Adding Immunotherapy With Chemotherapy in Advanced Biliary Duct Cancer: An Overview

Introduction:

Bile duct cancer, also known as cholangiocarcinoma, is a cancer of bile ducts located inside the liver. Cancer develops when the cells that line the bile ducts proliferate and accumulate to form tumors or cancer. There are three types of bile duct cancers according to the location:

• Intrahepatic Bile Duct Cancer: This cancer develops in the bile ducts that are located within the liver.

• Perihilar Bile Duct Cancer: It is cancer that develops at the hilum part of the ducts where the ducts exit the liver. These cancers are also called Klatskin tumors.

• Distal Bile Duct Cancer: It develops in the ducts that are outside the liver and near the small intestine.

What Are the Causes for Bile Duct Cancers?

• The exact reason for the formation of bile duct cancer is yet to be understood. Researchers have observed that gene mutations could be the reason for the abnormal multiplication of cells. Most of these mutations are acquired later in life and are not hereditary.

• Genetic mutations of oncogenes and tumor suppressor genes lead to bile duct cancer. Oncogenes are the genes that control cell growth and cell division. Tumor suppressor genes regulate the rate of cell division and cell death at the right time. The reason for these genetic mutations is not understood yet.

• Few researchers attributed these mutations to inflammation or some random events.

What Are the Signs and Symptoms of Bile Duct Cancer?

Bile ducts are located deep within the body. Any abnormality like cancer can go undetected for a longer duration. This cancer remains asymptomatic till it reaches its advanced stages. Sometimes, symptoms are displayed during the early stage of cancer, which helps in rendering a treatment with a favorable prognosis.

Symptoms depend on the location of cancer, either intrahepatic or extrahepatic.

• Jaundice: Bile is a fluid that is formed in the liver and then is sent to the small intestine through bile ducts. In the small intestine, this bile helps in the digestion of the fats in the food. Bile consists of a chemical called bilirubin. The rise in bilirubin levels causes yellow discoloration of the skin and eyes. Most of the time, jaundice is caused due to inflammation of the liver. It is not necessary that cancer only can cause jaundice.

• Itching: Increased bilirubin levels in the body causes itching or scratching of the skin.

• Greasy Stools: If the bilirubin is trapped in the liver and is unable to reach the small intestine, the body cannot digest the fats. These undigested fats are the reason the stools become greasy.

• Light-colored Stools: Bilirubin is a pigment that adds color to the stools. In the absence of bilirubin, stools may appear pale or light-colored.

• Dark Urine: Increased bilirubin in blood causes urine to become darker.

• Abdominal Pain: Smaller tumors do not cause any pain, but as the tumor grows, discomfort also increases, causing belly pain, especially below the ribs on the right side.

• Weight Loss: Loss of weight and appetite is observed in individuals with bile duct cancer.

• Fever: Some patients become febrile.

• Nausea and Vomiting: Stomach upset and feeling of throw-up are generally observed.

The symptoms that are listed above do not diagnose bile duct cancer. Medical attention and doctor’s intervention are necessary for an accurate diagnosis. These symptoms are common for several other conditions. Hence a careful assessment of the patient is needed.

How Is Bile Duct Cancer Diagnosed?

The diagnosis should begin with obtaining a complete medical history to check for risk factors and observe symptoms typical of this condition. Examination of the abdomen to check for any lumps, tenderness or fluid build-up is done. It is diagnosed by using methods like ultrasound, computerized tomography (CT scans), and magnetic resonance imaging (MRI) along with magnetic resonance cholangiopancreatography.

What Are the Treatment Options for Bile Duct Cancer?

Four types of treatment modalities are offered to treat bile duct cancer. They are:

• Surgical Treatment:

  • Partial Hepatectomy: Surgery is performed on the part of the liver that is affected due to cancer.

  • Removal of the Bile Duct: If the tumor is small, a part of the bile duct is surgically removed that is affected by cancer. Lymphadenectomy is also performed, from which the tissue samples are sent to the pathology lab for further investigations.

  • Whipple Procedure: A surgical procedure that includes the removal of the head of the pancreas, the gallbladder, a part of the stomach, and a part of the small intestine with the involved bile duct.

If the doctors find it necessary, chemotherapy is prescribed to the patient to prevent any chance of recurrence of cancer. This type of therapy is called adjuvant therapy.

• Palliative Treatment:

  • Radiation Therapy: It uses high-intensity X-rays to kill cancer cells. The following are the methods to deliver radiation to treat bile duct cancer.

  • External Radiation Therapy: The source of the radiation is outside the body. A machine is used to expose the body to high-energy X-rays to kill cancer cells. Newer methods are being created to improve the effectiveness of radiotherapy. They are:

  • Hyperthermia Therapy: The temperature of the body is intentionally increased to make the cancer cells more sensitive to radiation and anti-cancer drugs.

Radiation therapy mostly are prescribed before, during, or after surgery, along with other treatment modalities

• Radiosensitizers: Few drugs, called radiosensitizers, that cause sensitization of cancer cells, making them weak and susceptible to radiation are used in a few cases.

• Internal Beam radiation Therapy: It uses small devices like needles, seeds, and catheters to introduce the radioactive material directly into the tumor mass or nearby area.

• Chemotherapy: It uses drugs to destroy cancer cells. These drugs are either given orally or injected directly into the bloodstream. The following are the methods to deliver chemotherapy:

• Systemic Chemotherapy: If the drug is consumed orally or injected via veins or muscle, the drug enters the bloodstream. These drugs then identify and destroy the cancer cells anywhere in the body. Systemic chemotherapy is given in patients with unresectable, metastatic, and recurrent bile duct cancers. Few such drugs are:

  • Gemcitabine and Cisplatin.

  • Capecitabine and Oxaliplatin.

  • Gemcitabine and Oxaliplatin.

  • Gemcitabine and Capecitabine.

• Regional Chemotherapy: When a drug is directly placed onto the organ or the affected area, it enters directly into the tumor mass, thereby destroying the cancer cells.

• Immunotherapy: It uses drugs that enhance the body’s immune system to identify and kill cancer cells. Immune checkpoint inhibitor therapy is one of the immunotherapies that use drugs to inhibit a few receptors like PD1 (programmed cell death 1). Due to this inhibition, the immune system is allowed to display a normal immune response, thereby killing the cancer cells. One such drug is Pembrolizumab which was recently approved by the food and drug administration (FDA) for the treatment of advanced cancers. There are more clinical trials that are being conducted in humans to develop better treatment regimens that can produce a favorable prognosis. These studies have shown hope to people for a better quality of life.

In one study, the drug named Durvalumab, which provides immune therapy and is used in many patients gave promising results.

What Is the Role of Immunotherapy combined with Chemotherapy in Advanced Bile Duct Cancer?

A new drug called Durvalumab is being tested in various patients for its effectiveness against advanced bile duct cancer. Durvalumab is an immune checkpoint inhibitor. This drug blocks programmed cell death L1 protein that leads to the enhanced immune response of the body. When it is prescribed along with other drugs like Cisplatin and Gemcitabine, it displays an increased survival rate in patients. The risk of death is reduced by 20% after the use of this treatment regimen.

In 2018, the United States food and drug administration (FDA) approved its use in unresectable, stage III non-small cell lung cancer. In 2020, FDA approved Durvalumab as an orphan drug to treat advanced biliary tract cancer. After one and a half a year of study, researchers observed that the increased survival rate might display further favorable results. We have to wait for further studies to complete, hoping for favorable results.

Conclusion:

Biliary duct cancer is a rare and aggressive form of cancer that requires a much better prognosis.

Immunotherapy with chemotherapy has shown promising results in the initial stages of the trial. An increase in survival rate is a good sign for patients, and much better results can be expected at the end of the study.