Protocol for Liver Transplant for Patients with Hilar Cholangiocarcinoma

Additional Info

• Audio File:uab/ua191.mp3
• Doctors:Cannon, Robert
• Featured Speaker:Robert Cannon, MD
• CME Series:Medical Innovations
• Post Test URL:https://cmecourses.som.uab.edu/mod/quiz/view.php?id=4594
• Guest Bio:Robert M. Cannon, M.D., is an assistant professor in the Division of Transplantation, specializing in liver transplantation and hepatobiliary surgery. 
  
  Learn more about Robert Cannon, MD 
  
  Release Date: March 2, 2021
  Expiration Date: March 2, 2024
  
  Disclosure Information:
  
  Planners:
  Ronan O’Beirne, EdD, MBA
  Director, UAB Continuing Medical Education
  
  Katelyn Hiden
  Physician Marketing Manager, UAB Health System
  
  The planners have no relevant financial relationships with ineligible companies to disclose.
  
  Speakers:
  Robert Cannon, MD
  Surgical Director, Liver Transplant Program
  
  Dr. Cannon has no relevant financial relationships with ineligible companies to disclose.
  
  There is no commercial support for this activity.
• Transcription:Melanie Cole (Host): Welcome to UAB Med Cast. I'm Melanie Cole, and I invite you to listen, as we discuss the protocol for liver transplant for patients with Hilar Cholangiocarcinoma. Joining me is Dr. Robert Cannon. He's an Assistant Professor and Surgical Director of the Liver Transplant Program at UAB Medicine. Dr. Cannon, it's always a pleasure to have you join us today. Tell us a little bit about Hilar Cholangiocarcinoma or CCA. What is it and how prevalent is it?
  
  Robert Cannon, MD (Guest): Yeah. Well, thank you for having me. I'm always happy to be back. So Hilar CCA is a very rare tumor actually. It's only diagnosed in about little over one patient for every a hundred thousand people yearly. So it's something we only see sort of a few times a year. But, we would obviously see more in concentrated referral centers. And what it is, it's a cancer of the bile ducts. So your liver, one of the many functions it does is it's constantly making a substance called bile that helps us digest fat and the bile exits your liver and travels to your intestine through a tube called the bile duct. It's essentially a part of the plumbing of the liver. So cholangiocarcinoma is a cancer of those bile ducts.
  
  And in particular, a Hilar Cholangiocarcinoma and that's based off the location and what's known as in the liver hilum. So it's right where the ducts exit the liver and that's in a very difficult location to treat. Typically, it's fairly advanced by the time it's diagnosed because patients are often asymptomatic early on and then surgical resection by the time most people are diagnosed is no longer an option. And unfortunately we really don't have very good chemotherapy for these patients. So, typically it's carried a very poor prognosis because patients are typically advanced by the time they present.
  
  Host: So what's that been the standard of care when you do come across this situation? Tell us a little bit about the history of liver transplantation, liver transplantation alone, and with adjuvant therapies.
  
  Dr. Cannon: Yeah, so essentially most patients, the standard of care has always been surgical resection, complete removal of the tumor, which often requires a major liver resection as well. Oftentimes we have to remove two thirds or more of the liver along with the bile duct in order to completely remove these cancers surgically.
  
  Unfortunately, the vast majority of patients are already unresectable, due to a more extensive tumor, that can't be surgically removed at the time of diagnosis. So typically, chemotherapy has really been the only option for these patients, but the chemotherapy available has really not been very active against this cancer. So, survival has been very poor in patients who can't be resected, Even in patients who've undergone surgical resection, actually survival is not nearly as good as we see with other cancers that we can remove, such as colon cancer or even metastatic colon cancer. But seeing that, how much resection improved the outcomes, the group in University of Nebraska, early on first started a protocol where they would start very intensive neoadjuvant chemotherapy and radiation prior to transplantation. And they found early survival benefit there. So, then really the researchers at Mayo Clinic, really pioneered this and sort of developed the protocol variation of which is used by most transplant centers around the country who were doing this.
  
  And this involves, again, a very prolonged course of chemotherapy and radiation upfront, followed by staging to make sure that there's no disease that spread to the nodes and for the patients who make it through this protocol, they can then undergo liver transplantation. So, these were patients who were previously thought to be unresectable, which is essentially a death sentence.
  
  But now that patients are able to get through the protocol and can be transplanted, can really enjoy very good survival it's equivalent to, or sometimes even better than those who are able to undergo resection.
  
  Host: Well, you just touched on this briefly, as far as patient selection. So, what do they have to have completed before this would be an option? What's the criteria for entry into a transplant protocol, that's not amenable to resection? Tell us a little bit about who's considered unresectable or who fits the criteria into this protocol program.
  
  Dr. Cannon: Certainly. So criteria for resectability essentially, we have to think that we'll be able to remove all of the tumor completely, cause otherwise if you're leaving tumor behind, you haven't really helped the patient. So what makes the tumor unresectable is if it's either invading the main portal vein or hepatic artery, or if it's growing bilaterally into both sides of the liver, into the bile ducts, because we can't remove the whole liver and survive.
  
  So that's typically what makes people, patients unresectable. Another thought is, and that's in sort of cholangiocarcinoma that just arises out of the blue, which is the vast majority of them, in the United States. Now in the setting of primary sclerosing cholangitis, actually, some would consider all of those patients unresectable based on the fact that all of their bile ducts are abnormal and they have a much higher lifetime risk of cholangiocarcinomacarcinoma. So, patients with PSC in general, are just considered unresectable, by many programs and that'll allow entry into neoadjuvant and transplant protocol. In terms of specific selection for who's eligible, so after making the diagnosis, one of the biggest things is there clearly has to be no metastatic disease outside the liver.
  
  And there has to be no nodal metastasis as well. So, cancer that spread to the nodes, is a very poor prognostic indicator and those patients who have been found not to do well after transplant. So, metastatic disease or nodal metastases are one contraindication and the other is the tumor size.
  
  So, if they have a mass, that mass has to be less than three centimeters in order to qualify for the protocol. Finally, and perhaps most importantly is they can't have had a transperitoneal biopsy of the tumor itself. So, either a percutaneous biopsy of the tumor or more commonly an endoscopic fine needle aspiration of the primary tumor itself will rule patients out for potential transplant. Cause there can be peritoneal seeding that results in metastasis later. So, those are our sort of inclusion criteria for patients who we will considered for the protocol.
  
  But in general, you know, we really don't want the burden of deciding who's transplant eligible and who's not, necessarily to have to be on doctors in the community taking care of cholangiocarcinoma patients. We'd be happy to evaluate all patients with CCA and then we'll be happy to try and find the most appropriate therapy for them. It may be resection. It may be transplantation, or there may indeed be patients who unfortunately aren't candidates for either, but you know, we'd be happy to, sort of take on the care for all those patients.
  
  Host: Well you certainly are a preeminent expert in this field, Dr. Cannon. So for this to be successful, what neoadjuvant therapy is recommended and does liver transplantation following this type of therapy have efficacy in the treatment of CCA?
  
  Dr. Cannon: Certainly. So, yeah, it's a very well prescribed treatment regimen. And we have to get our regimens approved by the United Network for Organ Sharing in order to get transplant priority for these patients. So at UAB, our regimen is going to include induction with three to four cycles of the combination of gemcitabine and cisplatin, which is a very standard chemo regimen for this type of cancer. This will be followed by external beam radiation over a course of three weeks, during which time they're also getting five FU as a radio sensitizer. Finally they'll undergo catheter-based brachy therapy to the tumor and to get an extra radiation boost to the region. After they've completed their chemo, radiation, they'll then stay on maintenance oral chemotherapy until the time of transplant.
  
  Now, typically once they've completed the upfront chemo, radiation, once they have gotten their meld exception point, which is what will give them priority for transplant, they'll then have to undergo a staging laparotomy. During that, what we will do is dissect out all the portal lymph nodes and send those to pathology.
  
  Cause again, I think as we discussed earlier, they have to not have nodal metastases in order to get the benefit of transplant. So, this is where many patients who do drop out of the protocol and don't make it on a transplant; this is a common point of failure. And some of the data from the Mayo Clinic will suggest that up to 20% of patients will have positive nodes found at this staging operation. But if the nodes are not involved, then they can go on to transplant and the survival is really been excellent. So, one of the big determinants of survival and one of the important ones is whether this arises in the setting of primary sclerosing cholangitis, or sporadically. So, results are really excellent for patients with PSC. Five-year post-transplant survival for transplanted patients at Mayo Clinic, with PSC is 77%. So, that's as good as any other disease we do transplants for. Survival is not as good for patients with de-movo cholangiocarcinoma. Their five-year post transplant survival is only 56%, still much better than they would have had without surgical resection. And just with chemotherapy. Well, they wouldn't, they're not candidates for surgical resection, but I mean, with chemotherapy alone, so there's certainly a survival benefit for transplant for these patients.
  
  Host: So would transplantation with neoadjuvant therapies be better treatment than resection for patients with potentially resectable disease?
  
  Dr. Cannon: So that's a very interesting question and one, that's the subject of active debate. There is an ongoing clinical trial being run in France right now known as the transfil study. That should complete enrollment this year. And that may hope to give us an answer to that question, but that's certainly with the results we've seen with transplantation, that's certainly a question many in the field are asking. Now from a practical standpoint, in order to get transplanted with a deceased donor, at least, it's a requirement, that the patients be considered unresectable. However, with the living donor transplant, it could be potentially considered for resectable patients. Particularly if some of the data that we expect to come out over the next few years does prove that transplant would be superior even to resection.
  
  Host: Well you just, so my next question, which was appropriate prioritization for the deceased donor liver for CCA patients awaiting that. But so moving on from that, and before we wrap up, as the curative treatments remain challenging, what are some advances in hepatobiliary techniques that have improved the results and the outcomes of these tumors?
  
  Dr. Cannon: So really in hepatobiliary surgery, I think the surgery itself has not changed a lot, probably over the last 10 years, probably better adiuvant therapy I think it was one of the bigger things that's going to improve the survival. So a while back there was a trial known as the billcap study, which really, compared capecitabine orally in an adjuvant setting.
  
  Now it didn't include just Hilar Cholangiocarcinoma. It included other biliary cancers as well, but there was a significant survival benefit with oral capecitabine following complete resection of cholangiocarcinomas. And I think that's been probably the first improvement we've seen in awhile in survival and hopefully there will be some trials with some of the newer immunotherapies and checkpoint inhibitors. We don't know if there's any role for those in biliary tract cancers as yet, but I'd be interested to see what comes along.
  
  Host: And do you have any final thoughts for other providers? You mentioned briefly before that for community physicians and when you feel it's important, they refer, will you please reiterate that Dr. Cannon for us?
  
  Dr. Cannon: Certainly, I think if you have a patient with Hilar Cholangiocarcinoma, certainly send them over. We're happy to see them and evaluate them to see whether they'd be a resection or transplant candidate. And we love working with our partners in the community.
  
  Host: Thank you so much, Dr. Cannon, what a great guest as always you are. And a community physician can refer a patient to UAB Medicine by calling the mist line at 1-800-UAB-MIST. That concludes this episode of UAB Med Cast. For more information on resources available at UAB Medicine, please visit our website at UABmedicine.org/physician.
  
  Please also remember to subscribe, rate and review this podcast and all the other UAB Medicine podcasts. Until next time, I'm Melanie Cole.
• Hosts:Melanie Cole, MS