Hope Beyond Surgery: Optimizing Care for Cholangiocarcinoma

Domenech Asbun, MD

The management of cholangiocarcinoma continues to evolve, offering cautiously optimistic prospects for oncologists. While curative options remain elusive in this space, recent advances suggest potential avenues for improved outcomes.

According to Domenech Asbun, MD, some strategies that currently exist and continue to evolve include liver transplantation, immunotherapy integration, and surgical optimization. Still, further research is needed to refine patient selection criteria and optimize transplant protocols, and ongoing trials are exploring optimal dosing schedules and combination strategies with immunotherapy and other agents.

Further, lymphadenectomy and liver hypertrophy techniques continue to be underscored for resectable tumors. Implementing these techniques might improve outcomes for patients with cholangiocarcinoma and expand surgical eligibility.

Still, early detection and enhanced systemic therapies remain a challenge as noninvasive, scalable screening tools remain unavailable and chemotherapy, while often used, has evident limitations. Research efforts are exploring blood-based liquid biopsies, urine tests, salivary samples, and more as potential diagnostic tools. Experts also are focusing on the development of more efficacious systemic agents and exploring targeted therapies based on molecular profiling.

“If we get more effective systemic treatments and ways of attacking the cancer, it can make the survival better, and even survival after surgery,” Asbun told Targeted Oncology^TM, in an interview.

Asbun emphasized the importance of staying informed through established resources and collaborative networks. By doing this, oncologists can optimize patient care and contribute to the advancement of this field.

In the interview for Cholangiocarcinoma Awareness Day, Asbun discussed how the management of cholangiocarcinoma and treatment strategies continue to evolve and addressed unmet needs in early detection and systemic therapy.

Targeted Oncology: In your opinion, what has been the most exciting shift in treating cholangiocarcinoma?

Asbun: We are seeing some interesting series that show possibly a benefit to transplant in patients with unresectable cholangiocarcinoma. This is a small group of patients, highly selective, so a lot of patients do not qualify, and we do not have a robust amount of evidence to fall back on, but it is an interesting consideration.

What clinical trials have moved the needle in managing this disease?

Of the clinical trials that look at treatment of cholangiocarcinomas, some of the most important ones are also looking at the treatment of gallbladder cancer because they are rare cancers. They are basically all interconnected and so they get evaluated the same. The TOPAZ-1 trial [NCT03875235] is one important, recent trial that is looking at immunotherapy with durvalumab [Imfinzi], in addition to established systemic chemotherapy, gemcitabine and cisplatin.

Human Liver Anatomy: © nerthuz - stock.adobe.com

The TOPAZ-1 trial was a randomized, controlled trial in which 1 cohort got durvalumab, which is immunotherapy, with gemcitabine/cisplatin, and the other cohort got placebo with gemcitabine and cisplatin, and they saw how the overall survival [of the patient] was. This is for patients with unresectable biliary tract cancer, so cholangiocarcinoma or gallbladder cancer, or those who had had some type of treatment and had recurrence. In their survival analysis, the estimated 2-year survival for patients that got durvalumab was about 25%. For the patients that did not get durvalumab, it was near 10%. What that tells [us] is that it seems to be that the addition of durvalumab adds a pretty significant improvement in survival. The objective response rates for the durvalumab group were 26.7%, and 18.7% for placebo. Again, [we] see more of a response with durvalumab. Importantly, there were not any major differences in the rates of complications or of adverse events related to durvalumab, so it seems like it is just as safe as regular chemotherapy, but we added survival.

Another more recently published study, the KEYNOTE-966 study [NCT04003636], was looking at pembrolizumab [Keytruda] with gemcitabine/cisplatin vs placebo with gemcitabine and cisplatin, sort of in a similar structure. Here, their main finding they reported was median survival. They reported 12.5 months of median survival for patients that got pembrolizumab vs 10.8 months for patients who got placebo. This survival seems like not much, it is a little depressing, but it does give [us] an idea that this has a positive effect [and] maybe [we] can add to these results moving forward.

With just new options like these appearing, how are the standards-of-care for cholangiocarcinoma changing?

We are continuing to highlight the importance of lymphadenectomy in cholangiocarcinoma and making sure that you get an adequate lymph node harvest. This has been directly associated with overall survival prognosis. There is even a study that implies that in patients that had no possibly no positive lymph nodes initially, but then afterwards, did not get an adequate lymphadenectomy, they have worse survival than those that did get lymphadenectomy. Basically, taking out the adequate lymph nodes has an improvement on survival.

Looking at techniques to try to resect tumors that may not have been resectable otherwise, if [we] can make the part of the liver we are leaving behind bigger, [we] can hypertrophy it more. That sometimes gives better access to options for taking out the cancer, so we are continuing to improve our ways of hypertrophy on the other side of the liver. One important thing is, when we are talking about these types of chemotherapy, there is not good data on neoadjuvant therapy, so therapy before the surgery. We give it sometimes, and in some cases where it does not seem resectable, you will give the neoadjuvant therapy and hope that the tumor shrinks enough that it becomes resectable. But sometimes, the wins on the oncology side of things, for example, adding immunotherapy and seeing an effect, translates into a win on the surgical side, because those things can also help tumor receipt have enough of a response so that [we can] maybe proceed to surgery. We are not there yet, we have not proven that yet, but all of these advances benefit everyone that wants to try to treat the patient.

What novel targets or personalized approaches are on the horizon for the treatment of cholangiocarcinoma?

Further approaches when it comes to molecular profiling, immunotherapy, etc., and more of a specific role in the multidisciplinary approach. There are studies looking into, as I mentioned, transplant with small groups of highly selective patients. Not a lot of patients qualify for transplant in the studies, but those that do seem to have a better effect compared with those that did not get transplant. This is usually for patients with unresectable cancer. Sometimes when it is resectable, patients may benefit from things like ablation, radiation, or reversible electroporation, even transarterial chemoembolization, or transarterial radioembolization withyttrium-90 in some centers. All of these are things that have not been proven to fully have an established role in care, but they may provide a benefit, especially in patients where surgery is not an option. More and more, we are starting to see some type of benefit in individual patients.

Besides the challenges with neoadjuvant therapies, what other unmet needs exist in the space?

Better screening itself is not indicated because these tumors are rare enough, but a better idea of noninvasive, easy, scalable tests that could be used to maybe detect these tumors when they are still small [is needed]. One field of oncology essentially has to do with screening and with different ways of testing for signs of there being a tumor. They include things like a blood test, liquid biopsy, and there are some more preliminary studies that are looking at urine samples or even salivary samples to see if there are ways that you can pick up on on small indicators that either a patient is at risk or a patient is developing a tumor. These tumors are rare, so [they] do not qualify for population level screening, but they are deadly. If [one] can find ways to easily pick up on them, [we] might be able to have an impact on the patients that develop them.

What is the next step in research that could help revolutionize how we treat this disease?

Like screening, ways of detecting cancer quicker and ways of more effective systemic treatment is going to be important because chemotherapy has a benefit but has not shown to have a massive benefit and it is not something curative at all. If we get more effective systemic treatments and ways of attacking the cancer, it can make the survival better, and even survival after surgery.

Are there any resources or strategies you would recommend to community oncologists to help them stay updated on the advancements in the space?

There are a lot of guidelines, national and international guidelines. Probably the most well established, which most practitioners have probably heard of, are the [National Comprehensive Cancer Network (NCCN)] guidelines. That is a good place to start. A lot of these, especially something like the NCCN, when we first start looking at them, they seem intimidating. It has a ton of pages and very complex diagrams. But when one sits down and reads them, they are well structured and explained. [We] can kind of pick and choose the information that is needed.

Attending medical conferences, even online [is also beneficial]. Now, there are so many medical and surgical congresses and conferences that are published online that it is easy to just Google someone's past lectures on YouTube or on Google or anywhere you can find this information. There is a lot more access to information. If nothing else, make an oncologist or surgical colleague friend and give them a call every now and then if you have questions about a patient.