Cholangiocarcinomas (CCAs) are any cancers that occur along the biliary tree; they are extremely rare and carry a poor prognosis. This is especially true when the cancer is at an advanced stage or has metastasized to other parts of the body, which—given the typically late presentation of this disease—unfortunately, is common. 

How can physicians approach advanced or metastatic CCA in an evidence-based manner and give their patients the best chance for survival? To answer this question, we will be referring to 2 literature reviews: one by Ioffe and colleagues on the optimal management of patients with advanced or metastatic CCA, and another by Petrowsky and colleagues on modern therapeutic approaches for treating malignant liver tumors. 

A Range of Therapeutic Options 

The most important question in advanced CCA to ask is: Is it still resectable? Petrowsky and colleagues devoted much of their research to the various techniques, including highly innovative ones, of performing liver surgery.

Continue Reading

Recently, there has been much buzz around minimally invasive robotic liver surgery, which provides reprieve for problems surrounding laparoscopic liver resection, including limitations in vision and precision of motions. Ablation therapies also can be used to achieve local tissue destruction of liver tumors. 

Read more about CCA epidemiology

When metastasis does occur, it usually is at these sites: commonly, the local lymph nodes and the peritoneum; less commonly, the lungs and bone; rarer still, the brain. There are a few therapeutic approaches to treating CCA once it becomes unresectable, but none can be said to perform very well.

Systemic therapy, for example, is offered with palliative intent for unresectable or metastatic CCA. A landmark study in 2010 established the combination of gemcitabine and cisplatin as the standard frontline therapy for advanced/metastatic CCA. Later, another landmark study introduced oral fluoropyrimidine into the mix, demonstrating a small but statically significant improvement in median overall survival (OS). 

Radiation therapy is another treatment option, albeit also for palliative purposes for unresectable CCA. Historically, radiation therapy has not played a major role in the treatment of liver cancer.

“However, technological advances in the fields of imaging (for example, MRI and respiration-correlated CT), radiotherapy planning (for example, intensity-modulated radiotherapy) and delivery (for example, active motion compensation and image-guided radiotherapy) have allowed the safer delivery of ablative radiation to a defined cancer volume, while simultaneously sparing the remaining functional liver tissue,” Petrowsky et al wrote. 

Read more about CCA treatment

Immunotherapy is a therapeutic option approved for CCA patients with mismatch repair deficient (dMMR) tumors. This was based on a study involving the drug pembrolizumab and participants of 12 different tumor types, including CCA. Participants on pembrolizumab achieved a 53% objective response rate and 21% achieved a complete response.

However, another trial using pembrolizumab in patients with refractory solid tumors (including 104 with biliary tract primary tumors) recorded an overall response rate of 5.8% and a median OS of 9.1 months. In view of these findings, Ioffe et al commented, “The use of immunotherapy with checkpoint inhibitors has been tested in advanced CCA with disappointing results.”

Read more about CCA experimental therapies

A relatively new form of therapy is to target the mutations responsible for the cancer at the molecular level. Ioffe and colleagues noted, “Studies have shown that 11–15% of patients with biliary tract cancers have mutations in cancer risk genes, and experts have suggested that routine germline genetic testing may therefore be advantageous from a clinical standpoint in the care of these patients.”

One of the targets in CCA that has received the most attention is the fibroblast growth factor receptor (FGFR). Multiple agents are under evaluation targeting FGFR. The FDA has approved the use of pemigatinib and infigratinib (in 2020 and 2021 respectively) for treating patients with advanced CCA with FGFR2 fusion. 

Future Directions 

Ioffe and colleagues offer a realistic prediction about where the treatment landscape for advanced/metastatic CCA is heading:

“While research continues in this disease, we will see additional trials evaluating combination treatments for known targets, as well as new modalities towards novel targets. Furthermore, as we start to use these targeted therapies more widely, resistant mechanisms will emerge and studies guiding us on how to sequence these drugs will be of high importance.”

In summary, the treatment paradigm for CCA is: resect, and if unresectable, make it resectable (systemic therapy can sometimes successfully convert unresectable disease to resectable). If that fails, the focus shifts towards prolonging survival/palliative care.

A truly significant breakthrough in CCA treatment would be to break away from this tired paradigm and offer new possibilities for improving clinical outcomes. Currently, it seems that the best chance for this lies in genetic research and the development of gene therapies that target the disease at the molecular level. 

Having referenced a total of 111 studies for their literature review, Ioffe et al ended their paper by reporting that “the active and vibrant research in this disease allows for increased hope for improved outcomes in patients diagnosed with this aggressive cancer.” This should serve as encouragement to both healthcare givers and patients alike. 


Ioffe D, Phull P, Dotan E. Optimal management of patients with advanced or metastatic cholangiocarcinoma: An evidence-based reviewCancer Manag Res. Published online October 27, 2021. doi:10.2147/CMAR.S276104

Petrowsky H, Fritsch R, Guckenberger M, De Oliveira ML, Dutkowski P, Clavien PA. Modern therapeutic approaches for the treatment of malignant liver tumours. Nat Rev Gastroenterol Hepatol. 2020;17(12):755-772. doi:10.1038/s41575-020-0314-8