In terms of the biomarkers, are there any others that you would think are going to be particularly path breaking in biliary tract cancer that we should be doing? Standard is NGS [next-generation sequencing], the panel keeps expanding. Ruth, you alluded to liquid biopsies. Perhaps some people have started doing minimal residual disease testing post-surgery. Is there any other pathway that you are looking at, any other markers, ctDNA [circulating tumor DNA] or microRNA, or any other immune profiling studies? Mark, you’re in the forefront of all this, anything that hits the target in the short term?

 I think what many of us have started doing is combining tumor-based profiling with liquid biopsies. And liquid biopsies have already shown some utility in monitoring, for example, resistance mutations to FGFR inhibitors. My colleague, Marina Baretti, [MD,] had a lovely talk at ASCO [American Society of Clinical Oncology annual meeting], where she gave an overview of some of these data. We certainly have started considering patients for clinical trials of novel FGFR inhibitors if they have resistance mutations pop up on liquid biopsy. I think that’s the direction that the field may go in the near future.

This has been a very exciting, rich, and informative discussion. I’ve learned a lot from your experience in treating biliary tract cancer, and I’d like to conclude. Before doing that, I’d like to get a few final thoughts from all of you, and this may be something you’re looking forward to in terms of biliary tract cancer and further management. Let me start with you, Flavio, any final thoughts on this topic?

 Yes, my encouragement would be to have my colleagues help us expand the candidate pool for either curative surgery or transplantation because I think that’s where we want to get. I think as we learn more about this disease and find new targets, find new agents, let’s get patients there.

 I would have to echo Flavio there. I think this multidisciplinary team, like we have assembled here, is key to these cancers and is not always done everywhere. Therefore, I think this is how you move the field forward and try to get hopefully more curative options and long-term survival. We learn so much. I’ve learned so much just from this hour and a half listening to you all, so I think this is the key to the future of this field and for our patients.

 I think patients should get a profile of their tumor and support clinical studies, try to enroll in clinical trials that test novel targets.

 I would say pemigatinib was the first FDA-approved drug for cholangiocarcinoma, and just a few years later we have multiple approvals. So this is a super exciting time for our field, and I think we’re only going to continue to make progress if we continue to enroll in clinical trials. To all the patients, I think the clinical trials are great ways to get access to novel therapies, but also to help everyone else with this cancer. Thank you for participating.

I want to thank all the presenters. This is an exciting time for all of us. I want to tell you my personal story. I began this journey 15 years ago, and my seniors advised me then that this was not a good disease to treat, you can never make your career in biliary tract cancer. And here I am now 15 years later. It’s a great privilege to have this talented group of clinical researchers on this journey with me. I hope that this example will be an incentive for other young investigators, researchers, scientists, and advocates to join us on this journey because it requires a village. Today we are on a threshold of new beginnings of this cancer, with immunotherapy finally making headway. The durvalumab TOPAZ-1 study is positive. This hopefully will be the advent of new beginnings, the advent of new therapies in this cancer, and I look forward to the future with great optimism as never before.

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Closing out their discussion on the management of biliary tract cancers, experts share excitement for future evolutions in the treatment landscape.

Advanced Biliary Tract Cancers: Novel Biomarker Strategies

I think that in the final few minutes we have left, I’m going to pick your brain about what you’re excited about in terms of what targets, or what therapies, or where do we go next here. Flavio, let me start with you. In the surgical setting, do you have anything that is particularly exciting to you?

 Yes. I wanted to mention that I know we’ve been talking about biliary tract cancer, but I think back to the discussion of lumping versus splitting. I’m very excited about the EA2197 trial. Just to remind the audience, this is a trial specifically for incidental gallbladder cancer. Patients are being randomized to either upfront surgery, which is the standard of care, versus perioperative gem/cis [gemcitabine and cisplatin]. This trial has been a long time coming. I must give credit to my colleague, [Shishir] Maithel, [MD,] who’s the PI [principal investigator]. It’s been a labor of love to get this pushed through with your support, Dr Javle, and others. This is the first trial specifically for gallbladder cancer in the NCCN [National Comprehensive Cancer Network], so I think that’s very exciting. We’re hoping to accrue patients and get the data. The second piece as I keep mentioning is also another neoadjuvant therapy. We mentioned the neoadjuvant therapy for our intrahepatic cholangiocarcinoma trial. We want to now, in the discussion of targeted therapy, move those agents perhaps up in that setting, where we can learn from the resected surgical specimens what is going on in the tumor microenvironment with these targeted agents. I think that will be the next step and evolution as we apply these in earlier settings. That’s what’s getting exciting in our world.

Thank you, Flavio. In terms of newer agents, Ruth, and Mark, some of the agents we talked about already. Then pathways I’m excited about for instance are for PARP inhibition, and ATR inhibition. Some novel HER2 agents, for instance ... has completed a phase 2 trial. Recently there were very exciting results with HER2 ADCs [antibody-drug conjugates] in breast cancer. Perhaps these are targets to consider. There are ongoing trials in this space. There’s one with CPI-613, surufatinib, CTX-009. Ruth, are there certain pathways or targets that you see in the short term, some in the long term?

 We had a phase 2 study testing the olaparib/pembrolizumab in cholangiocarcinoma. I do believe there are patients with BRCAness phenotype in cholangiocarcinoma. It’s not just the 

 mutation; there are other additional mutations that are of the same pathway, and some of those patients do benefit from PARP inhibition. It’s interesting, I think there’s an added mechanism behind it, and some patients with the mutation do not respond. But we have seen very durable response in some patients with BRCAness phenotype. That needs to be further looked at. I know there is some intergroup study evaluating this further. I’m excited about finding more information about this pathway.

Thank you. Mark or anybody else, can you pitch in anything else that you’re looking forward to?

 I think the field of FGFR2 inhibitors is quite exciting. We have our first 2 approvals with pemigatinib and infigratinib. But often when these drugs are used over time, we see the emergence of resistance mutations in either the gatekeeper or the molecular break. I think we have next-generation FGFR2 inhibitors in development that overcome some of the resistance to the first generation of inhibitors, so those are drugs that I think are worth watching that may be transformative. There are several VEGF-targeted agents in development for cholangiocarcinoma. Personally, I’m a little skeptical because ramucirumab did not appear to have any activity in cholangiocarcinoma in a randomized trial, so it’s a little hard for me to imagine that this is going to be transformative, but I’m happy to be wrong, and I hope I am.

I think the HER2 space is something exciting to watch. There’s a bispecific antibody targeting HER2 and HER3 that I think you probably know more about that anybody, Milind. There are some data in HER2, which of course is an ADC in breast cancer that was studied in cholangiocarcinoma. I think the caveat there is that there were a number of pulmonary adverse events that were observed at a much higher rate than I think we would have anticipated from the breast cancer literature, so I don’t know whether that’s going to be feasible in biliary tract cancer. There’s a lot to watch. I’m happy to hear other thoughts.

Mark you’re always on the spot. I just must speak up for my colleague…ramucirumab was a negative study when combined with pembrolizumab. He had a single-agent study that was published in 

] a few months ago, and it's similar to gastric cancer with AVAGAST being a negative phase 3 trial, but he had ramucirumab. But anyway, I agree, the overall benefit of all of these agents, VEGF agents, should be quite modest.

Expert panelists provide comprehensive insight on novel targeted agents being investigated in advanced biliary tract cancers.

Novel Agents Being Explored in Advanced Biliary Tract Cancers

I’m going to move on now to overall treatment strategies and sequencing in biliary tract cancer. As you know, there have been many exciting developments, 3 drugs approved in 2 years. We have infigratinib, pemigatinib, and lucitanib. We have several others that are NCCN [National Comprehensive Cancer Network] designated. That is trametinib and dabrafenib for 

 fusions, you have larotrectinib, entrectinib. And certainly, for MSI [microsatellite instability]-high we now have pembrolizumab/dostarlimab. So, this is a very rapid trajectory. I’m going to get your opinion here, Ruth and Mark, especially, for how you decide to sequence therapy if the patient has an actionable mutation in the first-line setting, has no actionable mutation in the first-line setting, and then if the patient has an actionable mutation in the second- or subsequent-line setting. Can you give us a high-level view of those different categories? Ruth, let me start with you with first line, and perhaps Mark, you can talk about subsequent lines. So Ruth, first-line therapy, if there is an actionable mutation, say 

, or if there’s not an actionable mutation seen.

 It depends on what mutations, and also depends on the data from the prior trial, the response rate. I profile all the patients, and even before I have the results, I usually start patients on chemotherapy. If a patient is elderly, very sick, and unlikely to tolerate chemotherapy, then for sure if they have a mutation, I’ll try to get them coverage to treat them targeting those mutations. Also, if there’s a trial that tests those targeted therapies in the front-line setting, I always try to enroll those patients in the clinical trials. I think it’s a constant practice of weighing the risk and the benefit and also the adverse effect profile. A lot of those patients may not tolerate chemotherapy. Therefore, that’s sort of the general practice. If they have an MSI-high tumor, of course I will always give them immunotherapy up front. Then if they have an 

 fusion, the response rate is so promising with the FGFR inhibitors. I have the temptation to give it to those patients, especially if they cannot tolerate chemotherapy. So it really is case by case.

Wonderful. Mark, in the second-line setting, you mentioned there are data with FOLFOX [folinic acid, fluorouracil, oxaliplatin]. Ruth mentioned data with 5-FU [fluorouracil] and nanoliposomal irinotecan, and then a host of targeted therapies. So how do you make that decision in your practice?

 I think the overall survival benefit of FOLFOX or 5-FU and nanoliposomal irinotecan in the second line is pretty small versus placebo. In most cases, if there’s a truly actionable mutation that’s identified, I will choose a targeted therapy over chemotherapy in the second line. Particularly, if the patients have an 

 fusion or rearrangement where there really is an impressive response rate with many of these agents, or 

 or Rett [syndrome] or some of the others, particularly 

 V600E. The response rates are impressive. They’re clearly higher than chemotherapy in an unselected population and often are better tolerated as well.

In the context of advanced biliary tract cancers, panelists reflect on the optimal sequencing of agents throughout multiple lines of therapy.

Sequencing Therapy in Patients With Advanced Biliary Tract Cancers  

As you mentioned, there was a benefit seen with durvalumab, perhaps more in the Asian population. However, there was also a benefit seen in the Western population, although it was somewhat lower. I have to give you my personal anecdote. As you mentioned, the hazard ratio in gallbladder cancer was much lower, and the benefit appeared to be lower. Also, a smaller number of patients are included with gallbladder cancer. I just finished a discussion on the same topic with my fellow in the clinic, and the next patient I co-shared with a colleague of mine ... She had 2 patients with gallbladder cancer, and they had a very remarkable response with arterial disease. I went back and found that 1 had an 

 mutation, and I think the other had another 

 mutation—some DNA-repair mutation family. Do we need to learn a little more about these patients, including their molecular profile and their PD-L1 status? I’d like to get your opinion, Ruth—as well as Mark’s—about what’s known about the underlying immune profile of these tumors in TOPAZ-1 and what, if anything, is known about the underlying molecular profile.

 I’ll start. For the next analysis, we’re trying to roll out data, looking at the TOPAZ-1, and explore ration of the TOPAZ-1 data more with the subsequent meetings. Next, the data set is for a biomarker analysis. This is difficult, but there are many patients for whom we’re able to collect baseline tissue. The first role of analysis is looking at MSI [microsatellite instability] status, PD-L1 staining, and the tumor mutational burden. That will be the first round. The second role is to profile those samples and the relationship between the typical heart tumor vs the tumor with other genetic alterations, such as FGFR2 fusion and 

On the same line, a lot of researchers are looking at this. There’s a project sponsored by NCI [National Cancer Institute] under the Moonshot project, led by Tim Greten and ... and we collaborate on those projects. It’s very interesting. With the initial data rolling out, we should see more by looking at HCC [hepatocellular carcinoma] and intrahepatic cholangial as a spectrum. For sure, a subset of patients have heart tumors, and we’re trying to understand. I believe there’s subset of patients who benefit from immunotherapy combination. You have a global study that’s heterogeneous, and we haven’t found the way to define those patients.

Mark, the paper presented some data on PD-L1 and TAP [tumor area positivity] score. What’s your interpretation of these data?

 The main takeaway is that we don’t have a biomarker coming out of TOPAZ-1. The benefit of durvalumab was small but relatively consistent across the different groups. There appeared to be some benefit in PD-L1–positive and –negative patients, with slight enrichment for benefit in PD-L1–positive. But it was not enough that anybody would use that to make a treatment decision. I’d love to see the detailed molecular analysis. We’ve published an analysis of about 400 biliary tract cancers looking at DNA and RNA. We did some cluster analysis and found that patients with FGFR2-driven cholangiocarcinomas appear to have a particularly quiet tumor-immune microenvironment without a lot of immune infiltration. It would be interesting to see if there’s less benefit in that group of patients with TOPAZ-1, for example. Those data have been slow to come out, in part because it’s positive across all patients and there’s not much interest in splitting. But we need to move in that direction.

Thank you. Ruth, you pointed out very well the need for profiling across different populations as you’re doing. I want to refer you to a paper by a colleague of ours ... who published in 

and performed a similar cluster, as Mark mentioned. He pointed out that about 15% of patients had an immune hot cluster in cholangial ... population. Not coincidentally, that’s the number that you see in response with immune checkpoint inhibitors. Suddenly more direction is required, and Dr Yarchoan’s colleague Dr [Nilofer] Azad and some of us are doing an international study profiling across different countries.

Now Flavio, I was interested in the TOPAZ-1 study that some of the localized tumors, the earlier tumors, the hazard ratio was seemed to be even more substantial there than in the advanced. And same was for the current tumors after surgery. Do you see these results as having some implication from the surgical point of view?

 As a surgeon, I’m always very keen to see what these new regimens and targets are because I want to move them up in the treatment spectrum. I want to see these agents used in the neoadjuvant setting precisely to downstage tumors to resection, or even in resectable cases to see if we can minimize recurrence rates. This is the Achilles’ heel. We do this big operation, and then 2 years later half of them recur. The more we can get this information and these agents out, I just wish we could slow the delay and basically get these agents out getting studied in the neoadjuvant setting.

 I want to make a quick comment out of turn. I clearly think the TOPAZ-1 study is an important landmark for cholangiocarcinoma, but the response rate to gemcitabine-cisplatin-durvalumab in the study was unfortunately only about 26% if I remember correctly. Someone can correct me if I’m off by a couple of numbers. But we do have single-arm phase 2 data for gemcitabine-cisplatin-Abraxane, and the response rate is well over 40%. At this point, the locally advanced setting is in which I wouldn’t use gemcitabine-cisplatin-durvalumab. I’d spring for gemcitabine-cisplatin-Abraxane even though it’s only phase 2 data. I’m not sure if others agree with me, but it’s an important point.

 I’ll jump in, Mark. I was going to mention this later, but as you may know, we’ve taken the gemcitabine-cisplatin-Abraxane data based on the phase 2 study. With Milind and others, we’ve put together a 30-patient cohort for neoadjuvant therapy. We had 30 patients, and 22 of them went to surgery for intrahepatic cholangiocarcinoma; we’re waiting for long-term data. This was presented at ASCO GI [American Society of Clinical Oncology Gastrointestinal Cancers Symposium] earlier this year. But we agree. Having that combination, obviously we’re waiting for the phase 3 advanced trial to report. We’re excited. We want to see what you think has good efficacy, safety profiles, and so forth, and we want to move them up.

Shared insight on efforts to identify patient subgroups that may benefit more from immunotherapy in the setting of advanced biliary tract cancers.

Advanced BTC: Informing Use of IO Therapy in Specific Patient Populations 

Let’s talk a little about management of biliary tract cancer in the clinic with chemotherapy. Mark, if a patient comes to you, you’re going to have a discussion of the role of first-line chemotherapy. What do you expect? What do you do after this chemotherapy stops working? How do you approach it? What’s your discussion with the patient about the efficacy and toxicity of the therapy at a high level?

 At a high level, biliary tract cancers are clearly aggressive cancers. Unfortunately, they tend to be more resistant to treatment than many other cancers, but we have clear evidence that chemotherapy can prolong survival in this cancer. Before 2010, we borrowed chemotherapies from other tumors. Because this was such a rare cancer, there weren’t major studies establishing a standard of care. This is old news but in 2010, the ABC-02 study randomized patients to gemcitabine-cisplatin vs gemcitabine alone. The addition of cisplatin prolonged life by about 3 months over what gemcitabine did by itself. Since 2010, gemcitabine-cisplatin has been the backbone of first-line chemotherapy. Until recently we told our patients that survival with gemcitabine-cisplatin was about a year on average. Of course, some patients are above and below the average. Gemcitabine-cisplatin is the closest thing we’ve had to a standard of care for cholangiocarcinoma until this year. We’ll talk about new developments.

Thank you, Mark. What’s your practice in the second-line setting?

 We’ll talk a little more about targeted therapies, but all patients should undergo molecular subtyping. There’s a one-third chance you’ll find something that’s immediately actionable. In those cases, a biomarker-indicated therapy would usually come in the second line. For the majority of patients who don’t have something actionable, we have 2 standard therapies for second line, either FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] or FOLFIRI [5-fluorouracil, leucovorin, irinotecan], or 5-FU + liposomal irinotecan. Both therapies are supported with randomized trial data showing a small but meaningful prolongation of overall survival. In my clinical practice, more patients get 5-FU–liposomal irinotecan. Coming off first-line therapy, patients often have neuropathy, so it’s nice to give them a nonplatinum option.

Focused discussion on chemotherapy treatment options commonplace in patients with advanced or metastatic biliary tract cancers.

Advanced Biliary Tract Cancers: First- and Second-Line Chemotherapy

I want to switch gears to systemic therapy. Ruth, we’ve had gemcitabine-cisplatin for over a decade and several trials. Could you give us a high-level view of the problem in terms of drug development in biliary tract cancer in the first and second lines? Why you think we’ve had negative trials, other than the fact that this is a difficult disease?

 Over the years, we’ve participated in many trials. We’ve seen very promising phase 1 and 2 studies and high response rates, but then they don’t pan out. Some of the challenges are about this being a very heterogeneous disease. Also, patients tend to get very sick when they have advanced-stage disease, so medical management of the obstruction infection becomes challenging for those patients. In the last couple of years, we’ve made progress, and we have a lot of more options. Ten years ago, we had gemcitabine-cisplatin in a positive phase 3 trial. Then we looked at the VEGF pathway. We looked at the EGFR pathway. We looked at MET and MEK. We’ve looked at all those pathways, and we’ve had a lot of negative trials.

With more understanding of the tumor biology, I view all the trials in 3 areas. We’re making progress on chemotherapy combinations. We have gemcitabine-cisplatin, and we have FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] as a second-line [therapy]. The NIFTY study, which is a randomized phase 2 study, supports the liposomal irinotecan–5-FU [5-fluorouracil] combination as 1 of the second-line options. The NAPOLI-2 study tests the same combination in the Western population in the United States. It’s still ongoing, so we should have more data on that.

We have a triplet that was initially developed at [The University of Texas] MD Anderson [Cancer Center], gemcitabine-cisplatin-Abraxane. It shows a very high response rate and a very promising survival in the phase 2 study. It’s now being tested in a phase 3 trial. This has made it to the NCCN [National Comprehensive Cancer Network] Guidelines. I use it because of the very high response rate for downstaging in patients who are borderline resectable. We’ve seen some good success for robust patients, but that’s at the cost of some toxicities.

Then I looked at immunotherapy. This is the beginning. We’re starting to see positive data from immunotherapy. The additional immunotherapy in combination with chemotherapy is being tested. We hope to see more promising data following the positive TOPAZ-1 study. Then there’s precision oncology, which you presented earlier. About 40% to 50% of cholangiocarcinoma has targetable mutations. We see a lot more targeted therapy, and we know how to better use to select patients for those therapies. It’s a very exciting time. I can go into more detail, but I’ll stop here.

Ruth, to pin you down a little, should we be lumping or splitting? Should we be including all biliary tract cancers in a single trial of chemotherapy, or do you think there’s rationale to split it into different biliary groups?

 That’s a very interesting question. It’s a balance. We can see from the promising data on triplet chemotherapy that it provides benefit in a good group of patients, and that’s not a split situation. For immunotherapy biomarkers, how can we define the patients who will benefit and have a “hot” tumor? How can we convert a “cold” tumor into a “hot” tumor? Select all those patients? I don’t think we have enough information to do that, but you can see the very promising response rate of 30% to 40% from FGFR inhibitor, in patients with FGFR2 fusion. That support is split. With more options, [we now think about] when to do what. In the future, we’ll need to profile everybody.

We’re testing precision oncology as targeted therapy in the frontline setting, so we should have more data. With additional data, we may need to split in the front line. Find the targeted mutation and the profile that favors immunotherapy. In the second line or future lines of therapy, we may need to test them more. I had a couple of patients with Y90 [yttrium 90] and hypertrophy of the other side of the lobe of liver. [They were] robust up front, even unresectable, with a drop-off of CA [cancer antigen] 19-9. I attempt to do the triplet of chemotherapy and then try to bring the patient to surgery. We’ve seen good results from that. It’s a very complex answer. With biomarker development and more options, we can say at what setting we should lump them together at what setting we should split.

Shifting their focus to the advanced disease setting, panelists provide a comprehensive overview on systemic treatment modalities used in biliary tract cancers.

An Overview of Systemic Therapy for Advanced Biliary Tract Cancers

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.

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? 

Anjana Pillai, MD, an associate professor of medicine, medical director of the Liver Tumor Program, co-director of the Living Donor Liver Transplant Program, and director of Transplant Hepatology Fellowship Program at the University of Chicago, discusses sequential treatment in hepatocellular carcinoma (HCC).

The landscape is moving toward sequential treatment, as more first-line options are approved by the FDA, according to Pillai. Another focus will be determining which first-line therapies should be selected for each patient, especially as ongoing clinical trials conclude and report their data, Pillai says. If positive, several combination therapies may be utilized in the first-line setting, which will prompt the question of which approach should be selected for subsequent treatment, Pillai explains.

Treatment strategies for patients with HCC may be reminiscent of what had been seen in hepatitis C, where the space shifted from a handful of moderately effective drugs to a plethora of efficacious agents to choose from, Pillai explains. As such, it may not matter which drugs are selected for treatment, as they are all impactful, according to Pillai.

Once the many ongoing combination therapy trials report their findings, it will be easier to understand which patient populations will most benefit from these approaches. For patients who progress, emerging data will help to determine which agent should be used subsequently, Pillai concludes.

Anjana Pillai, MD, discusses sequential treatment in hepatocellular carcinoma.

Dr. Pillai on Sequential Treatment in HCC

Anjana Pillai, MD, associate professor of medicine, medical director, Liver Tumor Program, co-director, Living Donor Liver Transplant Program, director, Transplant Hepatology Fellowship Program, University of Chicago Medicine, discusses the importance of multidisciplinary discussion in hepatocellular carcinoma (HCC).

HCC comprises a wide range of research topics, such as surveillance, epidemiology, and biomarker development, says Pillai. As the field is rapidly evolving, the upcoming 2021 HCC-TAG virtual conference will spotlight the need for multidisciplinary care in HCC, Pillai explains. Presentations during the meeting will spotlight key nuances to treating patients with HCC across a spectrum of specialties, Pillai says. Ultimately, the goal of the conference is to shed light on the optimal way to deliver care to patients with HCC and improve outcomes, concludes Pillai.

Anjana Pillai, MD, discusses the importance of multidisciplinary discussion in hepatocellular carcinoma.  



Anjana Pillai, MD

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