Cholangiocarcinoma: Subtypes, Presentation, and Treatment Strategies

Paula Kennedy-Newton

Natasha, would you like to begin by talking about the differences between intrahepatic, extrahepatic, and hilar cholangiocarcinoma? What is the typical presentation for each subtype, and what brings patients in to seek treatment?

Natasha Pinheiro

Extrahepatic cholangiocarcinoma is when the tumor starts in the bile duct, right outside of the liver, in the space before it gets to the small intestine. These patients tend to have an obstructive type process because of the tumor’s location in the bile duct. Approximately 90% of patients present with symptoms of jaundice or biliary obstruction. They, in turn, have symptoms that are associated with jaundice, such as generalized pruritus, clay-colored stools, and dark urine. They are likely to have high liver function tests (LFTs) or liver function abnormalities, as seen in their AST, ALT, alkaline phosphate, and bilirubin levels. Some other common symptoms are abdominal pain, usually in the right upper quadrant; weight loss; fever; fatigue; and malaise.

Intrahepatic cholangiocarcinoma develops in the cells within the bile duct, both inside and outside of the liver. Those patients have a slightly different presentation, with the one commonality being a history of a dull right upper quadrant pain. Patients with intrahepatic cholangiocarcinoma are less likely to be jaundiced because of the lack of obstruction in the bile duct. They will also have some unintentional weight loss and tend to have elevated alkaline phosphatase levels. However, a lot of these patients are asymptomatic. Their lesions are usually detected incidentally during workup with their PCP, who might find abnormal liver functions and might screen patients for other conditions such as hepatitis and cirrhosis.

Hilar cholangiocarcinoma also occurs in the bile duct, in the area that leads out of the liver and joins the gallbladder. These patients will have similar symptoms to those with intrahepatic disease. They will sometimes present with jaundice, fatigue, pruritus, unintentional weight loss, and right upper quadrant abdominal pain.

So with the exception of extrahepatic cholangiocarcinoma, the triad of symptoms that patients typically present with is jaundice, weight loss, and right upper quadrant pain.

Paula Kennedy-Newton

If a patient presents with these types of symptoms and there is concern for cholangiocarcinoma, what are the most important parts of their initial workup? What tools should be used to obtain an accurate diagnostic picture?

Natasha Pinheiro

Often we’ll first check liver function, which is part of a basic metabolic panel or a comprehensive blood screening. We can add the CEA, CA 19-9, and AFP tumor markers. We're going to see that more in the workup for a patient with intrahepatic disease. We’ll also do imaging, often starting with an abdominal ultrasound, MRI of the abdomen and liver, and a CT of the abdomen and pelvis.

Depending on whether we're thinking there is bile duct involvement or stones, we can perform magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). There is also endoscopic ultrasound with or without biopsy, depending on where we're seeing disease outside of the primary area.

Paula Kennedy-Newton

Additionally with ERCP, if there’s concern for obstruction, stent placement can often be performed at that time as well. This can help to normalize LFTs and put patients in a better situation to get started with treatment and also to feel better overall.

Natasha Pinheiro

Yes, that’s correct. Do you want to talk about typical treatments once a diagnosis is made?

Paula Kennedy-Newton

Yes, absolutely. As you mentioned, imaging is an essential part of initial workup. We can't say enough about the importance of good-quality imaging, especially in patients with cholangiocarcinoma. It‘s so important that we know what we're dealing with in terms of the subtype and the anatomy of their particular cancer, including what structures are involved.

The first-line approach for patients with any type of cholangiocarcinoma, if possible, is surgical resection. Resectability is based on multiple factors, which is why having thorough and high-quality diagnostic imaging at the time of workup is so crucial. Surgical resection is the only treatment approach that offers the possibility of cure; patients who are able to have surgical resection have the highest overall survival rates. The goal with surgical resection is a complete resection with negative margins and regional lymphadenectomy. It can be quite complicated to determine if a patient is a surgical candidate, and these types of surgeries can be very complex. For this reason, it’s advantageous for patients to be evaluated at a larger center that performs a high volume of these types of surgeries and has surgeons who are able to determine if the surgical goals can be met and whether it is safe and most beneficial to proceed with resection.

As a side note, it’s important to mention that liver transplant may be an option for certain patients with hilar cholangiocarcinoma. This requires evaluation at a large transplant center by a multidisciplinary transplant team. Patients will typically complete a course of concurrent chemoradiation as the first step in their overall treatment plan.

Natasha Pinheiro

What about indications that a patient is a candidate for systemic therapy? Can you talk a bit about that?

Paula Kennedy-Newton

We frequently see patients whose disease is borderline resectable for one reason or another. In this scenario, neoadjuvant chemotherapy or chemoradiation can be used to try to improve their chances of getting to surgical resection. For patients who are able undergo upfront surgical resection, adjuvant chemotherapy is likely to be a part of the treatment plan. Patients who have positive microscopic margins (R1) or any degree of residual local disease (R2) at the time of resection and patients who have any positive regional lymph nodes will be strongly advised to undergo adjuvant chemotherapy. However, the National Comprehensive Cancer Network (NCCN) Guidelines¹ recommend consideration of systemic therapy even for patients who have an R0 resection because of the high risk of recurrence with this particular type of tumor and the concern that there could be microscopic disease that was not visible during surgery.

Our mainstays for neoadjuvant or adjuvant chemotherapy are either a gemcitabine- or fluoropyrimidine-based regimen. Also, for patients who have unresectable or metastatic disease at the time of presentation, chemotherapy is going to be our standard approach utilizing one of these regimens.

In my practice, our first line is typically gemcitabine in combination with a platinum agent, either cisplatin or oxaliplatin. Which combination to use is determined based on the patient's individual clinical presentation, including performance status and comorbidities. For patients who are younger with a good performance status and who wish to be treated aggressively, perhaps with the goal to downstage in order to get to surgical resection, triplet therapy with gemcitabine, cisplatin, and nab-paclitaxel can be considered. If a gemcitabine-based regimen is either not going to be tolerable for a patient or if they’ve received it already and had disease progression, then a fluoropyrimidine-based regimen such as continuous fluorouracil or capecitabine in combination with something like oxaliplatin would be our next option.

It is also important to mention that, per the NCCN Guidelines,¹ when making the determination regarding which systemic therapy would be optimal, clinical trials are the preferred option when available and should always be considered and discussed with patients.

The TOPAZ-1 study² was presented at the ASCO Gastrointestinal Cancers Symposium in January 2022. It showed that pairing durvalumab, an immunotherapy agent, with our standard chemotherapy combination of gemcitabine and cisplatin improved overall survival by approximately 20% as compared with patients being treated with gemcitabine and cisplatin alone, regardless of PD-L1 expression status.

Natasha, I'm sure you’ve had patients who come to the clinic excited about an immunotherapy agent that they’ve heard about and wanting to know whether it could be an option for them. Any time we can add something in concert with what we’re already using standardly to provide better overall control and longer duration of control is an exciting development. The addition of durvalumab is something that we're now considering first line in patients when we're treating them with gemcitabine and cisplatin. This is especially important for patients who have a history of cirrhosis and who could potentially have a mixed cholangiocarcinoma and hepatocellular carcinoma (HCC) diagnosis. If that is a concern, adding durvalumab can be beneficial because immunotherapy is one of the mainstays of treatment for HCC.

Natasha Pinheiro

With regard to systemic therapy, do you see a space in the treatment of cholangiocarcinoma that leaves us the option for next-generation sequencing (NGS)? Within a workup, when should NGS be completed?

Paula Kennedy-Newton

NGS is tremendously important in obtaining the full clinic picture for our patients with cholangiocarcinoma. For patients with chemo refractory disease that has progressed through the first- and second-line chemotherapy options or for patients who have not been able to tolerate chemotherapy, NGS can reveal additional treatment options. Ideally, NGS will be completed early as part of a patient’s initial workup, as recommended in the NCCN Guidelines.¹ This can be accomplished either through sequencing tumor tissue from biopsy or surgery or by testing the circulating tumor DNA to identify targetable molecular abnormalities.

Patients with cholangiocarcinoma tend to have molecular abnormalities and tumor characteristics that make them candidates for certain targeted therapies. For example, patients with MSI-high tumors or tumors that have a high tumor mutation burden would be candidates for treatment with pembrolizumab. Pembrolizumab is another immunotherapy agent that is used frequently for several different indications and tends to be well tolerated. The FIGHT-202³ study evaluated single-agent pemigatinib (Pemazyre) for patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. It showed an overall response rate of 36% and medium duration of response of 9.1 months. Infigratinib is also useful for patients with FGFR2 fusions. Patients with IDH1 mutations can receive ivosidenib, and patients with HER2-positive disease can be treated with trastuzumab plus pertuzumab. That's just to name a few; there are many other potential targetable alterations in cholangiocarcinoma.

I cannot stress enough the importance of NGS and having the information that it provides in our back pocket to use if patients experience progression through standard systemic therapy options. That being said, we use systemic therapy to try to prevent progression of metastatic disease, but oftentimes we'll use chemotherapy in conjunction with more liver-directed therapies. Natasha, can you speak to those?

Natasha Pinheiro

Sure. I’d like to talk about the hepatic arterial infusion pump, which is used for liver-directed chemotherapy. These pumps can be found at a lot of larger centers, including mine (Memorial Sloan Kettering Cancer Institute). Hepatic arterial infusion pumps are approximately the size of a hockey puck and are placed into a patient’s abdominal cavity. The patient has a catheter that goes into one of the larger arteries that feeds into the liver, which allows us to treat directly into the liver. We usually use floxuridine, a fluorouracil-based drug, and we are able to administer it at significantly higher doses into the liver than we could ever give it systemically because the liver regenerates itself. We have been using these pumps for patients with cholangiocarcinoma who otherwise have disease control outside of the liver or no extrahepatic disease.

In treating the liver directly and with high drug doses, the hope is to give us overall control of the liver disease, ideally creating the potential for a full resection. We would start by resecting what we can, especially for multifocal liver disease. For bilobar disease, we resect what is appropriate, place the pump, and then treat the disease that remains directly with floxuridine. The goal is to control it to such an extent that we can perform a second surgery and ideally leave the patient without disease.

These pumps were originally used for patients with colorectal cancer with liver-only metastases. We have been using it to a lesser degree in cholangiocarcinoma for about the past 20 plus years. However, the population of people in North America who present with cholangiocarcinoma is significantly smaller than the percentage of patients with colorectal cancer, which could account for this difference.

The downside to treating directly into the liver with floxuridine is liver toxicity. In order to somewhat offset this, patients do not receive floxuridine every cycle; instead, treatment is alternated with flushes—typically with heparin and saline—to help take away any sort of inflammation that could occur in the liver. On week 1, patients will get a flush, and it dwells in the pump. Two weeks later, they’ll receive the floxuridine. Two weeks later, they’ll get the flush, and then 2 weeks later, they’ll get the floxuridine. If at any point a patient’s LFTs go beyond what their baseline numbers were, then we then would add the steroid dexamethasone into the flush to help decrease the inflammation in the liver.

There are very few centers that can perform this. A center must have physicians and hepatic surgeons who are versed in the placement of the pump as well as medical oncologists who are trained in the management of floxuridine in the pump. There are very specific guidelines regarding how it is dosed based on the patient's LFTs. It is a very specialized and almost niche treatment, but it has offered a lot of positive outcomes for patients with liver-only disease.

Paula Kennedy-Newton

Does radiation therapy play a significant role in the treatment options for certain patients?

Natasha Pinheiro

For institutions that don't have access to the pump or for patients with more diffuse disease, there is always external beam radiation. This also tends to be used for patients with unresectable disease or for whom surgery is inappropriate based on other medical comorbidities.

Stereotactic body radiation therapy can similarly be used for patients with unresectable disease or for whom surgery is not appropriate because of other comorbidities. Another option is ablation, which includes radio frequency, cryoablation, microwave, and percutaneous alcohol ablation. With ablation, we will likely also treat the patient with some sort of systemic therapy—often an oral drug such as capecitabine or gemcitabine—with the radiation. There is also artery-directed therapy, including transarterial embolization, chemoembolization, radio embolization, and Y-90 microspheres. These are all typically performed at large, comprehensive cancer centers, where they have interventional radiologists who are specialized in these liver-directed therapies. We also often use systemic therapy—either a gemcitabine- or fluorouracil-based drug—in conjunction with the liver-directed therapy.

Paula Kennedy-Newton

Finally, another treatment option that’s important to mention is best supportive care. This should be discussed with patients who experience progression through our standard treatment options, who are not able to tolerate them, or who are experiencing overall clinical decline. We frequently involve our palliative care colleagues for their expertise in symptom management to optimize quality of life.

We have now reviewed the principles of workup and treatment for cholangiocarcinoma, including surgery, systemic therapy, liver-directed therapy, best supportive care, and a combination of all. With that being said, I think a point of emphasis in our discussion is the lasting importance of how we begin when patients with cholangiocarcinoma present to us; the key elements of their initial workup that will affect the entirety of their treatment course, most notably high-quality imaging, endoscopic intervention to optimize liver function, and NGS testing. We can’t underestimate the importance of a solid beginning.