Bile duct cancer, also called cholangiocarcinoma, is a type of cancer that affects the slender tubes that carry the digestive bile fluid. The liver is anatomically connected to the small intestine and the gallbladder via the bile duct. Cholangiocarcinoma is rare and can develop in people at any age, but it generally occurs in those aged above 50 years.
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The study of bile duct cancer is relatively challenging. Around the world, research on the cause, diagnosis, and treatment of bile duct cancer is ongoing at many medical centers.
Research on bile duct surgery
To treat bile duct cancer, doctors are continually trying to improve ways to bring more people to the surgical table. Liver transplantation is considered the best treatment option for bile duct cancer, but other choices are also being analyzed. For instance, technical removal of cancer in the liver by surgery can be done, but this may lead to not much healthy liver left after surgery.
Portal vein embolization is a method used to block the transportation of blood to one part of the liver. As this particular portion of the liver is compressed, the remainder portion of the liver expands to compensate for this. After a few weeks, the expanded side of the liver exhibits improved health status, thereby increasing the possibility of surgical resection of the tumor on the contralateral side.
New molecular insights into bile duct cancer research
Over the last few years, researchers have made significant progress in understanding the molecular biology of bile duct cancer and identifying possible targets. For example, mutations in various genes have been associated with this type of cancer, and drugs targeting such genetic alterations have shown promising outcomes in clinical trials. The potential therapeutic targets in bile duct cancer include:
- The isocitrate dehydrogenase 1 (IDH1) gene encodes a critical enzyme involved in cellular metabolism. A malfunction of this gene or its protein product gene is associated with increasing levels of abnormal metabolites that promote cancer growth. Interestingly, mutations in IDH1 have recently been associated with bile duct cancer. Researchers observed that the P2RX7 (P2X purinoceptor 7) gene was turned down (downregulated) in bile duct cancer cells with mutations in the IDH1R1 gene. They also found that the genomic DNA sequence around the P2RX7 gene (i.e., the non-coding regulatory DNA sequence within the P2RX7 locus) is methylated in bile duct cancer cells. DNA methylation is a chemical change that can turn genes off through epigenetic pathways. Drugs that target the IDH1 protein have shown promise in clinical trials for bile duct cancer.
- The fibroblast growth factor receptor 2 (FGFR2) gene provides the instruction to synthesize a receptor tyrosine kinase involved in cell growth and differentiation. FGFR2 is a crucial protein for bone development, especially during embryonic development. It helps to signal specific immature cells in the developing embryo to become bone cells and form many different cell types. Mutations in the FGFR2 gene have also been implicated in bile duct cancer, and this gene showed an excellent prognostic value in patients with this type of cancer receiving systemic chemotherapy.
- KRAS (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is a gene that encodes for the KRAS protein, a small GTPase that plays a critical role in cellular signaling. Mutations in the KRAS gene are common in many cancers, including bile duct cancer. Drugs that target KRAS are currently in development, and there is hope that these drugs may be effective in treating bile duct cancer. For example, farnesyltransferase inhibitors (FTIs) are a class of drugs capable of blocking farnesylation, a class of post-translational modification that allows KRAS to attach to the cell membrane, where it can be activated and promote cell growth. FTIs block farnesylation, preventing KRAS activation and thus inhibiting cell growth.
- The protein kinase cAMP-activated catalytic subunit alpha (PRKACA) gene encodes a kinase enzyme capable of phosphorylating multiple cellular substrates in cancer cells. PRKACA-mediated phosphorylation activates a diverse range of signaling pathways that drive tumorigenesis. Researchers have recently discovered that PRKACA gene rearrangements are common in intraductal oncocytic papillary neoplasms of the bile duct.
Liver transplantation and its research
In the USA, research on liver transplants is being done in people whose intrahepatic and hilar bile duct cancers remain without spreading. However, when both lobes of the liver are affected, tumor removal is not possible with surgery. In this condition, the surgeon cannot recommend a transplant. In a high number of individuals, a liver transplant is not a choice, as finding a liver donor is extremely difficult.
There is always a danger of cancer to recur in transplant surgery. People who have undergone surgery are likely to survive for five years in a ratio of 1:5.
However, recent research results also state that the danger of acquiring cancer again is lowered by undergoing chemoradiotherapy (a combination of radiotherapy and chemotherapy) before surgery. Almost 50% of such liver transplant patients live for five years or more after completion of surgery. It has also been seen that 4 of 5 patients survived for five years after undergoing chemoradiotherapy before surgery. This treatment is associated with severe side effects and is only available to a small subset of patients with early-stage, localized cancer.
Therapies related to research on bile duct cancer
1. Chemotherapy and radiation therapy
To boost the performance of radiation therapy, researchers are evaluating different techniques. Three-dimensional conformal radiation therapy (3D-CRT), stereotactic body radiation therapy (SBRT), and intensity-modulated radiation therapy (IMRT) are radiation therapy modalities widely used in clinical practice due to the ability to conformally deliver radiation to tumor targets while minimizing dose to normal tissue. Intraoperative radiation (IORT) and proton beam radiation therapy techniques can be used but are generally unavailable.
For bile duct cancer, a mixture of new drugs is being tested as the effect of chemotherapy is not adequate. Studies are undergoing for delivering chemo drugs in different ways. For example, the combination of chemotherapy and embolization is called trans-arterial chemoembolization (TACE). Chemotherapeutic agents are frequently administered as microbeads to occlude and fill the hepatic artery.
2. Light therapy
Photodynamic therapy (PDT) is performed to destroy cancer cells using light. First, an agent sensitive to light and acceptable to the cancer cell is consumed. Then, bright light is shone on the cancer cell, which destroys the cancer cells by stimulating the drug. Second, a small stent (a tiny tube) is inserted into the bile duct to clear obstructions and restore normal bile flow to the intestine. A few problems came up while doing this trial. During this trial, the stent works efficiently along with PDT and more so than with only the stent.
- The efficiency of having a stent is not known in its early stages.
- Previous studies have shown that stenting alone is insufficient to achieve optimal outcomes in patients with biliary obstruction.
This trial has closed, and the results are awaited.
The drug administered with PDT is thought to be destroyed by the body. Conversely, doctors also consider that a small portion of the drug remains in the body even a month after treatment, which keeps growing and shows up during further treatment. Phase 4 of the research is investigating the duration of the stay of the drug in the body and the possibility of side effects during a second dose.
3. Radiofrequency ablation (RFA)
Cancer cells can be eradicated by heat through radio waves. Radiofrequency is one form of electrical energy used in ablation. Research says that bile duct cancer that cannot be removed from the liver by surgery can be controlled by RFA. Some researchers have hypothesized that recurrent bile duct cancer following liver surgery may be amenable to control.
RFA ( By Gujarat Liver Cancer Clinic - Dr. Hitesh Chavda)
4. Combined therapies
In 2022, the United States Food and Drug Administration (FDA) approved durvalumab (also called Imfinzi) in combination with gemcitabine and cisplatin for adults with advanced or metastatic biliary tract cancer. To evaluate the efficacy of durvalumab, a randomized trial called TOPAZ-1 was conducted. This test study showed that durvalumab plus chemotherapy improved overall survival and progression-free survival in patients with bile duct cancer.
References
- Cholangiocarcinoma (bile duct cancer) - Symptoms and causes (2023). Available at: https://www.mayoclinic.org/diseases-conditions/cholangiocarcinoma/symptoms-causes/syc-20352408 (Accessed: 1 September 2023).
- Bile Duct Cancer Research | Cholangiocarcinoma Research (2023). Available at: https://www.cancer.org/cancer/types/bile-duct-cancer/about/new-research.html (Accessed: 1 September 2023).
- http://www.cancerresearchuk.org/about-cancer/bile-duct-cancer/research-clinical-trials/research
- Patel, T. (2011) "Cholangiocarcinoma—controversies and challenges", Nature Reviews Gastroenterology & Hepatology, 8(4), pp. 189-200. doi: 10.1038/nrgastro.2011.20.
- Cancer Treatment Research (2023). Available at: https://www.cancer.gov/about-cancer/treatment/research (Accessed: 1 September 2023).
- https://rarediseases.info.nih.gov/diseases/9304/bile-duct-cancer
- Zhang, Xing, et al. "IDH1 as a frequently mutated gene has potential effect on exosomes releasement by epigenetically regulating P2RX7 in intrahepatic cholangiocarcinoma." Biomedicine & Pharmacotherapy 113 (2019): 108774.
- Rizzato, Mario, et al. "Prognostic impact of FGFR2/3 alterations in patients with biliary tract cancers receiving systemic chemotherapy: the BITCOIN study." European Journal of Cancer 166 (2022): 165-175.
- Bannoura, Sahar F., et al. "Targeting KRAS in pancreatic cancer: New drugs on the horizon." Cancer and Metastasis Reviews (2021): 1-17.
- Berndt, Norbert, Andrew D. Hamilton, and Saïd M. Sebti. "Targeting protein prenylation for cancer therapy." Nature Reviews Cancer 11.11 (2011): 775-791.
- Singhi, Aatur D., et al. "Recurrent rearrangements in PRKACA and PRKACB in intraductal oncocytic papillary neoplasms of the pancreas and bile duct." Gastroenterology 158.3 (2020): 573-582.
- US Food And Drug Administration. "FDA approves durvalumab for locally advanced or metastatic biliary tract cancer. 2022." (2022).
Further Reading