Biliary Tract Cancers: Surgical and Perioperative Treatment Strategies

Transcript:

Milind M. Javle, MD: Why are we talking about surgical resection? It turns out, Dr Rocha, that this patient is surgically resectable, but unfortunately, the risk of recurrence is too high. Could you highlight what your approach is and how this has changed over the years for surgical as well as perioperative therapy?

Flavio G. Rocha, MD, FACS, FSSO: Yes. These hilar cholangiocarcinomas are probably the most challenging operation that we do in the abdomen. The reason is it’s a very extensive procedure. It’s a bile duct resection, a liver resection, and you’re then making anastomosis of the bowel to the remnant liver. So first and foremost, when we evaluate patients, we look at 2 things. One is, are they fit for a major operation? Unfortunately, sometimes I see patients who may have anatomically resectable lesions, but they’re not candidates for a big operation. Once we’ve cleared that hurdle, then it’s a question of, is the disease localized? And so, are we going to make a difference with surgery? Certainly, if there are metastases, then we’re not able to help that patient with surgery. As we home in, then we look at the local resectability. As I mentioned we have to make sure there’s going to be adequate liver, so enough liver remnant behind that is not obstructed.

We know, as we covered earlier, we really want those patients drained, especially if they don’t have enough of a liver remnant. With a lot of the staging we see, people think of just looking at the length of the bile duct, thinking that cancers just grow up and down. But cancers grow in 3 dimensions. You have to think 3-dimensionally about the tumor. Is it invading a major blood vessel, like the portal vein or hepatic artery?

Then lastly, we have strategies now to augment the liver. The liver is an amazing organ because it grows back pound for pound in 6 to 8 weeks after we resect it. If the liver remnant is too small, we can ask our interventional radiologists to do an embolization to the tumor side and grow the remnant. So, you can see this is a very involved process.

Now, contrast that with a distal cholangiocarcinoma, which we sometimes can’t distinguish from pancreas cancer, and so that operation is a Whipple procedure, which some of you may be familiar with. It’s got its own challenges as far as resecting the head of the pancreas. Gallbladder cancer then is somewhere in between, because you’re taking out the gallbladder, the liver, and more importantly, getting the lymph nodes, so you get proper staging. Then the intrahepatic cholangiocarcinomas are basically a liver resection, with those caveats.

Milind M. Javle, MD: Are their situations where you would consider neoadjuvant therapy? And do you think that akin to other GI [gastrointestinal] cancers, there’s a higher rate of neoadjuvant therapy administration now in the community? Can you also reflect on the NEO-GAP trial?

Flavio G. Rocha, MD, FACS, FSSO: Yes, absolutely. I think this is an area of active investigation. For a long time, as we will get to, there wasn’t a lot of evidence for additional therapy for these biliary tract cancers. It was really just, can you operate? Yes. If you can’t operate, then chemotherapy or other local therapies. What’s happened over time is, and we’ve used the paradigm of other tumors, as you mentioned, so we know that, for example, in gastric cancer, esophageal cancer, and rectal cancer, it’s been a neoadjuvant or perioperative strategy. And pancreas cancer is going that way. So, there’s really not a reason to think that cholangiocarcinoma is not similar to that. Coupled with the fact that we know from historical data that if you resect the cholangiocarcinoma, particularly intrahepatics, the recurrence rate is very high. So, we know we’re not getting all the disease with surgery alone. I tell patients I can only remove what I can see and feel with my hands. I cannot take care of the micrometastatic disease.

To that effect, we did start studying a regimen that was based on Drs Shroff and Javle’s phase 2 data with gemcitabine, cisplatin, nab-paclitaxel, which was the GAP regimen. My colleague Shishir K. Maithel, MD, FACS, from the Emory Winship Cancer Institute in Atlanta, Georgia, and with the help of our multidiscipline group, put together a protocol to give preoperative GAP to patients who had what we termed technically resectable but oncologically high-risk intrahepatic cholangiocarcinoma. So, these patients could have an operation, but they typically had a large tumor or satellite lesions, and they may have had portal lymph nodes that were either suspicious or positive.

That’s been another interesting story because traditionally, surgeons did not collect those lymph nodes. But as we learned with AJCC [American Joint Committee on Cancer] staging being updated, that portal lymphadenectomy should be part of this operation, particularly for the staging information. But we know those patients are at higher risk for recurrence. We did accrue 30 patients to the trial. They all received the NEO-GAP trial regimen. The end point of the study was just feasibility, could we deliver the therapy if we get patients to surgery? This was presented by Dr Maithel at ASCO [American Society of Clinical Oncology] annual meeting. It’s under review for publication.

I can share the data from the abstract. We did have about a 23% partial response rate, a 90% disease control rate, and we got 73% of those patients to surgery and completing all the therapy. The other data are still not quite mature, and we do have the molecular information that we’re still looking at. But it showed that you can deliver this regimen safely in the preoperative setting and get patients to the operation safely and not have an increased signal of complications. I think this is going to be the strategy going forward. I know we’ll get to the rest of the topics, and so should it be neoadjuvant, should it be perioperative, and which agents and what combinations should we use?

Milind M. Javle, MD: Thank you, Dr Rocha. So, Drs Shroff and Koay, the standard still remains surgical resection, right? Hopefully, we will move in the direction of neoadjuvant therapy. The figures are sobering. The median overall survival after this ostensibly curative surgery is still about 2 years, not that much more than pancreas cancer. What adjuvant chemotherapy and adjuvant chemoradiation strategies would be the next topic of discussion? Dr Shroff, could you reflect on some of the BILCAP [trial] data and some of the trials that are ongoing in this space?

Rachna Shroff, MD: Yes, absolutely. I think we know that surgical resection alone is probably not enough. The hard and fast data we have right now is the BILCAP trial, which was looking at 6 months of adjuvant capecitabine after resection. To Dr Koay’s point earlier, for better or for worse, we continue to lump all of these tumors together. This BILCAP trial had a mix of intrahepatic and extrahepatic and hilar tumors. I think that is probably where we’re falling down a bit in terms of trying to optimize strategies for adjuvant treatment. Because as you mentioned, I think even with 6 months of adjuvant capecitabine, we have a lot of room for improvement.

There’s the ongoing ACTICCA study, which is looking at gemcitabine and cisplatin vs capecitabine in the adjuvant setting. We’ve had some adjuvant studies already looking at gemcitabine-based regimens. Thus far, gemcitabine and oxaliplatin and things like that have not necessarily been positive. But the gemcitabine and cisplatin vs capecitabine study is what everyone is looking forward to, to understand.

I don’t know about you, Dr Javle, but I do have my own personal biases about who I’m giving adjuvant capecitabine to vs more of a gemcitabine and cisplatin approach. There are certain high-risk features that make me a bit more nervous, but that’s all just anecdotal. Right now, prospectively, the answer remains capecitabine. I’m sure you can comment a bit more on the radiation aspect in terms of the data.

Eugene J. Koay, MD, PhD: Yes, in terms of extrahepatic cholangiocarcinoma, the way we usually approach it is to think about what is the risk of recurrence. This is largely based on the surgical pathology findings after surgery is done. If they’re relatively low risk, like say they have negative margins and no lymph nodes, and early stage extrahepatic cholangiocarcinoma, in that situation, we tend to follow the BILCAP study and offer just adjuvant capecitabine. But if they have any higher-risk features on the surgical pathology, like say there’s a positive margin, or there are lymph nodes, or it’s an advanced T tumor stage. There is a phase 2 single-arm study we generally follow called the SWOG S0809 study, where they gave some adjuvant chemotherapy for several cycles, and then follow that up with adjuvant chemoradiation, a long course, 5 to 6 weeks of radiation. That study showed that in patients who had both R0, so margin-negative resections, or R1, margin-positive resections, and in those more advanced TNM [tumor, node, metastasis] stages, the survival rates were quite promising, ones we hadn’t seen in extrahepatic cholangiocarcinoma, or gallbladder cancer, which was also included in that study. So those were encouraging, and that’s what has guided our practice. But we need to understand this better.

I think the pioneering work that has already been mentioned that Dr Shroff has done with her recent study with the GAP regimen, and then Drs Maithel and Rocha, they’re leading the way in terms of bringing multiple institutions together to be able to study these diseases in much finer detail, in more granular ways, so we can start to really dissect what is the right way of treating extrahepatic, intrahepatic, gallbladder cancer, individually. I think we have a lot of excitement to look forward to. But there remains a lot of research to be done.

Milind M. Javle, MD: Yes, clearly, there’s work to be done. I think Dr Shroff was alluding to the fact BILCAP was a positive phase 3 trial, the first one in this space. But it was really a negative trial on intention-to-treat analysis. It was a positive trial on protocol analysis. So it is a modest standard. And, like her, I sometimes extrapolate, for whom do you use gemcitabine and cisplatin, for whom do you use capecitabine? Hopefully, the ACTICCA trial will educate us further.

Dr Koay mentioned this important trial, SWOG S0809, which unfortunately, was not a randomized trial. So, we don’t know how they did without radiation. But the trial proved an important point, that patients’ tumors that were margin positive, with the addition of radiation, had survival that was almost equal to those who were margin negative. It’s certainly a modality we need to consider. I think the neoadjuvant setting is a space to go. My colleague, Hop S. Tran Cao, MD, FACS, is also investigating checkpoint inhibitors like durvalumab in the neoadjuvant space. Dr Rocha?

Flavio G. Rocha, MD, FACS, FSSO: Yes, I was going to comment on the disease-specific trials. In the BILCAP study, the majority of patients had distal cholangiocarcinomas, about 33% to 35%. We are now starting to have disease-specific trials. I have the opportunity to bring up the EA2187 trial, which in the United States, is the first gallbladder-specific trial, which is looking at this perioperative strategy for incidental gallbladder cancers, T2 to T3, using gemcitabine and cisplatin. It’s an interesting story because BILCAP was the standard as the trial was being designed. Dr Maithel was the national PI [principal investigator] for that trial as well, so perioperative gemcitabine and cisplatin vs upfront surgery and adjuvant gemcitabine and cisplatin. That’s accruing now. We hope to have that information. The other interesting piece that you mentioned is, are there other trials in this space? I know in Japan the ASCOT trial was just published in the press.

Milind M. Javle, MD: Yes.

Flavio G. Rocha, MD, FACS, FSSO: That is looking at adjuvant S-1 for biliary tract cancer; that’s now the standard of care in Japan. They had a trial in progress poster here looking at their new adjuvant trial, looking at gemcitabine, cisplatin, and S-1 vs surgery first. We’re going to have more information. They did also include ampullary cancers in that trial. The other ongoing neoadjuvant trial in Europe is the GAIN trial. They’re also looking at gallbladder cancer, and they’re using a perioperative strategy there as well.

Transcript edited for clarity.