of these are an option. An online trial finder tool is also available in the Cancer Research UK website.

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Useful websites for bile duct cancer (cholangiocarcinoma)

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Cancer research UK

National Comprehensive Cancer Network - guidelines for patients

European Society for Medical Oncology  - a guide for patients​​​​

The Cholangiocarcinoma Foundation