Dr. Rachna Shroff:
Welcome to The ASCO Post Roundtable Series on Immunotherapy Strategies for Hepatobiliary Can-cers. I'm Dr. Rachna Shroff and I'm the Chief of the Division of Hematology/Oncology at the Univer-sity of Arizona Cancer Center. And joining me today are two of my dear friends and colleagues. Nilo, can you introduce yourself please?
Dr. Nilo Azad:
Absolutely. I'm Nilo Azad. I'm a medical oncologist here at Johns Hopkins focusing on GI cancers and early-phase drug development.
Dr. Shroff:
And Anthony.
Dr. Anthony El-Khoueiry:
Anthony El-Khoueiry, also GI oncologist at USC and Chief of the Section of Developmental Thera-peutics.
Dr. Shroff:
Today we'll be discussing the treatment and management of hepatobiliary cancer with three pa-tient case studies. Our third and final installment will focus on localized hepatocellular carcinoma. And so with our experts, I'm going to launch us into a case and then I'm sure there will be plenty of conversation to be had in the space of localized disease when we think about HCC.
So this is a 52-year-old male with a history of hepatitis C that's treated and in remission. He's fol-lowed in the hepatology clinic and surveillance imaging shows a 5.2-cm liver mass that washes out. AFP is 6.2, and labs are within normal limits.
The patient has a good performance status and has no history or is not an active drinker or has any drug use history. You'll see the imaging here of the lesion and multiple slices through it in various phases. So what would you do next? I'll start with Dr. El-Khoueiry. I would imagine that just like all of us, that these types of cases are discussed in a multidisciplinary tumor board format. So if this patient were to come to your clinic, can you tell us what that tumor board conversation would look like in terms of workup that needs to be done and what considerations could be given for therapeutic approaches?
Dr. El-Khoueiry:
I just want to second what you said. With hepatobiliary cancers at any stage of disease, these mul-tidisciplinary discussions are critical because a lot of these patients end up needing multimodality therapy over their journey. Now in this situation, this is an early-stage cancer with liver-limited disease, solitary lesion. Really the first fork in the road, does this patient have underlying cirrhosis that's advanced enough to cause portal hypertension and warrant a transplant type approach vs somebody with either no cirrhosis or very early compensated cirrhosis where resection is still pos-sible because we have to realize that still at today, these are the two main curative modalities, re-section vs transplant.
So some of the details we do not have here. Does this patient have varices? Do they have large spleen? I don't think we saw their platelet count either, which again would take us down the road of resection vs transplant. And besides that, if we choose to go down the road of transplant, then we start thinking, are we going to do some sort of bridge or downstaging therapy? In this case, the patient has a solitary tumor that's just above 5 cm, so just outside Milan criteria. So the bridge treatment would really have the aim of downstaging to within Milan.
Dr. Shroff:
Great, thank you. So Nilo, in your tumor board, are there conversations in terms of if you're just outside of Milan and you want to think about downstaging and such, this case aside, let's pretend that this is somebody like Dr. El-Khoueiry mentioned, it’s somebody that has cirrhosis and consid-eration of transplants as being given. What is your typical approach with your tumor board and your multidisciplinary team in terms of potential bridging or downstaging therapies in the liver-directed space?
Dr. Azad:
Yeah, we have a weekly tumor board that's attended by our interventional radiologists, our radia-tion oncologists, our transplant surgeons, and our hepatobiliary surgeons as well as us. And so I think we're very collaborative in how we try to take care of these patients. Sometimes there is some discrepancy in terms of the fact that there are different modalities that would be appropriate for the same patient. And so which one are we going to target? Often we'll have patients that will meet with the different providers, hear about the side effect profile of the different locoregional therapies and then make a decision based on that. But in this circumstance, based on the solitary lesion but the size that it is, we likely would be considering something like a yttrium-90 in this cir-cumstance. And if it were just a little bit smaller, TACE would fall a little bit higher on the list.
Dr. Shroff:
Yeah, I think we have a similar approach with a radioembolization Y90 type of bias. Anthony, is there anything different that you all do at your institution?
Dr. El-Khoueiry:
No, look, I would say level one prospective phase III comparison of Y90 and TACE does not exist. However, smaller studies have suggested consistently that Y90 radioembolization has some superi-ority to TACE, especially in the setting of, as Nilo said, solitary lesions where you can actually achieve high levels of radiation like radiation segmentectomy type approaches. It really seems to perform better than TACE. So that is the current bias in the United States, and I think that's there to continue for the time being.
Dr. Shroff:
So we also discussed this patient at multidisciplinary tumor board and as mentioned the tumor is just outside of Milan criteria and we decided to approach it with a Y90, but then interim imaging actually showed three new lesions that were just adjacent to the primary mass. Very small, patient feels well and actually a decision was made to surgically resect the patient instead. And at that point pathology showed at that surgical resection, a moderately differentiated hepatocellular car-cinoma. Four tumors in total, no vascular invasion, margins were negative, and no lymph nodes were seen. So the patient recovers well from surgery and then is referred to see medical oncology for postoperative follow-up and to discuss next steps. So Anthony, what do you do now? You have a surgically resected patient with the pathologic features as described, multiple tumors, but all com-pletely resected. Do you offer any postoperative or adjuvant therapy and what does the data in this space look like?
Dr. El-Khoueiry:
Yeah, so let's first recall that the risk of recurrence globally for HCC after resection, if we take all commerce, it really sits around 50% to 60%. So this is a tumor with a high risk of recurrence. The risk of recurrence is even higher with certain high-risk features, which include multiple tumors, tumor larger than 5 cm, microvascular invasion seen on histology, high AFP pre-op, and I'm not sure if I'm not... infiltrative type disease. So there are certainly high-risk features that one has to be con-scious about. For a long time we had no adjuvant data in this setting. More recently over the past year we saw data from IMbrave050, which looked at the combination of atezolizumab/bevacizumab vs best supportive care post resection in high-risk patients.
And the data's early and needs to continue to mature. What was reported was the interim RFS, re-currence free survival analysis, which really shows a RFS superiority with atezolizumab/bevacizumab at 1 year. But the curves seem to merge together with longer follow-up but again, is this due to censoring and not enough events? It's unclear. So that's why we need the longer follow-up. We also don't have OS data. So currently there is no regulatory approval for this combination. It is being used clinically when you can get it for really high-risk patients and that's been reasonable pending the more mature data that hopefully will come out this year.
Dr. Shroff:
Yeah, I agree. I think the RFS data was interesting, but I think longer term follow-up and under-standing because at the end of the day what the overall survival impact is I think will be important. There was also some deaths in the atezolizumab/bevacizumab arm that I think made people a little wary or worried. Again, just making you want to see a little bit more data to be able to understand this. Dr. Azad, what's your current practice at Johns Hopkins? Are you guys using adjuvant atezoli-zumab/bevacizumab? Again, if you can get it.
Dr. Azad:
I will admit that has been given on occasion to patients that have excellent performance status and have very high-risk disease. It isn't always failproof that we can get it and I don't think it's being used ubiquitously. I do think that the toxicity component should give us pause though. If my memory serves the grade 3/grade 4 toxicity was over 40% and so as you might expect, but I think that that's still substantial in the adjuvant setting for something that hasn't gotten a proven overall survival benefit. But we do know that if these patients recur, we are in a really difficult position in terms of being able to think about future cure and so I am very interested in these data over the next year.
Dr. Shroff:
Let's pretend that this patient receives atezolizumab/bevacizumab in the adjuvant setting and does well after completion of therapy for 13 months and then is found to have two new liver lesions and pulmonary metastases. AFP is 23, patient still has a good performance status, et cetera. So I guess the question is in somebody who gets atezolizumab/bevacizumab in the adjuvant setting, Anthony, what would you do next to now treat what is essentially recurrent metastatic hepatocellular carci-noma?
Dr. El-Khoueiry:
Well, that's an uncharted territory question. So I'm assuming I'm going to interpret this as the pa-tient having completed the 12 month course and then had another 13 months where they were disease-free. Right, so 2 years? In that setting as our practice and other tumor types beyond 2 years, you could potentially go back to atezolizumab/bevacizumab as your first-line regimen. In this disease we have the luxury of also choosing a PD-1/CTLA-4 regimen as our first line instead. Now, but you said the patient recurred. I kind of as an oncologist rushed to systemic therapy options but if I go back, you said patient only recurred with two lesions in the liver.
Dr. Shroff:
But also pulmonary metastases.
Dr. El-Khoueiry:
Oh, also pulmonary. Yes, so systemic therapy would be appropriate, but I guess what I was getting at is some of these patients recur with oligometastatic disease or liver-limited disease where actu-ally there is decent on cherry-picking or doing liver-directed therapy and doing well for a while prior to doing systemic. Now in this patient with recurrence in more than one organ, including ex-trahepatic, I would start with systemic. If we have a good response, then potentially pursue it with some local modalities to see if we can get them some period of being disease free.
Dr. Shroff:
Anything else that you would do differently, Nilo?
Dr. Azad:
No, I really do like always keeping your mind open with oligometastatic disease to how we can think about this in an aggressive way in healthy patients and that can tolerate that. But I would ab-solutely agree with starting with systemic therapy and I think starting with the CTLA-4 combination makes sense in terms of picking between that and a TKI, if the patient tolerated their initial immu-notherapy well without autoimmune side effects. So I think that would help me kind of make that decision.
Dr. Shroff:
Great. Well, so in terms of key clinical takeaways, I think the landscape of localized hepatocellular carcinoma is evolving, but it clearly requires continued multidisciplinary management and en-gagement. In the setting of somebody with cirrhosis, and within Milan criteria, workup as Dr. El-Khoueiry mentioned for transplants should be considered and bridging therapy may be needed. But outside of Milan criteria or in somebody that is not necessarily with cirrhosis or has early-stage cirrhosis, they should be taken for surgical resection if that is an option since that is also a curative approach.
Data suggests a role for adjuvant atezolizumab and bevacizumab for 12 months in high-risk patients as we defined, but longer-term follow-up is really needed to better understand the impact on overall survival as well as some of the safety signals that we're seeing initially.
So this brings us to the end of this case. Please see the other segments for further discussion about the latest research in hepatobiliary cancer or visit ascopost.com. And I'd like to thank doctors Azad and El-Khoueiry for their fantastic comments and insights. Thank you very much.
