Martin Gutierrez, MD: Going back to the discussion where Andrew left it. In absolute resection I think the adjuvant is kind of subtle and hopefully will follow the BILCAP data. I think when it comes to the R1 and R2 resection, I think the radiation portion is an important tool if you wish to try to improve in some degree the control of the disease. Either our brachytherapy-like approach is VRT [variance reduction technique] or a form of radiation therapy are things that we can use. Also, you can consider a liver-directed therapy some of these in instances to have a NET [neuroendocrine tumor] in the case of patients who have at least an R1 or R2 resection.

Ghassan Abou-Alfa, MD, MBA: Along that line, if anything, the SWOG study included some form of chemotherapy plus radiation. Teresa, this was done in the US. But I’m curious, how did you read it? For radiation, we know from other diseases like the pancreas that it’s a question of being overdone and that’s it in Europe. But tell us a little about how you read the SWOG data?

Teresa Macarulla, MD, PhD: Yeah, I think in Europe, it’s not so clear what the role of radiotherapy is. We can consider after some induction chemotherapy in locally advanced adjuvant treatment. It is never used, or it’s not our standard because we don’t have randomized data that demonstrated that.

Ghassan Abou-Alfa, MD, MBA: Fair enough. By the way, we know that, if anything, the radiation therapy question is still being asked. We know that SWOG is still trying to see what the carry-on will be after SWOG S0809. But with this, I would like to go back still to the radiation question and look more about timing. Andrea, independent of data, if we were to radiate, when?

Andrea Wang-Gillam, MD, PhD: Generally, I’ll give systemic therapy and then end up with radiation. That’s generally my approach. I think a radiation technique has also evolved. Certain centers have a different technique or a different technology. We have MRI [magnetic resonance imaging]—guided radiation, so the radiation is very precise if there is a tumor. The toxicity is small. We now use more radiation, because in the past we worried about radiation toxicity and certain things such as biliary stricture and other complications. Now we have seen radiation toxicity decrease, so we use it a little more.

Ghassan Abou-Alfa, MD, MBA: Sure. So you, however, leave it to the same, like what we know of in pancreatic cancer.

Andrea Wang-Gillam, MD, PhD: Right.

Ghassan Abou-Alfa, MD, MBA: Andrew, your thoughts on radiation?

Andrew Zhu, MD, PhD: Two things. When you talk about the biliary tract cancer recurrence, the pattern of recurrence is very critical to select radiation or not.

Ghassan Abou-Alfa, MD, MBA: I like that.

Andrew Zhu, MD, PhD: As we know, data has clearly demonstrated that you do have the local recurrence for patients following perihilar. But if you have gallbladder cancer, your risk is actually mainly for distant metastasis. For that reason, I think I will probably have a lower threshold for patients with perihilar cholangiocarcinoma undergoing surgical resection to be considered for radiation. But also, the margin status is very important. Clearly R1 will probably persuade me to consider radiation more.

With regard to the sequencing, there are really no clear data to guide us. But I tend to agree with Andrea. I think for patients who follow the surgical resection, particularly those with positive nodes, I will start with systemic treatments, because I do think the risk to develop distant metastasis is probably the major worry for these patients. Then if we actually successfully administer a few cycles of systemic therapy, maybe I’ll consider the adjuvant radiation at that point. But again, we don’t have the right study to reassess the sequencing question.

Ghassan Abou-Alfa, MD, MBA: I love what you’re saying. If anything, Dr Zhu is bringing up a very critical point, which is that it all depends on the pattern of recurrence. At the same time, I would say that he’s bringing a rather indirect but very important point about a component of where does, for example, neoadjuvant approach come into play and what I like to call neoadjuvant plus adjuvant, like peri-adjuvant. In other words, this is something that really covers the surgical intervention from beginning and from end to try to prevent on the recurrences based on the pattern that we just heard in regard to the different diseases. I’ll ask if Teresa has any experience, and maybe not because we don’t necessarily have data on this. But what are your thoughts about a peri-adjuvant, or let’s call it a neoadjuvant, therapy prior to resection in cholangiocarcinoma?

Teresa Macarulla, MD, PhD: I think it’s a very interesting approach. One of the other things is the multidisciplinary team. These patients have to be presented in a multidisciplinary group just to see if the surgeons say to you, “This is very complicated because they have a high tumor mutational burden. I can do it.” But on these satellite nodules that you can say, “I can technically leave it, but this could be a systemic disease.” I think this is the perfect setting to do the neoadjuvant treatment for me with chemotherapy probably or start with chemotherapy and then let’s see if we can go to surgery. But yeah.

Ghassan Abou-Alfa, MD, MBA: Yeah. Well, Andrew, please.

Andrew Zhu, MD, PhD: I just want to add that we actually designed a clinical trial answering this very specific question. The design was very simple. We gave 3 cycles of GemCis [gemcitabine, cisplatin]—based regimen, reassessed. For a patient who could definitely go for surgery, they will actually proceed with surgical resection. But if not, we would consider other liver-directed treatment, including radiation. The problem is the enrolling was so slow. We were forced actually to shut down the study. But you know, this type of thinking definitely has been entertained in the past. But I also want to say this approach probably will be applicable only to intrahepatic cholangiocarcinoma. For distal bile duct cancer, perihilar, this approach is still facing tremendous challenge. As we all know, these patients coming in with obstructive jaundice. They’re just begging for something. If you delay and you say, “You know, we’re going to plan a few cycles of chemotherapy,” you may actually lose the surgical window.

Ghassan Abou-Alfa, MD, MBA: I totally agree. If anything, Dr Zhu is talking to us about the nice work that he did. Actually, as the chair of task force, I remember very well that study, which was a great, simple, well-done study. But sadly the accrual was really limited. It’s back to the same point that Dr Macarulla is bringing up, which is to bring the multidisciplinary team into that discussion and make sure that the surgeons know what the potentials over here. They have to consider that giving the neoadjuvant approach before going to surgery definitely will become a challenge. I would say that thankfully we are definitely having a collaborative approach, and it’s definitely getting better and better. We are very proud of it, all of us. I would say that maybe our colleagues who do pancreatic cancer are doing this a little more promptly than what is in biliary cancers. But definitely it’s on the way.

With this said, and we consumed quite a bit of time on important thoughts with regard to adjuvant therapy, I would say that the best we can hear from this conclusion is that we don’t have yet a final answer about the adjuvant therapy for cholangiocarcinoma. Nonetheless, it seems all of us by default—not because we have anything else, and of course we want to make sure we do everything we can for our patients—we are probably defaulting to the BILCAP study with the capecitabine. This is with an understanding that sometimes—as we just heard with regard to limited resections with an R2 or possibly some R1s—maybe a radiation therapy component can be there even though SWOG S0809 is still awaiting to see what the follow-up for it will be. At the same time, we heard about the challenges with regard to a peri-adjuvant, neoadjuvant followed by adjuvant therapy with regard to accrual. But at least the thought is still on the table, and hopefully we’ll see it carry on.

Transcript Edited for Clarity