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Dr. Ghassan Abou -Alfa:
Welcome to The ASCO Post roundtable series on updates on hepatobiliary cancer. I'm Ghassan Abou -Alfa from Memorial Sloan Kettering Cancer Center, New York City. Joining me today are two of my colleagues. Dr. Shroff, I’ll let you introduce yourself.
Dr Rachna Shroff:
Hi everyone. I'm Dr. Rachna Shroff from the University of Arizona Cancer Center and I'm delighted to be here.
Dr. Abou -Alfa:
Thank you. Great seeing you as well. And Dr. Finn?
Dr Richard Finn:
Hi, I’m Richard Finn. I'm a medical oncologist at the Geffen School of Medicine at UCLA and the Jonsson Comprehensive Cancer Center. Thank you for having me.
Dr. Abou -Alfa:
Great seeing you both as well. Today we'll be discussing recent updates in hepatocellular carcinoma and biliary tract cancers and integrating these new developments into four patient case studies. Our third installment will focus on adjuvant therapy for biliary tract cancer. Let's go ahead and look into this case of a 52-year-old man diagnosed with intrahepatic cholangiocarcinoma, 7 cm in size with one positive periportal lymph node. Surgery resection revealed a 7.2-cm T3a and 0 intrahepatic cholangiocarcinoma, AJCC stage III disease. One month after surgery, the patient recovered, is doing very well and has no symptoms. The question to Dr. Shroff is, should we just watch the patient with surveillance alone? Or give them a form of adjuvant therapy and in this case, what therapy would you choose? Let's say capecitabine for 6 months or gemcitabine cisplatin for 6 months? Or anything else?
Sure. This is a rapidly evolving field; I think in a good way because historically we haven’t really had a lot of prospective data to support this. But what we've always known is that with cholangiocarcinoma there's a high risk of recurrence even with surgical resection. The minority of patients who are able to undergo surgical resection, out of those about 60% or so typically recur between intrahepatic and extrahepatic cholangiocarcinoma. Also, there are certain high risk features that this patient has in terms of a larger tumor, the periportal node, etcetera, that would suggest that there could be a higher risk for recurrence. The strongest evidence that we have to date is based on the BILCAP study, which was a study that compared 6 months of adjuvant capecitabine to observation in all biliary tract malignancies, so this included intrahepatic cholangiocarcinomas, but also had extrahepatic and gallbladder cancers. There was an improvement numerically in the median overall survival with 6 months of capecitabine in the intention to treat but after analysis it did not hit statistical significance. It just kind of missed the bar with a hazard ratio of 0.8, but the recurrence-free survival similarly improved. I think when you look at the guidelines from NCCN and ASCO and most of the bodies, the suggestion would be 6 months of capecitabine as the standard of care. But like I said, that's an evolving field. We have the ongoing ACTICCA study that is comparing capecitabine to gemcitabine and cisplatin. And then of course there are other studies that have been done and completed as well. In my opinion, I would do capecitabine in this patient.
Dr. Abou -Alfa:
Fair enough. You are totally right, it’s quite an evolving field that you have a lot to discuss about. Let's start with dissecting the first point. Dr. Finn, there was some work and I would like to comment specifically on the SWOG S0809 study. It was a limited study, but nonetheless it was very intriguing and valuable published in JCO by Dr. Ben-Josef and colleagues that looked into the combination of this type of chemotherapy plus an additional therapy—your thoughts?
This patient is lucky, they were resected. The only way to cure this disease is with resection, but we know they're going to recur. Personally, I think based on the strongest data with all the limitations that we heard from Dr. Shroff with the BILCAP study, capecitabine is probably the best option for this patient. It is a little unclear to me where the benefit would lie in radiation for an intrahepatic cholangiocarcinoma. Perhaps, for patients who have, and keep in mind these are three different diseases, maybe even four, bile duct cancers. There's intrahepatic, there's perihilar or Klatskin, there's extrahepatic, and then there's gallbladder, which is a totally different beast. And we know these are all different molecularly and how they anatomically behave. So as far as radiation is concerned, which is a focal approach, I see that as a possibility for patients who have Klatskin type or extrahepatic tumors, but I think the key part of managing these patients is systemic treatment.
Dr. Abou -Alfa:
Fair enough. I hear you loud and clear on that and I kind of go back to a question for Dr. Shroff over here. We've been struggling with that question for a while. We have, as you may recall, a very big meta-analysis that suggested maybe in certain patients there could be a valuable benefit for adjuvant therapy, especially within lymph node positive disease, but at the same time we're still struggling with regard to the options. And interestingly, the option that I even posed to you in the beginning for gemcitabine cisplatin, some of our colleagues are expressing the same dissatisfaction that you brought in with regard to the BILCAP study, that after all in regard to the intent to treat, did not necessarily fare out where we would like it to be, they are really even using gemcitabine cisplatin. With all this said, do you think after all, maybe the whole concept of adjuvant therapy is not really the right one for biliary cancer and maybe we should consider a neoadjuvant/adjuvant approach in that disease?
I think if we take what we've learned from pancreatic cancer, gastric cancer, and the other GI malignancies that have high risks of systemic recurrence and failure after resection, there is a strong argument to start to shift our way of thinking and to think about peri-operative approaches or neoadjuvant approaches. Especially, I think as our systemic therapies get better, and as we have a better understanding of the molecular complexities of the disease and the role that some of these targeted therapies could be playing. I think, considering moving gemcitabine/cisplatin, now gemcitabine/cisplatin/durvalumab, and whatever else we're thinking about that has demonstrated good efficacy in the metastatic and advanced setting into a neoadjuvant space, needs to be explored. We've seen completion of the NEO-GAP study, which was neoadjuvant gemcitabine/cisplatin and nab-paclitaxel, in what was defined as a high-risk resectable cholangiocarcinoma population. The study was completed demonstrating safety, feasibility, and ability to get these patients to the OR. Because at the end of the day I think time helps us understand biology and helps us consider those “right” patients for surgery and so a neoadjuvant approach really speaks to that and we've shown better outcomes in pancreatic cancer. It is something that we need to be thinking about and exploring better in biliary cancer. Especially as Dr. Finn mentioned, each of these diseases are very different. So, I think a neoadjuvant approach to intrahepatic cholangiocarcinoma needs to be considered separately from, say, gallbladder cancer.
Dr. Abou -Alfa:
Well, great thoughts. I like it very much. You mentioned one thing which of course we can ask Dr. Finn to talk about as well. What do you think about a role for a checkpoint inhibitor in regard to neoadjuvant, adjuvant or what you're going to call together peri-adjuvant before and after?
This disease has been in search of new treatments for some time. Like pancreatic cancer, chemotherapy still plays an important role. But we recently saw data with durvalumab and gemcitabine/cisplatin. This study, published recently in the New England Journal of Medicine Evidence that showed in patients with advanced biliary malignancies that gemcitabine/cisplatin/durvalumab was superior to gemcitabine/cisplatin in regards to improving overall survival and response rates, PFS, and actually was very well tolerated, virtually the same as gemcitabine/cisplatin. And now that we have a regimen that shows activity greater than gemcitabine/cisplatin, I think it does pave the way to moving this into the perioperative setting. In several cases, again, can we take a patient who is unresectable and make them resectable? Someone who's borderline resectable, who we can give a course of preoperative chemoimmunotherapy in hopes of inducing a response that makes them resectable. Also, this idea of determining the disease biology, and that's what has come out of pancreatic cancer is the idea that, do you want to resect a tumor that is technically resectable, but is going to develop lung metastases or liver metastases 3 months later? That's where the idea of neoadjuvant treatment gives us some time to better understand how aggressive this tumor is and maybe select patients better for surgery. IO, I think holds a lot of potential for this disease, like every tumor type, there is a subset of patients who get a benefit from IO. Combining it with chemotherapy we've been able to beat that hurdle in a phase III three study and improve survival versus standard of care. But still, the role for single agent IO needs to be further evaluated, probably based on biomarkers and come up with better ways to identify the patients that benefit.
Dr. Abou -Alfa:
Yes, this is very important. And again, maybe this tells and illustrates to our colleagues how much we continue to struggle with a very important question. And to be fair, it doesn't mean that we're not doing great work, everybody acknowledges all the great work happening globally in regard to the adjuvant therapy for biliary cancers. But at the same time, it shows that the evolution of systemic therapy as we always do in the disease is happening as we speak and as such, it will definitely have its impact in regard to the adjuvant, neoadjuvant or what we call peri-adjuvant therapy. So as such, we're not going to leave you without any answer per se. I totally agree with what Dr. Shroff mentioned a default that we can depend on because it simply is the only positive study, limited though, but still the only positive study is the capecitabine based on the BILCAP study. However, we really have to continue to consider a very open and frank discussion with our patient regarding whether adjuvant therapy for biliary cancer remains ill-defined. On the other hand, I also like what both our colleagues mentioned in regard to a peri-adjuvant approach that's still under investigation. And also, I’d like to add to what Dr. Shroff mentioned about the approach itself. I also add what Dr. Finn mentioned in regard to the use of the checkpoint inhibitor within that setting. This brings us to the end of this case. Please see the other segments for further discussions about the latest data in hepatobiliary cancer, or visit ascopost.com.