 Gang, how are we doing with this disease so far? We have increased recognition, more diagnoses, multidisciplinary care to get patients resected. With adjuvant therapy, there are some standards now. Are we doing better?

 I think so. We are seeing these patients, particularly for intrahepatic cholangiocarcinoma, for much longer than we ever did before. I’m not sure the prognosis has changed that much for perihilar or gallbladder cancer, but I think there are many options. There are promising clinical trials, and being in this business, you’ve got to be an optimist.

 There is that patient I see now who has what I call smoldering, quiet cholangiocarcinoma, where they may go 2, 3, 4 years with systemic therapy, liver-directed therapies, resections here and there. It feels like in that subgroup, we’re doing OK. Then there’s the other kind that feels more like pancreatic cancer; that’s a mean cancer and grows faster. Do you all see that same pattern in your patient base? Katie?

 I see enormous heterogeneity, and a lot of it is linked to the anatomy and how compromised the liver is by the tumor. Patients who have poor drainage and poor liver function out of the gate that we don’t successfully decompress have a very poor prognosis, while patients whose livers are working well and whose tumors aren’t impinging on a major duct do much better. You’re right, there’s biologic heterogeneity and that anatomic heterogeneity that I mentioned.

I saw a patient yesterday who is on her seventh line of systemic therapy, various iterations of gemcitabine, as well as 5-FU [fluorouracil] and the partner drugs. I’ve been treating her for 7 or 8 years now, and she has metastatic intrahepatic cholangiocarcinoma. There’s a huge spread of possibilities, and I do tell patients that, while the median survival from our phase III data tends to be still less than a year, we’re looking eagerly to this ongoing SWOG trial of GEM/CIS/Abraxane [gemcitabine, cisplatin, paclitaxel] vs GEM/CIS [gemcitabine, cisplatin] to see if we might change that benchmark. The median remains less than a year. Unlike a lot of other GI [gastrointestinal] cancers, the standard deviation is huge. There’s a much bigger splay in the possibilities.

 Maybe that goes back to our biology differences, and we may be able to figure that out at some point and not just let it play out in front of us. Sameek?

 I was going to add to what Katie and Milind have said. The idea that these patients have good hope and outcomes is there, it’s true. I have found myself keeping other people away from these patients who are thinking there is no hope or chance for long-term survival. I have to be very aggressive about making sure we unblock the ducts because when someone has a blocked duct and a problem, that’s going to impair ability to treat them, but it’s not the end of the world, right? You keep trying. Sometimes you unblock it from below with a stent, through ERCP [endoscopic retrograde cholangiopancreatography]. Sometimes you unblock it from the top, or sometimes you do both. Then you find a way to get them therapy. One thing I’ve seen is dismissal, like this diagnosis means there’s no hope. That’s not true at all. I advocate and push. When my patients get hospitalized, it’s not uncommon for me to have to push people to go beyond what they’re looking at. We have effective therapies; this is just a blocked duct, and we have to get them past this blockage. One thing I’ve learned is that we have to work with our colleagues and show them, “You know what, this patient could be here 5 years from now; we just have to get past this duct.”

 I agree. There is a battle we have with our colleagues who want to have that “goals of care” discussion from the get-go when we can turn these folks around. On the flip side, these patients can get complicated quickly. Katie alluded to external biliary drains—they can be high output or get dehydrated. You can watch them melt in front of you, so they do require additional support. This is not a casual patient who you see once a month. They take a lot of management and maintenance, and it speaks to the quality of life that these folks go through. We do ask a lot of our patients. This particular group has to go through a lot, but many of them are willing. With the right support, including palliative care, we can have a positive output and outcome for our patients.

Videos

GI oncologists react to a prognosis for patients with newly diagnosed advanced cholangiocarcinoma and discuss how they counsel patients on goals of care and treatment expectations.

Advanced Cholangiocarcinoma: Current Patient Prognosis

 We’ll talk later about curing these patients and surgery, adjuvant chemotherapy, etc. In that patient where it doesn’t look possible due to metastatic spread and we’re getting tissue, I would love your thoughts on how you specifically communicate with your IR [interventional radiology] groups about tissue acquisition when you know you’re going to want molecular profiling on a patient. With intrahepatic cholangiocarcinoma, usually the amount of tissue is not the problem; there’s plenty there, but it requires special advice with IR. Milind, what do you do when you want that kind of biopsy?

 John, I feel strongly about this because we often have patients referred to us who have an inadequate tissue diagnosis. There’s reluctance, more on the part of physicians than the patients sometimes, about getting another biopsy. We have to realize that to get a biopsy and get adequate NGS [next-generation sequencing] requires a good amount of core biopsies—generally 10 unstained slides and 1 actual slide. I’ve learned with experience that the amount of tumor tissue in the liver has to be more than the amount of tissue required in extrahepatic sites. The hepatocytes have a lot of DNA by themselves, so when you get a core biopsy from the liver, it has to be an even larger core or more than 1 core. That way, you have more than 40% tumor contact to get adequate NGS. With extrahepatic tissue, sometimes you are worried you may not get enough of a sample in the lung; even 30% is inadequate.

With extrahepatic or hilar cholangiocarcinoma, it’s a greater challenge. I agree with the points that Sameek made. We don’t have enough tissue. Frankly, our tools for diagnosis are imperfect in that setting at this time.

 Do you have to take your IR person out to lunch or give them a cup of coffee? How do you make sure? Do you put it in the order? How do you deal with that?

 Well, IR generally loves [cholangiocarcinoma cases] because we give them a lot of business there.

 They send us the fruit basket at Christmas, right?

 It’s critical to have advanced endoscopy colleagues, ERCP [endoscopic retrograde cholangiopancreatography] specialists, who have the tools to do the intraductal biopsies and not just brushings. If you have a patient with cholangiocarcinoma, you may want to send them to a center that has advanced endoscopy, not someone who doesn’t do ERCPs very often.

 Yes, we are spoiled, aren’t we? We have incredible teams around us that are remarkably skilled at these kinds of things, and not everybody has access to that. Adequate tissue is important for not just next-generation sequencing, IHC [immunohistochemistry], molecular profiling, etc. With the role of liquid biopsies, we did a nice job of covering how that can be supportive and supplemental; it may be useful over continuity but may even play a role in the diagnosis.

Best practices for working with other colleagues to ensure adequate tissue collection occurs when conducting a biopsy on a patient suspected of having cholangiocarcinoma, as well as considerations for next-generation sequencing.

Cholangiocarcinoma: Importance of Adequate Tissue Collection

 Let’s look at the work-up and overview of this disease. I’m always impressed with our colleagues in surgery and GI [gastrointestinal] who are charged with diagnosing, particularly extrahepatic and Klatskin or hilar, tumors. Milind, do you want to walk us through that original presentation diagnosis, the role of gene testing, etc?

 Klatskin tumors—also known as perihilar tumor, or hilar cholangiocarcinoma, extrahepatic cholangiocarcinoma—are complicated. These patients present with jaundice. There’s a subtle mass or none at all. There’s a malignant-looking stricture, and the ERCP [endoscopic retrograde cholangiopancreatography] comes back with cytology as nondiagnostic. It’s only 20% to 25% of the time that cytology is useful. If you have an associated lymph node, then you can get an endoscopic ultrasound and a biopsy. However, there’s a substantial proportion of patients—perhaps one-third—for whom the diagnosis is made on clinical grounds, where you have a mass, a stricture, and an elevated

CA [cancer antigen] 19-9. The consensus is that this is perihilar cholangiocarcinoma. These patients unfortunately go through investigation after investigation to come to the diagnosis.


The diagnosis of intrahepatic cholangiocarcinoma is relatively straightforward. You have a mass, or an infiltrate. If it’s amenable to needle biopsy, it is done, and then a diagnosis can be made. The diagnosis is one of exclusion, as we’ll discuss later. Immunohistochemical profile helps us narrow it down. We don’t need a lot of unnecessary diagnostic steps with a good immunohistochemical picture there.

 I struggle with this, particularly with the difficult-to-diagnose that you referred to. I felt crazy a year and a half or more ago when we were in tumor board, and they kept trying to do brushings that were stented; surgeons don’t want to act without a diagnosis. We don’t want to give chemotherapy or radiation without a diagnosis. I raised my hand and said, “Could we do a circulating test? If we found a cancer mutation, maybe that’s enough.” Where do you all think that is? I know there was an abstract; our friend Pashtoon Kasi published an abstract at ASCO GI [American Society of Clinical Oncology Gastroinstestinal Cancers Symposium] about this. Do you all think that’s appropriate? Is that enough? Is that just a lead? How do you incorporate that kind of testing?

 That’s a good question. Can we use a cell-free DNA test at initial diagnosis to say it’s cancer? That’s an interesting proposition. The challenge could be that not all intrahepatic or hilar cholangiocarcinomas are going to have a mutation on such a cell-free DNA test. The cell-free DNA tests that we have today are not as big in terms of the number of genes. If you don’t have a mutation represented on one of those gene panels from one of our current liquid biopsies, you may miss a diagnosis. Only a fraction of the patients with cholangiocarcinoma will have such a mutation; we can talk about the breakdown of those genes that we do expect.

The other thing is that not all cell-free DNA tests are going to adequately represent someone’s tumor. A characteristic that affects a liquid biopsy is the tumor site, so what organism infiltrated the tumor burdens. You can have a small tumor that is obstructing a duct, or in the distal duct, but does not have a large tumor burden, so you may not see a lot of cell-free material. The mutations may not catch something. Those 3 things can end up leading you to a false-negative. If positive, it is helpful, but if it’s negative, it’s not necessarily going to be helpful for early diagnosis.


I completely agree with Milind, but there could be a diagnostic escapade of things that happened to make the diagnosis. I am particularly pushy about it because we need the tissue at some point. The diagnosis can be made clinically. Sometimes you need to get someone started on treatment because they’re having a lot of trouble, but the tissue is really critical because it can help guide us for future therapies that are quite beneficial. I think we’ll talk about them today. Without that tissue, it’s hard to make such testing possible. While cell-free DNA is available, there are some caveats. I’m one of the biggest proponents of cell-free DNA as a tool and research tool at the moment, but a few things are going to get missed for various reasons: tumor burden, organ site effects, and whether you’ve even got the right probes for your test to capture the alteration. I worry about missing things that could really help people. I would never want to miss microsatellite instability. Even a 5% miss is a big miss, in my view, for microsatellites.

 I keep coming back to the tissue-informed cell-free DNA testing vs just casting a net. A negative doesn’t really help you, but if you had a positive, it would at least give us enough to say cancer or not. Katie, what would be a standard on the West Coast for this approach?

 We don’t use it routinely as part of diagnosis. I’ll admit, in some of those difficult cases where on the nth endoscopic attempt at a SpyBite intraductal biopsy or US biopsies, we keep getting atypical or suspicious results but nothing confirmatory. I have sent it before and felt reassured that when I see a 

 mutation, if there is a tumor with all the caveats that Sameek shared, it doesn’t confirm the primary sites. I may still have to infer that from the anatomy. It is not validated as a diagnostic test. In tumor board, there are cases where we try extremely hard, but I have seen us wait too long to start therapy, being uncomfortable with strong suspicions. Sometimes we have to make a clinical decision.

Types of assessments that are used to help appropriately work up a patient suspected of having a bile duct cancer.

Cholangiocarcinoma: Appropriate Diagnostic Work-Up

 This disease has changed. You are experts in this disease; you can carve out a career in bile duct cholangiocarcinomas. That suggests that there’s more of it out there and that we’re seeing an increase in the number of patients diagnosed with this disease. It’s mostly intrahepatic cholangiocarcinomas that we’re diagnosing. I’m very interested in your reflections on this. When I started, the cancer textbook had a big, thick, “unknown primary” chapter. That chapter has gotten skinnier and skinnier with molecular profiling and better understanding of the disease. This initial presentation of a large lesion in the liver with satellite lesions,we used to call it “metastatic unknown primary.” Now we recognize this pattern of when you have this large thing up in the top of the tree and some others scattered around; that may be cholangiocarcinoma. It’s a shift in just diagnosis. Katie, do you think that’s right, or is there something else going on here?

 That’s part of it, but I also think there’s a true incident. There’s an interesting paper from an immuno-oncologist, Shoop Saha and team at Harvard, where they looked at the incidence in SEER [Surveillance, Epidemiology, and End Results] database of cholangiocarcinoma and cancer of “unknown primary,” and they found an almost identical scope or scale of decrease in cancer of “unknown primary” diagnosis and increase of intrahepatic cholangiocarcinoma. On top of that, there was a greater increase just beyond that amount in the intrahepatics. We think the risk factors for intrahepatic cholangiocarcinoma are quite similar to HCC [hepatocellular carcinoma]. Many of those, including nonalcoholic fatty liver disease and the tale of the hepatitis C virus epidemic, are still relevant in increasing the intrahepatic component as they are for HCC.

 Are there other habits that we are doing? Who’s your typical patient you’re seeing with this? Younger, older? Men, women? No one?

 I’d say the age is somewhat lower than what you expect for many of the GI [gastrointestinal] cancers. The typical patients we see nowadays have intrahepatic cholangiocarcinoma. I want to reflect on something you said earlier, John, about making a career in this disease. I asked my colleagues in Boston years ago, “Can I make a career in biliary tract cancer?” He said, “That’s never happened,” and here we are. Going forward, in terms of why there are changes in the spectrum of these diseases, we have to reflect on the fact that lifestyles are changing. Obesity is an epidemic, particularly in Texas. We have one of the highest incidences of obesity in the nation and a correspondingly higher incidence of HCC and intrahepatic cholangiocarcinoma. I agree with Katie that part of it is this reclassification, but a lot of it is an increase from lifestyle changes that have led to an increase in intrahepatic cholangiocarcinoma.

 I’d like to interject to say that there’s also regional and geographic heterogeneity at play. In certain parts of the world, this intrahepatic increase may be because of nonalcoholic fatty liver disease and risk factors like obesity. One other risk factor we didn’t talk about that’s highly prevalent in Asia is fluke infection: Opisthorchis- and Clonorchis-type infections in freshwater fish. That’s the dominant cause in other parts of the world. While we may see an increase due to exposure to certain lifestyle risk factors here, in other places—Asia in particular—there can be fluke infections, and the waxing or waning public health measures may impact whether that risk factor comes into play.

 Sameek, I always think about the classic board question of the inflammatory bowel disease, with cholangitis and getting cholangiocarcinomas. All that is still true, but this is outside that, right? We’re not seeing more IBD [irritable bowel disease] necessarily leading to this?

 Any type of inflammatory state with constant healing and remodeling of the liver parenchyma can contribute, like in other sites of the body through inflammation and carcinogenesis. The fluke example is a good example of a different etiology in some parts of the world that genetically also looks different from what we see in North American intrahepatic cholangiocarcinoma. We don’t see the same pattern of some of the driver genes here that we’ve seen in other parts of the world at the same prevalence. They may still occur but at a different rate. That speaks to the intrinsic differences that can drive carcinogenesis. That also makes the epidemiology, and the associations among obesity, inflammation, geographic differences make the epidemiology harder to make these connections. That plays into the phenotype we see in our patients.



 Sorry, John. I never answered your question about the typical patient I see. The typical patient with intrahepatic cholangiocarcinoma, which is the most common that we see now, is middle-aged, presenting with some metabolic syndrome-type feature often discovered incidentally—liver enzyme elevation with statins, investigation of reflux, or something nonspecific. I see like a dimorphic type of picture. There’s another group of younger people who, often women, who have advanced disease at presentation with abdominal pain, back pain, or jaundice. I see both types of disease presentations.

Factors that may contribute to the rise in the number of cholangiocarcinoma cases being reported, as suggested by GI oncologists.

Rising Incidence of Cholangiocarcinoma

 Katie, is this 1 cancer? Is it 3 cancers? Is it more than that? Who gets it? Give us a little background on risk factors.



 Cholangiocarcinoma is one of the more complicated and heterogeneous cancers that we deal with. As you alluded to, it’s not really a single entity. The first place to start is looking at the anatomic heterogeneity of the disease. As Sameek introduced, we’ve got parts of the bile ducts that occur arise within the liver. We call those intrahepatic cholangiocarcinomas when they develop a cancer. Akin to your tree analogy, those are the little twigs that bear the leaves of the tree high up. Those little twigs can form a cancer. The bigger branches can form a more intraductal but large duct cancer. Right where those big branches converge to form the big trunk of the tree itself, those are some of the most difficult cancers, called hilar or perihilar cholangiocarcinoma, occurring at the bifurcation of the intrahepatic right and left hepatic ducts where they join into becoming the main hepatic duct. Both hilar cholangiocarcinomas were formerly known by the eponym Klatskin carcinoma. Even our nomenclature is confusing, with 3 different names—hilar, perihilar, and Klatskin—referring to the same thing.



Below the hilar claim to carcinomas, we have what we call distal cholangiocarcinoma. Anatomically, those are the cancers that arise distal to the cystic duct where the common bile duct meets the pancreas. Those 3 locations have very different clinical presentations based on both their location and genetics, which we’ll talk about in a moment. From location alone, those that are inside the liver have a lot of room to grow and spread before they cause symptoms often. An intrahepatic cholangiocarcinoma might become quite large before it starts to press on the capsule or obstruct the duct; unfortunately, they can be very advanced at the time of diagnosis.



Conversely, as cholangiocarcinomas start to grow in the distal bile duct or hilar locations, they will cause obstruction; people get yellow or dark urine and present with obstructive jaundice at an earlier stage. Their stage, complications, and requirements for percutaneous or endoscopic drainage differ widely, but patients’ experiences differ quite a bit, whether it’s intrahepatic, hilar, or distal.



You also asked about the biology, and this is where it gets interesting. This is a renaissance in the disease in that just in the past few years, we’ve learned that these anatomic locations are not only structurally and anatomically different but also seem to have different biologies. With the advent of available next-generation sequencing that can perform genomic analysis, even with small amounts of tissue, we’ve seen that intrahepatic cholangiocarcinomas have very different hilar and distal mutation profiles on the whole. As we start talking about treatments later, we’ll discuss some that are targetable by therapy.ut We see driver mutations, like 

 mutations, occurring in around 15% of intrahepatic cholangiocarcinomas but almost never occurring in the distals. The distals and hilars are more likely to have a KRAS or HER2 [human epidermal growth factor receptor 2] driver, so they’re genomically and anatomically different. Lastly, this probably reflects a different cell of origin, whereas the intrahepatic cholangiocarcinomas arise from those little twig-like ducts and form a cholangiole cellular carcinoma-type histology and may arise from hepatic progenitor stem cells. The more hilar and distal seem to arise from more epithelial cells.



 This makes no sense to me. I went into GI [gastrointestinal] cancer because it was easy. I could just give everybody FOLFOX [5-fluororacil, leucovorin, oxaliplatin], and I was good, right? It was right- vs left-sided colon cancers. Now you’re telling me that the same pathway has different biology depending on if it’s intrahepatic, gallbladder. They kept throwing curve balls at us when we were bundling these cancers. I like what you’re saying, that somehow these lining cells have different functions, maybe different characteristics and, therefore, different vulnerabilities. Does anybody else know why this might be, why we’re seeing these differences? I like your answer, but does anyone have any other explanation?



 Embryologically, these cancers derive differently. You have the perihilar, or the distal cholangiocarcinoma, developing along with the pancreas. I think of this as the entire continuum of the GI tract. Esophageal cancer is not the same as gastric cancer, just as it’s not the same as colon cancer. The biliary tract can be regarded as a continuum that has developed differentially during embryogenesis and development. I think of perihilar and distal more akin to pancreatic cancer in terms of genetic profile, as well as actionable or non-actionable. Intrahepatic cholangiocarcinoma is really its own entity, almost like a different disease. Gallbladder cancer, at times, looks more like breast cancer, with 15% HER2 amplification. We have been confusing ourselves and patients. Patients ask me, “What do I have? Do I have biliary cancer, bile duct cancer, or cholangiocarcinoma? What exactly do I have?” We need time; granularity will come in terms of these being different entities.



 I’ve been very interested in the colon cancer world with the microbiome and the interface between what’s outside the body and what’s inside the body. This might have something to do with this as well, that the carcinogenic insight, or instigating problem, may be different along that pathway, too. What you’re exposed to in the lower common bile duct and the gallbladder… Different exposures may lead to different kinds of cancers. Sameek, any other thoughts from your angle?



 The genetic characterization of these cancer types throughout the biliary tree supports our clinical diagnosis, the clinical and embryologic distinctions. What you said about the microbiome having a potential impact on the local inflammatory environment, certainly, the bile ducts are not without bacteria. Many of the cholangiocarcinomas that we see have some connection to some inflammatory disorder, but many don’t. That doesn’t mean it’s not a lack of inflammation in the bile duct and the tree. It’s particularly challenging for patients to understand that it’s 1 disease that’s really 10 diseases. The granularity will come with time as we learn more about these cancer types.

GI oncologists explain the complicated nature of cholangiocarcinoma as it relates to the disease’s underlying pathogenesis.

Heterogeneous Nature of Cholangiocarcinoma

®, “Clinical Updates on the Treatment of Advanced Cholangiocarcinoma.” I’m Dr John Marshall from The Ruesch Center for the Cure of Gastrointestinal Cancers at Georgetown University in Washington, DC. I am excited because I’m going to learn a lot from these smart people who have joined us on our broadcast. Let’s start with Dr Kate Kelley from the Helen Diller Family Comprehensive Cancer Center in San Francisco, California. Katie, good morning. How are you doing?
 

 Good morning. Thank you for having me.



 We’re glad to have you. Next, Dr Sameek Roychowdhury from The James Cancer Hospital and Solove Research Institute in Columbus, Ohio. Sameek, welcome.



 Last, but not least, Dr Milind Javle from The University of Texas MD Anderson Cancer Center in Houston, Texas. Milind, welcome.



 We’re going to dive in deep on what’s going on in cholangiocarcinoma. There is quite a bit of new data, both on the molecular and management side and on quality of life. There were some interesting new updates, many of whose authors are joining us from the 2021 ASCO GI [American Society of Clinical Oncology Gastrointestinal Cancers Symposium]. It was supposed to be in San Francisco, but we all did it from Zoom.



Let’s dive right in. Sameek, I’m going to let you kick us off. Talk about cholangiocarcinoma. When I was trained, this really wasn’t a diagnosis, but it’s become a hot item and has some subtleties to it.
 

 I did not see a lot of cholangiocarcinoma in my fellowship training. I’ve come to see a lot of it now, and cholangiocarcinoma is cancer affecting the liver. I think about the liver as 2 types of cells. The cells are sort of the factories and cities of the liver, the hepatocytes. These cells are the conduits of the liver—the arteries, veins, and the bile ducts. Each liver cell type can be affected by cancer. Cholangiocarcinoma is a bile duct cancer, so it can be seen anywhere—in a small or large duct in the liver, in a duct that’s just outside the liver. That’s often how we think about cholangiocarcinoma. Is it intrahepatic, inside the liver; perihilar, just outside the liver; or in a distal duct that exits the liver. That’s how we and our surgical colleagues think about the anatomy that affects the resectability of cholangiocarcinoma. It also tells us how patients present. With a tumor in a bile duct, people can have pain in their right upper quadrant, nausea, cholangitis, infection, as well as fever and weight loss. Those are the typical presenting symptoms. We’ve seen an increase in diagnoses of cholangiocarcinoma. Around 10,000 patients a year probably have bile duct cancer in the United States. It’s hard to estimate how many people get this cancer worldwide. I’d be interested to see what our colleagues have to say about the incidence and prevalence of this disease and how it can be confused with other diagnoses.



 I like your factory analogy. I always use trees because it looks like a tree to me: The common bile ducts are the trunk of the tree, the gallbladder is a little knot off the side of the tree, the wooden parts of the tree are the intrahepatic cholangio, and the leaves of the tree are the liver. We all have our analogies we use to teach our patients, as well as our fellows and others around us, about this disease.

Dr Sameek Roychowdhury, of the James Cancer Hospital Solove Research Institute, describes what cholangiocarcinoma is, specifically highlighting how the disease often presents in patients.

Milind Javle, MD, The University of Texas MD Anderson Cancer Center

Articles

Advanced Cholangiocarcinoma: Current Patient Prognosis

Cholangiocarcinoma: Importance of Adequate Tissue Collection

Cholangiocarcinoma: Appropriate Diagnostic Work-Up

Rising Incidence of Cholangiocarcinoma

Heterogeneous Nature of Cholangiocarcinoma

Cholangiocarcinoma Described