Cholangiocarcinoma (CCA) is a highly aggressive group of cancers that occur in the biliary tree and are classified according to their location: intrahepatic, perihilar, and distal. It is one of the most common primary hepatic malignancies, second to only hepatocellular carcinoma. It has a global annual incidence of 0.3 to 6 per 100,000 population and a mortality of 1 to 6 per 100,000 population. 

Because CCA is a rare cancer, there is still much we do not know about it; however, our knowledge of it has improved over the years, particularly in the areas of diagnosis and therapies. Prognosis remains poor, with a 5-year survival rate after resection of just 7%-20%. In addition, tumor recurrence rates remain high. 

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Researchers conducted a thorough review of the available scientific literature around the mechanisms of CCA and its management and published their findings in Nature Reviews Gastroenterology & Hepatology. This study in itself is an expert Consensus Statement, endorsed by the European Network for the Study of Cholangiocarcinoma (ENS-CCA). The researchers also provided suggestions on what they believe should be the next frontiers in CCA management. For the purpose of this article, we will be focusing on current and future CCA therapies. 

Surgical Resection 

Because CCA symptoms tend to become noticeable only during advanced stages of the disease, the majority of patients are not suitable candidates for surgical resection. Only around 25% of CCA patients are deemed eligible for surgery.

In addition, the majority of patients have tumors that are classified as large, with a median size of 6 cm, further complicating the resection option. The current goal of surgery is to achieve a complete margin-negative resection (R0) while ensuring that an adequate future liver remnant remains. In advanced disease, lymph nodes are often involved and have to be resected as well. 

In order to exclude occult metastatic disease, staging laparoscopy is usually carried out prior to resection. Increasingly, surgeons are resecting and reconstructing the hepatic artery and the portal vein. However, patients with CCA that abuts on the hepatic artery or the portal vein have a poor prognosis, and surgeons should be careful to weigh the small potential benefits of resection against the surgical mortality rate. Patients with distant metastases are unlikely to benefit from resection altogether.

Liver Transplantation 

Liver transplantation is considered when complete resection is impossible; however, some have opined that the high rate of recurrence (around 50%) does not justify the procedure. A multicenter retrospective study that was carried out paints a different picture: researchers studied 216 patients with early-stage, unresectable perihilar CCA that received neoadjuvant chemotherapy with liver transplantation and discovered they had a 5-year disease-free survival rate of 65%. 

Other similar studies looking into the effects of neoadjuvant chemotherapy combined with liver transplantation also show that they improve patient survival rates. However, liver transplantation as a management strategy does come with obvious limitations: the waiting list is notoriously long, and patients need to be on lifelong immunosuppression therapy. 

Palliative Chemotherapy 

There are 3 main criteria to consider when assessing the suitability of patients for palliative chemotherapy treatment: 

  • Patient fitness according to the Eastern Cooperative Oncology Group Performance Status (ECOG-PS). Patients with scores of 3 and above are unlikely to benefit from treatment. 
  • Distribution of the disease. 
  • Availability of tumor profiling. 

Research indicates that the first-line use of chemotherapy drugs cisplatin and gemcitabine is beneficial in patients with advanced CCA. Studies have shown that the combination of these 2 drugs improves overall survival compared to gemcitabine alone. Currently, researchers are exploring the efficacy of triple-chemotherapy, which is cisplatin and gemcitabine combined with another chemotherapy drug. 

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Future Recommendations 

The authors of this study pointed out a few key areas that require more research in the years ahead. For example, there is an urgent need to better identify risk factors for CCA so that early detection (and prevention) is possible. Currently, known risk factors of CCA account for only 20% of cases. More should also be done to address patients with known risk factors of CCA, such as improving treatment in hepatitis B and hepatitis C, as well as encouraging healthier lifestyles, such as reducing tobacco and alcohol consumption. 

We also need a better grasp of how environmental risk factors interact with genetic and molecular determinants in causing the disease. We need to ensure that CCA data coding is accurate and audited, as well as commit to conducting molecular profiling on a wider scale. 

In addition, it is important that we rethink how CCA is classified. “New classifications of CCAs based on the combination of clinical, radiological, histological, genomic and molecular features, and later evaluation of their associations with prognosis and treatment response, are mandatory,” the study team wrote. We need to be better at incorporating new data into our existing paradigms of CCA. 

CCA is usually treated in dedicated centers that are equipped with multidisciplinary expertise. This collaboration between disciplines, as well as international collaboration in the area of CCA research, will become increasingly vital as we seek to deepen our understanding of the disease. 

Among the areas of CCA that require research are: 

  • The identification of specific single nucleotide polymorphisms (SNPs) that are associated with CCA. 
  • A more thorough investigation into the factors that cause resistance to primary and secondary CCA therapies. 
  • The development of new adjuvant strategies.  
  • The use of artificial intelligence to process large quantities of CCA data.  

Researchers across the globe are studying CCA from various angles. It is our collective effort that will reinforce the link between basic and clinical science and improve the quality of life of our patients. 

References

Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. Published online June 30, 2020. doi:10.1038/s41575-020-0310-z

Macias RIR, Banales JM, Sangro B, Muntané J, et al. The search for novel diagnostic and prognostic biomarkers in cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis. 2018;1864(4 Pt B):1468-1477. doi:10.1016/j.bbadis.2017.08.002.