Case 4: 67-Year-Old Woman With Intrahepatic Cholangiocarcinoma



Ghassan Abou-Alfa, MD, MBA:This is a 67-year-old Caucasian woman without any known risk for cancer, including cholangiocarcinoma, who was admitted with acute abdominal pain, nausea, and vomiting. The imaging findings on the CT [computed tomography] scan and the MRI [magnetic resonance imaging] of the abdomen showed multiple intrahepatic lesions of undetermined nature and 2 small lesions in the lung, left lower lobe. Biopsy of the hepatic lesions was suggestive of intrahepatic cholangiocarcinoma. I’ll start with Amit. What’s cholangiocarcinoma?

Amit Singal, MD:When you think of liver cancer, there are actually multiple types of liver cancer. As we’ve talked about for the first 3 cases, we focused on hepatocellular carcinoma [HCC], the most common type of primary liver cancer, which comes from the cells of the liver. Cholangiocarcinoma is the second most common primary liver cancer, and it comes from the actual bile ducts, typically of the liver.

Ghassan Abou-Alfa, MD, MBA:Fair enough. Farshid, to help our friends, our colleagues, how do you treat it? It’s a stage IV disease here, understandably.

Farshid Dayyani, MD:Historically, recurrent unresectable metastatic cholangiocarcinoma we treat with systemic treatment. Based on the ABC-02 trial, a combination of cisplatin plus gemcitabine was superior because they followed up with the second-line FOLFOX trial, which showed a survival over gemcitabine alone. That’s been our standard for a long time. I think the field is moving. There’s more molecular understanding of the biology of cholangiocarcinoma.

Ghassan Abou-Alfa, MD, MBA:We’ll come to that, but if anything, this lady should get gemcitabine-cisplatin.

Farshid Dayyani, MD:Definitely. She has the correct parameters.

Ghassan Abou-Alfa, MD, MBA:I totally agree. Let me, before we dissect a little further, reference the other systemic therapies. Riad, let’s assume there are no 2 small lung lesions over here. The disease is disease in the liver only, 1 mass that is rather large, and there are some satellite lesions around. This is a classic scenario we see in cholangiocarcinoma. Is there anything you can help with here, from the interventional radiology standpoint?

Riad Salem, MD:Well, I’m glad you asked because the reality is—and I’ve been waiting for this case to talk about this a little more—I think 1 of the things we’re really lacking is more prospective controlled trials actively combining the local and the systemic therapies. This is true of HCC, and this is true of cholangiocarcinoma. So you’re right, this is a very common scenario, that central lesion with the scalloped anterior liver with a couple of lesions. The reality is, if you pick a patient who has good liver function, we have very few adverse events when you do a chemoembolization or radioembolization in that area. And nobody is suggesting that you do that in isolation.

What you would do, however, is hope to augment the results because, at the end of the day, the results you’re quoting from the ABC-02 trial aren’t that impressive. This is what you mentioned. There are level 1 data, I get it, but the survival is still 11 months or so. One of the nice things would be to try to combine these types of things in a more prospective manner. This is 1 of the disease conditions in which it’s completely lacking. Everything is still systemic in terms of treatment options. That’s my bias as an interventional radiologist. But again, if you pick the right patient, you know you can control your adverse events and you’re not going to deny anybody the standard of care, which is what I think you were alluding to.

Ghassan Abou-Alfa, MD, MBA:Fair enough. I totally agree. Now, Farshid was about to discuss the potential biologic therapies. But let’s talk a little about the biology of the disease itself. What do you know about that?

Amit Singal, MD:Cholangiocarcinoma is an aggressive tumor. We know that liver cancer overall, both HCC and cholangiocarcinoma, have a relatively poor prognosis. This is a disease for which the 5-year survival remains less than 20%. But I think when I think of HCC and I think of cholangiocarcinoma, I think of cholangiocarcinoma as actually being more aggressive even than HCC. These cancers are typically found at a late stage. We don’t have an identifiable target population as much as HCC. There are really no screening recommendations per se. Of these tumors, unfortunately, most of them are found advanced. Even when they are found early and you are able to resect them, there’s a high recurrence risk, and the survival is just not as good as it is for many other cancers that we see.

Ghassan Abou-Alfa, MD, MBA:Absolutely. Farshid, I do next-generation sequencing on this patient. What are the things, if any at all, that you would like our colleagues to look for?

Farshid Dayyani, MD:I think the list is growing, but as of today, I thinkIDH1mutations,FGFR2alterations. I think for extra biliary or extra liver disease, we look for HER2 alterations.

Ghassan Abou-Alfa, MD, MBA:Like a gallbladder, for example.

Farshid Dayyani, MD:For gallbladder, for example. And there are subtypes, such asBRAFV600E mutations, where we have some data with combinations of MEK and RAF inhibitors. These are the ones at the minimum, but if you send for next-generation sequencing, you get obviously a much larger panel, MSI [microsatellite instability] status, for example, as well, for the very small proportion that might be MSI-high.

Ghassan Abou-Alfa, MD, MBA:Let’s dissect this a little further, and let’s start where you ended. Tell us a little more about MSI-high disease, which ultimately pertains not only to cholangiocarcinoma but to all diseases. But in MSI-high disease, what does it mean? What do you treat with? How common is it?

Farshid Dayyani, MD:Microsatellite unstable tumors, MSI-high tumors, have a higher rate of mutation. As you know, pembrolizumab was the first drug that was approved independent of histology for all solid tumors that are MSI-high in the second subsequent line of treatment. The rate of MSI-high disease depends on the site of disease. For liver cancer, it is in the single digits, depending on what series you look at. For colorectal cancer, it may be as high as 15% or 20% for early-stage disease. But there is a much higher probability of response and durable response with checkpoint inhibitors in the MSI-high population. It’s definitely worth testing the patients because if they are MSI-high, they would potentially significantly benefit from checkpoint inhibitors.

Ghassan Abou-Alfa, MD, MBA:Fair enough. Again, as Farshid said, this kind of population is rather limited. It will make less than 5% even. It’s not something we’re going to commonly see, but nonetheless, it’s totally vetted and legitimate to check for MSI-high patients. Especially, of course, if the history—family history, especially, might suggest that or pertain to it.

But I’m definitely more intrigued, and admittedly we are all heavily involved in regard to this work. But theIDH1, if anything, is a mutation that will actually make an alteration with regard to the ability to 2-hydroxyglutarate, which likely is normal in all our Krebs cycle. But we bring in alpha-ketoglutarate, which if anything, is actually an oncogenic protein and as such can cause an unprecedented uncontrolled growth of the tumors. Lately we have a report that looked at ivosidenib, which is an anti-IDH1, versus placebo in second-line setting with a crossover that allowed patients on the placebo to go to the IDH1 inhibitor. It showed actually an improvement in progression-free survival as well as overall survival. These are definitely robust data that at least will bring in a potential for the anti-IDH1to come into play.

Transcript edited for clarity.

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