Flavio, we often see patients in our clinic who have had resected intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and then it’s confusing in terms of do we give them capecitabine per the BILCAP study, do you do chemoradiation? Who are the patients who don’t need adjuvant therapy? Can you educate us on this topic?

 I can give you my perspective certainly, and I think I’ll rely on my colleagues as well to chime in. I think as we’re getting more patients to surgery, this is becoming a very important question. For a long time, there was no adjuvant therapy, and in fact if you look back, the initial trials mainly done in Japan did not show any benefit. BILCAP, as you mentioned, was the first one to really show a benefit, although as you know it took about 10 years to accrue. It was a very mixed population, and the majority of patients had distal cholangiocarcinoma, so it’s always a question as to how applicable [the data] are to other tumor sites. In the end, it is the standard of care that we have. I know there are other trials that are in development, [such as] the ACTICCA trial that had been amended to compare now gem/cis [gemcitabine and cisplatin] with capecitabine. We’re obviously eagerly awaiting those results. We did have the STAMP trial that was presented at ASCO [American Society of Clinical Oncology annual meeting], looking at specifically node-positive hilar cholangio and other extrahepatic cholangiocarcinoma, which did not show a signal. But I certainly don’t think it needs to be abandoned. I think the field is ripe. We did mention earlier about the patients who have MSI [microsatellite instability]-high tumors, what is the role of immunotherapy in the adjuvant setting? I think that’s another area that’s ripe for investigation.

 I’ll just add systemic-therapy wise, BILCAP was a complicated study that has some concerns about the statistics that were done, and whether you include patients who started the drug or you include all comers changes whether it’s positive or negative as a study. There are now some data from Japan with S-1 [oral fluoropyrimidine], which is a similar drug, where the curves are almost superimposable with BILCAP, so I think we have a little more confidence that adjuvant therapy is beneficial in this cancer. Obviously gemcitabine with cisplatin is now the basis of our treatment in advanced disease. It seems logical that we should be moving that to the adjuvant setting, but there was a randomized study of capecitabine versus gemcitabine and cisplatin where gemcitabine and cisplatin did not appear to improve outcomes over capecitabine.

So at least for now, I agree, capecitabine is the closest thing we have to a standard of care for adjuvant therapy. Whether particularly high-risk patients, patients with nodal disease or R1 [microscopic tumor] resections would benefit from radiation, I think is an unanswered question, but many of us would do that. Some of us would add in gemcitabine for particularly high-risk patients based on SWOG S0809 even though that’s a single-arm study. There are a lot of unanswered questions, I wish we had more data.

Videos

Experts provide brief perspective on the use of adjuvant treatment approaches for patients with biliary tract cancers.

Understanding the Role of Adjuvant Therapy in Biliary Tract Cancers  

Anjana, we don’t have a lot of time to discuss transplant, but you are our transplant expert here. Could you briefly describe in just a few lines, what are the indications for transplant in biliary tract cancer?

 Of course. I think that depends, again, on the location of the tumor. What’s tried and true is the Mayo [Clinic] protocol for hilar cholangiocarcinoma, the class of tumors we’re talking about. For those patients, there are very specific inclusion/exclusion criteria that centers that do it often follow. It could even be a modified version, but the inclusion criteria are always the same. You have to have a tumor radial size under 3 cm. You need ideally pathologic confirmed hilar cholangio, but as you stated, that’s not always easy, even with cholangioscopy and FISH [fluorescence in situ hybridization]. But in that case, you need a CA19-9 [serum marker] of at least greater than 100 U/mL and the presence of a radiographically malignant stricture. You can have metastasis and you can have positive nodes. Those patients undergo lead-in chemoradiation for 6 weeks and then maintenance chemotherapy to transplant, ideally with staging every 2 to 3 months. That’s where living donation is ideal because then you can schedule that surgery.

Now, back to what Flavio was talking about as far as peripheral lesions, there are multicenter and international data for, incidentally found most of the time, smaller peripheral cholangiocarcinomas that have excellent survival, though very early. We have also adopted what you all do ... with intrahepatic cholangio. We follow the same inclusion criteria there as well. These are patients with intrahepatic cholangio who are unresectable without metastases who have at least 6 months of stability on chemotherapy. Then we offer them a transplant. I do feel like we have a relatively high rate of dropout, probably not as much as you see in metastatic colorectal [cancer] for transplant. This is another aspect of it; we’re are sometimes seeing them too late, and so when is the right time is also something we struggle with. But the ones who have undergone that protocol, right now we have 9 patients for whom we’ve done that in the last 5 years, and hopefully, we too will get those data out there soon. I think that more and more centers are thinking about absolutes and overall survival. As you all showed at Methodist, yes, your 1-, 3-, and 5-year survival rates in these patients who get transplants versus who don’t are significantly higher, and maybe not necessarily the metrics that the transplant community likes to hold onto. That’s a point of debate too, but it is an option that patients do quite well with.

Before closing out their review of early-stage biliary tract cancer treatment options, panelists consider the role of transplant in the setting.

What is the Role of Transplant in Early-Stage Biliary Tract Cancers? 

 Flavio, you raise important issues. I also wonder about the role of surgery in some of these patients who have MSI [microsatellite instability]–high, but we should move on. As I expected, this panel has a lot to say because you know so much, but we’re running a little behind. I’m going to go to the next topic, which is the principles of management. I’m going to discuss this a little because this is an early stage. I’m going to get your opinion, Anjana and Flavio, because these are the kinds of patients you might end up seeing. For early stage biliary tract cancer, what are some of those surgical considerations? If you see a large mass, Flavio, would you automatically say this is resectable or unresectable, or is there a rule for multimodality therapy today?

 You’re hitting on what we struggle with in our clinic all the time. The standard of care for localized disease is still surgery, and that’s what all of us want as the goal to get patients to try to get the best long-term outcome. We must focus on a couple of different biological parameters, though. Typically, it’s rare that we’ll see a small peripheral liver lesion that’s clearly resectable, perhaps even minimally invasive. More often than not, we’re seeing a large tumor or a tumor with, let’s say, satellite lesions. The multifocality of intrahepatic cholangiocarcinoma can sometimes be challenging because we don’t know if this is truly a T2 disease or intrahepatic metastases or M1 disease. This is something where we’re trying to refine our management strategy.

The other piece that makes it complicated is the lymph nodes. Often we’ll see patients that perhaps have some liver disease and may have some enlarged lymph nodes perhaps due to their cirrhosis, but are they also perhaps involved with cancer? We know that lymph node–positive disease is obviously going to do a little worse, and maybe those patients should get some up-front therapy, whether that’s systemic therapy or locoregional therapy. Hilar cholangiocarcinomas are probably the more difficult ones because typically, as Ruth suggested, they present with locally advanced diseases that render them either irresectable. Then we have to think about other strategies. As we’ve refined the systemic therapy and the targeted therapy, my hope is to get these in the preoperative setting, particularly for that patient population. I’m curious to hear what Anjana has to say.

 Thank you. I agree. I talked to Milind quite a bit through our oncologist and other specialists throughout the United States, when we see some of these patients, [regarding] the approach because it’s so varied. In our practice and maybe it leans to because we do offer transplants, we get maybe some more locally advanced disease. As you said, we always try to see if we can resect these patients. Unless it’s PSC [primary sclerosing cholangitis] or hilar cholangiocarcinoma, transplant is clearly a pure outcome. We try to see if there’s resectability that can be achieved. For patients who have these nodes that you’re mentioning or more infiltrative-type tumor, we do an up-front which is our protocol of chemotherapy. Then we do radioembolization with Y90 [yttrium-90] or TARE [transarterial radioembolization] because in our practice—this may be a Chicago-based thing—in certain centers, [depending on] where you train, you see that nice contralateral hypertrophy that you’d see with portal vein embolization but with the additional tumor adverse effect that TARE offers. That gives us some idea of the biology of these tumors because you have to wait about 3 months to see that ultimate hypertrophy. That’s usually our practice and there are data. UCLA published their data a year or so ago in the 

. They had very varied tumor types. It was all lumped together in various locoregional therapies. The idea is that multimodal therapy has better, longer outcomes. There’s a role for it in the right patient. I guess that’s what you’re asking: who is the right patient? You do it for everyone. Are there specific criteria? We don’t have enough to know, other than center experiences and talking among ourselves.

 Thank you, Anjana and Flavio. There’s a lot to unpack there. You discussed surgically resectable disease, preoperative chemotherapy, and preoperative TARE in an attempt to hypertrophy the contralateral lobe. Clearly, there’s a role for multimodality therapy in the management of even surgically resectable diseases. Anjana, you touched on an interesting point. When you have a locally advanced disease that is perhaps not resectable, there’s a struggle in terms of the best approach. Do you use radioembolization? Do you use radiation therapy? Do you use hepatic arterial infusion therapy? Chemoembolization in some cases? How do you decide on the choice of liver-directed therapy, or is it mostly center dependent? How do you make that decision? Let’s start with you Anjana and then go to Flavio.

 That’s a great question. I often stress that you have to do what your center is really good at. That’s how you get optimal outcomes because we don’t have a true standard of care of which locoregional therapy is ideal. We have data on TACE [transarterial chemoembolization], we have data on TARE, we have data on SBRT [stereotactic body radiation therapy]. I’ve been in conferences where there are debates based on where you practice what’s better. You can always show your data and say, “We do this really well. Everyone should get this.” Or “We do this really well. Everyone should get this.” I don’t necessarily agree with that 1 size for everybody. You have to do what’s best at your center that will give the best outcome.

We don’t personally do a lot of HAI [hepatic artery infusion] because it makes transplant a little difficult, and our surgeons don’t love it. We also see the downstream effects of the biliary issues with it. This could be biased because we see these advanced patients in the sense of liberty compensation after they’ve had HAI for a while, so we don’t do that often. But we’ve used other modalities that you’re describing, including TACE and SBRT, but we tend to move toward TARE. I really think it’s center and expertise dependent.

 This is where the key is the multidisciplinary discussion. Have all the stakeholders at the table. We also offer the whole gambit from locoregional therapies to transplants. We have a very active hepatic artery infusion program. We have an institutional trial, and we’re participating in other trials because there’s a reasonable rationale for this. Sometimes we have these discussions because we don’t want to burn bridges. For example, if patients have previous TARE, they aren’t candidates for HAI. However, the reverse is possible. A transplant is still possible after HAI. I sometimes hear my transplant colleagues saying that it might be more difficult, but it’s not mutually exclusive. What’s interesting is that the data on HAI have evolved to say that patients with lymph node–positive disease may benefit from HAI prior to surgery. That’s evolving. We haven’t considered the role of adjuvant HAI after resection because the majority of recurrences for intrahepatic cholangiocarcinoma are going to be in the liver. It takes a village to discuss and make all the options available to patients with an eye on treatment sequencing and making sure bridges aren’t burned.

 That’s a great way to explain it as far as bridges not being burned. I agree. I’m not saying I don’t like HAI. I’m saying our center experience. You are absolutely right: we do transplants after HAI. I’m not a surgeon. I can tell you only that our surgeons don’t love that field.

Centering discussion on early-stage biliary tract cancers, expert panelists consider the respective roles of surgery and embolization strategies in this setting.

Treatment Options for Early-Stage Biliary Tract Cancers

 You highlighted the role of biomarker testing. Ruth, is this standard in your practice? One barrier you face for biomarker testing is that often tissue is the issue. We don’t get enough tissue. How do you deal with this situation, in which we want biomarker testing yet not be able to [have it]?

 For everyone who’s going to get systemic therapy, we’ll try to get a tumor profile. We run into a situation in which there’s an insufficient amount of tumor for molecular testing. We try to use circulating DNA as liquid biopsy profile. Although we’re moving ahead and still collecting data, we try to look at the concordance between tumor profile and liquid biopsy profile. In the case when there’s no tissue for profiling, we use the liquid biopsy to generate some data, make sense of those data, and select therapy.

 Any other comments from the group? Flavio, Anjana, or Mark, do you have any? Flavio, do you profile patients who have surgery?

 I just had a question about that. Although these agents aren’t approved in the localized or resectable setting, we’re starting to learn a little from resected specimens that do get profiled, that the mutational landscape might be different between those with advanced disease and earlier-stage disease. The reason why this is important is that as we move toward treating these patients with neoadjuvant therapy, that might become relevant. Curious to hear from the group if others are getting profiling on localized disease.

 We are. We do on every specimen. Exactly to your point. Also, most of these tumors recur even with resection after 5 years. It’s usually a 30% survival. It’s especially important in that sense, so you have an idea based on how they present. Hopefully, we can talk about this a little more in the role of transplant in some of these patients. All that changes what’s historically considered standard of care and what we’re doing in a lot of our institutions.

 Thank you. I often tell patients that molecular profiling isn’t just about targeted therapy. It also has prognostic implications. I saw a patient a couple of weeks ago with a small, resected tumor, 2.5 cm in extrahepatic cholangial but had 

 G2M mutation. Would I approach that patient different if they had, for instance, an FGFR2 fusion? We’re learning. I’m not sure we’re there yet, but if you don’t look, we’re not going to find. We try to profile all stages. I’m with you on that. Without that, we’re not going to develop new therapies. Mark, I see you have a comment.

 These patients should get profiled at the time of surgery, but that brings up all sorts of challenges with what to do with the information. If you find an intrahepatic cholangiocarcinoma, and your plan is to implement 6 months of adjuvant capecitabine and then you find that the patient is mismatched repair is deficient, what do you do with that? If you find that the patient has a 

 [human epidermal growth factor receptor 2] mutation, do you add anti-HER2 agents in the adjuvant setting? To be prepared, find answers that make your management more complicated.

 Mark, I’ll jump in because I had a recent case, and because we’re talking about our experiences of a patient who had a large right-sided intrahepatic cholangiocarcinoma and a history of Lynch syndrome. On that biopsy, we obtained the MSI [microsatellite instability]–high status, treated the patient with several months of pembrolizumab, had a dramatic response, and resected the patient—who now has 5% viable tumor left negative lymph nodes. Much to your question: what do we do now?

Panelists share their perspectives on molecular testing guidelines for patients diagnosed with biliary tract cancers.

Guidelines for Molecular Testing in Biliary Tract Cancers

While we are on the topic of cancer and the extent, surgeons stage them better than anyone else, Flavio. We often see them in the locally advanced in metastatic stage. Could you briefly touch on the staging of these different cancers from a high level?

 Thank you, Milind. I’ll echo what Mark was saying. Colon cancer metastatic to the liver, which is something else that I treat, is much more common than intrahepatic cholangiocarcinoma, so we do have to do our due diligence to exclude a GI [gastrointestinal] source. As far as staging, surgeons are very visual people. Cross-sexual imaging is key for staging and preoperative planning. Typically, a high-quality multiphase CT is what we rely on because we want to see what the extent in the liver is and what the relationship to vascular structures might be. Of course, for preoperative planning purposes, how much liver can we leave behind? The other important piece for hilar cholangiocarcinoma specifically is looking at the extent of biliary involvement, because these tumors tend to be at the confluence. We must make a decision as a surgeon whether we’re going to go to the right or left, or to take out the liver. We want to have high-quality imaging via MRCP [magnetic resonance cholangiopancreatography] if possible. If that’s not conclusive, then that’s when we rely on direct cholangiography to get a good image.

Those are the things we probably use most frequently. There are some preoperative classification systems, so the bismuth chelate is probably the 1 that most people are familiar with. It looks at the up-and-down extent. Think about the bile duct, but that’s only 1 dimension. We know cancers don’t grow in 1 dimension; they grow in 3 dimensions. More recently, we adopted the Blumgart staging system for hilar cholangiocarcinoma, so we look at both the biliary involvement as well as the extent of vascular involvement to determine resectability. That’s how we determine the staging. Certainly, once the pathology is out, then we tend to follow the AJCC [American Joint Committee on Cancer] guidelines. Those have been recently updated in the eighth edition [of the 

]. It was nice to see that intrahepatic cholangiocarcinoma was split out from paracellular carcinoma, and we have some guidelines about the lymph nodes and their significance as well.

Mark, there’s been so much excitement about targeted therapy in cholangiocarcinoma. There’s so much focus on immunotherapy in biliary tract cancer. Could you highlight a little about the various pathways that are of interest? Then is this a hot tumor or a cold tumor? Is this tumor immuno-responsive or is it not immuno-responsive? How do you judge all these things in the clinic?

 This is such an important topic, so thanks for giving me the chance to answer. My recommendation for medical oncologists who don’t treat this cancer all day is that all these patients should absolutely get molecular testing done. In particular, molecular testing that includes not just DNA but also RNA is very helpful because these tumors often have rearrangements or other alterations that happen at the RNA level that can be missed with DNA sequencing. The joke that I tell our oncology fellows is that cholangiocarcinoma is the lung cancer of the GI oncologist, and a huge percentage of these patients have something actionable that you find if you order molecular subtyping. How often is it? About a third of patients have some alterations, some pathway that can be targeted as standard of care. I’m not talking about something on a clinical trial. I mean standard pathway with an FDA-approved or NCCN [National Comprehensive Cancer Network]–recommended agent.

What pathways are we talking about? For the first time, we have drugs approved for cholangiocarcinoma that target FGFR2 fusions or rearrangements. Milind was instrumental in developing some of these drugs. This is found in about 15% of patients with intrahepatic cholangiocarcinoma, so it’s not extrahepatic. It’s intrahepatic cholangiocarcinoma. We have 3 drugs—pemigatinib, infigratinib, and likely futibatinib very soon—that can be used to target this. 

 mutations are also common in intrahepatic cholangiocarcinoma. We have itacitinib, which can prolong PFS [progression-free survival] in the subgroup of patients. You never know what you’re going to find. You find mismatch repair deficiency, high TMB [tumor mutational burden], and 

 [human epidermal growth factor receptor 2] is quite common, particularly in extrahepatic cholangiocarcinoma and gallbladder cancer. You never know what you’re going to find until you order the testing, and it’s critical that patients get this done.

I think there was a second part to your question, about immunotherapy for cholangiocarcinoma. I’m sure we’ll be talking about this in more detail, but in general, unfortunately, biliary tract cancers tend to be relatively immune resistant. The response rate to anti–PD-1 or anti–PD-L1 therapy in unselected populations of biliary tract cancer is in a range of 5% to 10% if you look at the totality of all the data. Some studies are a little higher, some a little lower. If you were to subtract the patients who have mismatch repair deficiency or high TMB, the response rate would likely be even lower than that. This is an immune-resistant tumor type. Part of the reason why the interest in immunotherapy is in combination with other agents is because the activity isn’t high enough as a single agent.

Comprehensive insight on staging biliary tract cancers followed by an overview of molecular testing and targetable clinicopathologic features.

Biliary Tract Cancers: Staging and Clinicopathologic Features

Ruth, you’ve certainly treated a lot of biliary tract cancers, both with immunotherapy as well as with standard therapy. We’ll get to that, but I’m going to talk to you a little about the presentation. The Cholangiocarcinoma Foundation did a survey about the latent period between symptoms and actual diagnosis. I was shocked that the duration was something like 22 months. That was the median duration for the time when the diagnosis was established. In your practice, what percentage of patients are found with incidental findings or findings on a routine scan? [How many] people have elevated LFTs [liver function tests] while getting a statin? What are the common symptoms of presentation in your clinic for the different types of biliary tract cancer that Flavio discussed?

 That’s a very interesting question. It depends on the source of the referring physician. We have patients who present with advanced-stage biliary cancer because they’ve developed symptoms of weight loss and jaundice. We also have patients under surveillance because they have chronic liver disease and cirrhosis. For patients under surveillance, we tend to make the diagnosis a little earlier, but the majority of patients are still diagnosed with locally advanced or advanced-stage disease. That emphasizes the importance of surveillance on patients with chronic disease, as Anjana presented earlier. In my practice, It’s probably half and half. Half the patients are diagnosed at a relatively early stage. They’re resectable or borderline resectable with some downstaging bridging them to resection. Half the patients are diagnosed with advanced-stage disease, with palliative therapy as the main treatment option for those patients.

I just saw a patient who had a perihilar mass, a biliary duct dilation, and went from hospital to hospital in Texas to get a diagnosis and pathology. It saddens me to see these patients under multiple work-ups with abscesses and problems. They sometimes reach a stage when they can’t be treated at all. Ruth, how much of the poor prognosis that we see in our patients is related to this problem and difficulty in diagnosis? There’s a long period by the time they get care for the cancer.

 We’ve seen that in some patients. Sometimes it takes multiple tries to get the tissue diagnosis. Getting tissue to make a diagnosis, especially for hilar cholangiocarcinoma, is very challenging. Sometimes we use SpyGlass for ERCP [endoscopic retrograde cholangiopancreatography]. Sometimes we try to biopsy the perihilar lymph nodes with EGD [esophagogastroduodenoscopy] or EUS [endoscopic ultrasonography]. It’s challenging. Sometimes it takes many tries. There’s an urgent need for additional diagnostic measures to make a diagnosis. This is a very active field. How we can make the diagnosis earlier when the tissue biopsy, the diagnosis, is very challenging?

 Flavio, the extrahepatic perihilar cholangiocarcinoma was described by a surgeon, [Gerald] Klatskin. In his original definition, the only way to diagnose this is by surgery. Surely there are other mechanisms and methods that you use to make a clinical diagnosis in the absence of pathology. How do you deal with this situation in practice?

 Milind, this is a very important and timely topic because this highlights some of the changes in biliary tract cancer. Unlike intrahepatic cholangiocarcinoma, where you have a mass that you can stick a needle in, hilar cholangiocarcinoma can be extremely difficult to diagnose on pathology preoperatively. A lot of the delay happens because there’s this persistent attempt at trying to obtain endoscopic brushings and all these other modalities. To be honest, the sensitivity is a flip of a coin. This is a big issue.

The problem is once the biliary tract is cannulated and obstructed, you’ve contaminated that liver. The patient ends up having this spiral of cholangitis with trapped ducts. I’m always very keen on seeing these patients right away just when you get the imaging before they’ve had any procedure. For a fair amount of the time, we’re making this diagnosis based on the imaging alone. I take plenty of patients to the operating room without a clear pathologic diagnosis of a cholangiocarcinoma, because a biliary stricture and a patient who doesn’t have PSC [primary sclerosing cholangitis] is a cancer until proven otherwise. There are some other very rare autoimmune entities that can present with biliary strictures. But at the hilum, unless you’ve had a bile duct injury or you have known PSC or IBD [inflammatory bowel disease], that’s a cancer.

Thank you, Flavio. I just want to reiterate that the diagnosis of perihilar or hilar cholangiocarcinoma is often a clinical 1. As Flavio mentioned, it’s often hard to get a pathologic diagnosis, and these patients are often treated based on radiological findings of CA 19-9 levels and sometimes FISH [fluorescence in situ hybridization] findings, and these patients are honestly best managed at a tertiary center where these patients can get a quick diagnosis and start treatment.

I’m going to move on a little to staging, but I don’t want to miss the opportunity of discussing the diagnosis of intrahepatic cholangiocarcinoma. Mark, these are often diagnosed as adenocarcinoma in the liver. Based on the current immunochemical information radiology, do you believe that a mass presenting in the liver needs extensive work-up to prove it’s not intrahepatic cholangiocarcinoma? Or can you rely mostly on pathology and radiology today?

 That’s a good question. As everybody knows, many cancers spread to the liver. When you have adenocarcinoma of the liver, it can be quite unclear whether it’s a primary liver cancer or a metastasis. One thing that our pathologists have started doing often is adding on albumin FISH, which can give you some confidence that this is a primary liver tumor and not a metastasis. In general, we attempt to get EGD and colonoscopy to feel a little more confident that there’s no other GI [gastrointestinal] malignancy that’s mimicking a cholangiocarcinoma. Often, we’ll get PET [positron emission tomography] scans or some other modality to rule out some other primary if the pathology is a little unclear. But increasingly, all these patients do get molecular subtyping. We’ll be talking about this, and there are some mutations that if you find them, they increase your confidence that this is a primary cholangiocarcinoma.

Expert perspectives on the presentation of biliary tract cancers with specific insight to the challenges inherent in reaching a timely diagnosis. 

Challenges in Diagnosing Biliary Tract Cancers

Before we get there, Anjana, you mentioned that you’re seeing more patients in your clinic now, and that’s also my experience. We’re seeing a lot more biliary cancer, and I’m amazed that some fellows come to my clinic and say they want to specialize in biliary tract cancer [BTC], which nobody ever did in the past. What has led to this? Do you think there’s an increase? Is there a role in geography, ethnicity? Could you also highlight some risk factors that you alluded to earlier?

 Absolutely. I agree. We’re all seeing more. Of course, you had a recent paper, which I tweeted about, in 

that showed that incidence updated to your database that’s reflective of all our practices. The study that I like to quote was from the 

a few years back, but it showed that only 30% of these tumors have identifiable risk factors. In the United States, we don’t see liver flukes. When I educate my patients, I talk about stones and cortical cysts being a risk factor, but that’s a minority of the patients that I see with biliary cancer.

Of course, there’s underlying cirrhosis and hepatitis B and C, but we don’t see tons of hepatitis B. Hepatitis C, with new direct antiviral therapies the last 8 years, has also decreased. The number of patients I see often have de novo with no underlying liver disease and no identifiable risk factors. Of course, we always think about obesity, metabolic syndrome, alcohol, and smoking, but we haven’t identified 1 true risk factor for which we can truly say, “If you have this and this without underlying liver disease, then you’re at increased risk.” Then, there’s PSC [primary sclerosing cholangitis]. Historically, that’s always been the link with PSC, UC [ulcerative colitis], and cholangitis. Almost 50%, maybe 70%, of our practice has no underlying liver disease, which makes it challenging how to identify these patients early, risk-stratify them, or screen for them.

Anjana, you raise an important point about PSC. Clearly, there’s excitement in immunotherapy, in BTC, or in all cancers, but we’re going to see these patients who have PSC, ulcerative colitis, and Crohn disease, and then we’re going to talk about immunotherapy and checkpoint inhibitors. We’re certainly going to send these patients in your direction for hepatology guidance. What plans do you have in mind?

 It’s a difficult question because most of these autoimmune-type patients were typically excluded from these clinical trials, so it’s not a patient population that we have tons of data with. These checkpoint inhibitors can also mimic. Very rarely do you get these immune-related events where they can mimic a PSC or IgG for cholangitis. PSC is a different entity than true autoimmune hepatitis. In that sense, there’s not that fear of a flare or that significant decompensation. Depending on how advanced the PSC is and their Child-Pugh score, as a group we’d determine chemotherapy, including immunotherapy, but my sense is that the well-compensated patient with PSC should do OK with immunotherapy.

Wonderful. I’ve treated some patients. I’m going to jump to Mark. Mark, you’re a resident I/O expert. How are you considering treating these patients who have an underlying autoimmune disease, maybe PSC, maybe ulcerative colitis? I’ve had patients with other diseases, underlying multiple sclerosis, ankylosing spondylitis—that sort of thing.

 This is an area where it would be great to have more data. In general, we’re usually willing to offer immunotherapy for patients who have no severe underlying autoimmune disease and who aren’t on active immunosuppression. In every case, you must weigh the risks and benefits. We’ll be talking about the new data for immunotherapy in biliary tract cancers. Clearly, this is an important development, but the absolute benefit in terms of median survival is modest. There’s a risk of exacerbating underlying autoimmune disease. My willingness to add durvalumab in frontline treatment for PSC is a discussion, but it’s not something I would offer to everybody.

Shared insight on the global incidence of biliary tract cancers and which risk factors most impact the likelihood of disease.

Incidence and Risk Factors for Biliary Tract Cancers

® titled “The Evolving Landscape of Biliary Tract Cancers.” I’m Milind Javle. I’m a professor in the department of gastrointestinal [GI] medical oncology at The University of Texas MD Anderson Cancer Center. I’m privileged to have an experienced panel with me. Joining me in this discussion are my colleagues Dr Aiwu Ruth He from Georgetown University MedStar Health, Dr Anjana Pillai from the University of Chicago Medicine, Dr Flavio G. Rocha from Oregon Health & Science University, and Dr Mark Yarchoan from Johns Hopkins Medicine. Would you all please introduce yourselves briefly? Let me start with you, Dr He.

 Thanks for having me. I’m Ruth He. I’m a GI medical oncologist working at [MedStar] Georgetown University Hospital in Washington, DC, with a research focus on hepatobiliary cancer.

 Hi, thank you for having me. I am Anjana Pillai. I’m an associate professor of medicine at the University of Chicago [in Chicago, Illinois]. I am a hepatologist, which slightly different from what everyone else does. But I direct our liver tumor program, and we see a number of patients with both HCC [hepatocellular carcinoma] and bile duct cancer. That’s my clinical and research focus.

 Hello. My name is Flavio Rocha. I’m a professor of surgery and the division head of surgical oncology at Oregon Health & Science University [in Portland, Oregon]. I serve as the physician in chief of the Knight Cancer Institute as well. I’m a surgical oncologist by training and a hepatobiliary surgeon. I’m happy to be here with this esteemed group.

 Hi, my name is Mark Yarchoan. I’m a medical oncologist at Johns Hopkins, focusing on hepatobiliary tumors. I lead a research laboratory focused on immunotherapy for liver cancers. It’s a pleasure to be here.

Wonderful. Welcome, and thank you for joining us. I’m very excited to discuss this topic, which has seen a lot of changes, particularly over the last 4 to 5 years. We’ve divided our discussion into several modules. We’ll first discuss the landscape of biliary tract cancer. We’ll be discussing staging, some of the newer therapies, targeted approaches, and then finally there will be an open discussion.

Let’s start with the landscape of biliary tract cancer. Biliary tract cancer is often referred to as 1 entity, but it seems to be diverse anatomically, perhaps pathologically. Flavio, could you clarify what types of malignancies are included in this definition? How are these cancers similar or different?

 That’s a great place to start, Milind. Biliary tract cancers become a catchall phrase for anything that involves biliary epithelium. The biliary epithelium starts in the liver with the small bile ducts and then coalescences the major hepatic ducts down to the common bile duct and all the way into the head of the pancreas. It’s a long geographic spread. The gallbladder, as you know, is an outpouching that’s connected to the biliary tree. They get lumped together in a lot of studies and trials, but they’re very different biologic entities. When you have the intrahepatic cholangiocarcinoma with the ones in the bile duct, they’re presenting as liver masses. The operation to remove them is to do a liver resection, for example. Contrast that with hilar cholangiocarcinomas, which are usually lumped in as extrahepatic cholangiocarcinomas. Those are typically 1 of the more challenging operations that we need to do with surgeons because they involve not only a liver resection but also a bile duct resection. The proximity to the portal vessels also sometimes require a vascular resection reconstruction.

Gallbladder cancers are even their own entity because they’re mostly diagnosed incidentally after a cholecystectomy for suspected benign disease, which comes back with cancer and pathology and then typically requires resection. The distal cholangiocarcinomas, which are also considered extrahepatic cholangiocarcinomas, are often hard to diagnose preoperatively and sometimes get mixed with pancreatic cancer because the operation to remove them is a Whipple procedure, which is the same for pancreatic cancer. They’re also different biologically in the way they present in their patterns of recurrence. I’ll let my colleagues weigh in on some of the molecular differences as well.

Thank you, Flavio. That was very insightful. I have to say that in my practice, patients often get confused. Do I have a bile duct cancer or cholangiocarcinoma? Do I have gall bladder cancer? Do I have Klatskin tumor, extrahepatic cholangiocarcinoma, or perihilar cholangiocarcinoma? Anjana, what approach do you use to educate them about the differences and this colloquialism, which are often confusing, not just to patients but sometimes to providers?

 That’s such an important question. You’re absolutely right. It’s not just patients. I feel like sometimes we get an incorrect diagnosis of maybe someone having intrahepatic, but it’s perihilar or hilar. We have a multidisciplinary clinic, so that means it’s myself, our surgeon, and 1 of our oncologists that are often available at the same time. We do a lot of our education through diagrams. We have a basic diagram of the liver, the bowel ducts, the gallbladder, and all the ducts, and then we draw and put the location. This is intrahepatic. This happens X amount of time. This is hilar, perihilar, and extrahepatic, just as Dr Rocha said. Then also explain if they have underlying liver disease, which is a good chunk of my practice—why that’s also important, and how that can affect their therapies.

Wonderful. This is very insightful because we realize that they’re grouped under 1 umbrella. However, they’re distinct. I wouldn’t call them disparate, but they’re distinct in terms of anatomy, in terms of surgical management and molecular pathology. I’ll ask Mark to give some input on that in a few minutes.

Opening their discussion on biliary tract cancers, a multidisciplinary panel of experts consider how specific subsets of these malignancies differ from one another.

Flavio G. Rocha, MD, FACS, FSSO, Oregon Health & Science University

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