Meet The Professors. Now, what was his life situation before this, and what kind of condition was he in?

Transcription

1 Meet The Professors Clinical Investigators Consult on Challenging Actual Cases of Patients with Gastric, Pancreatic and Hepatobiliary Cancers I get the feeling we could do the whole symposium just on gastric cancer. Maybe we ll think about doing that at ASCO or something. But, anyhow, we do want to cover some of these other areas. We need truth in advertising here we made a mistake. This is actually a man, right? That s correct. Yes. So we re not going to fake it. We were wrong. It was a 92 you said his wife wouldn t be happy if we call him a woman. All right. So can you talk a little bit and we just want to kind of use this as a way to get into the issue of HCC and kind of what s new. But what about this patient? Sure. This is a 92-year-old gentleman, or as we say in Florida, a middle-aged guy, who was admitted to the hospital with pneumonia and, at the time of the admission, had some abdominal bloating, a little bit of abdominal pain. So his physician got an ultrasound of the abdomen, which showed a large mass in the right lobe of the liver, which was about eight centimeters. Now, what was his life situation before this, and what kind of condition was he in? He was in pretty good condition. He was living alone or living with his wife, and they were living independently, rather. So he s retired and was getting around. He had had cardiac bypass surgery about 10 years ago, recovered nicely from that, had a little hypertension, hyperlipidemia, some knee replacements and some cataracts, the usual things. But in reasonable shape overall, and certainly mentally quite with it. So, are you you re in Naples, or outside of Naples? No. Fort Myers. So I guess you have a lot of people in this age group. Quite a few. Quite a few. And actually, Ghassan, we get a lot of questions about the 85, 90, 95. We don t hear about the 70. We hear about these people, and particularly like this man who seems to be so healthy. But then he started to have problems and got admitted, and what happened? He had a needle biopsy done, which showed a hepatocellular carcinoma. He had a somewhat elevated alpha-fetoprotein of about 65 at diagnosis. His liver function tests were otherwise, believe it or not, normal, and he had no evidence of cirrhosis. He was negative for hepatitis B and C. And because he had kind of a slow recovery from the pneumonia, he was discharged temporarily to a long-term care facility, but that was only for about two weeks, and then returned home after that. What was his reaction and his wife s reaction to this situation after pretty good health? He was pretty mellow about things. I mean, he s a very matter-of-fact guy. So he was not as taken aback as you might imagine. And he was he would kind of go with whatever the recommendations were. Where was he from? I m assuming since nobody s from Ft Myers Yes. He was, I believe, from the Midwest and retired down for about 20 years. Alan, what would you be thinking in this previously healthy can you maybe, before we ask Alan to comment, say anything about his imaging, his CAT scan, what it looked like? 1

2 DR ENZINGER: Yes. This was, again, about an eight-centimeter mass. We did an MRI scan, also. He had no evidence of any distant metastasis elsewhere. He didn t really have any ascites. And it was something that, if it wasn t a 92-year-old, you could potentially consider more local options. So that was one of my things I d like the faculty to address as far as local versus systemic treatment of this. Did you say it was one, one inch? How large was the tumor? Eight centimeters. So, Alan, I guess I can serve the really hot questions here. When we do the video, we ll wait until you re fully here. And incidentally, if you have more questions about gastric or anything, submit them on the PDA, and Alan and Dan Haller will deal with them. We ll post them. We ll you, if you give us your , and let you know when they re posted. What would you be thinking in this man? I was racking my brains to think if I ve ever treated a 92-year-old with therapy for cancer. Obviously, I m hearing the music in the back. It s distracting. I apologize. The issue, of course, is age is not the marker we should be looking at. It s physiologic age. Having said that, 92 is really on the high side. I think I m more concerned about the performance status, because in HCC performance status is clearly the predictor of who will do poorly and who won t. So what was his performance status before this started? He is no longer a two to three. He s back to a one at this point. So, at least theoretically, when we talk about performance status, we try to say related to cancer symptoms. So if this is really an ECOG-1, then I would have a I would work the patient up and I might even resect the patient, if the patient had resectable disease. But I think you don t take these options off the table until you find a reason not to do those things. Ghassan, what s the oldest patient you ve seen go for a resection? Ninety-two is, again, pretty far away. Less than 92, apparently. But I think this is a very, very important case, because it really brings a critical epidemiologic aspect. Actually, I m curious. Do we know at all what the etiology of his HCC I m guessing probably it s hepatitis C? No. He was negative. Because we have this old population of men and women who have hepatitis C, unfortunately, because of dental work and this is really kind of bringing up an important health concern for us about the silent epidemic of hepatitis C that we are harvesting now as HCC after the 10 to 30 years hiatus until develop. So this is a population we re going to see. What was his body habitus? Was he obese, diabetic? No. No, he was normal weight. Do you see people with steatohepatitis with diabetes that that s what you think it s from? It s hard to imagine that this is where it s coming from, because he lived to 92, if he s diabetic and morbidly obese. But nonetheless, it s a point well taken, that we re seeing more of those patients. And I think they will populate going forward, about 20 to 25 percent of our clinic in regard to HCC and related to NASH or nonalcoholic steatohepatitis. Lowell, did you figure out so he had what, community-acquired pneumonia, or what was going on that he got pneumonia? Was it unrelated, do you think? It was probably unrelated. And he was recovering from this at that point. Right. I mean, it s possible that he may have aspirated a little bit, too. He was getting some abdominal pain and that sort of thing. So I guess is that the disco next door? I don t know. But could you envision a man like this going to a major surgery? 2

3 Probably not. I would probably be more interested in other local control measures, if there were things other than a major resection that we could do for him, although none of them are going to be that easy. Do you think he would have considered it, even knowing what the He probably would not consider a major resection. And I haven t presented that to him yet. I kind of just to tell you what I did with him, I decided to punt and see whether his ECOG performance status would improve. I did actually start him on Nexavar, but I was chicken to give him full dose. So I gave him a half dose, 200 BID, of Nexavar, sort of so I could temporize for a month or two and see if he was improving or not. And now at this point, he actually just came into the clinic about a week and a half ago, and he s still looking good, still has normal liver function tests. His alpha-fetoprotein, however, has significantly increased to, like, 300 something. So that s gone up, but still good performance status and normal liver function tests. So the faculty has got a bunch of questions. Bob? DR WOLFF: I just wanted to make a point about performance status, because it can be a moving target. And one of the things I take a lot of time doing in my practice is sort of seeing which way the wind is blowing, perhaps with more than one visit. Because there s a huge difference between a patient who s got a PS of two headed toward three versus a patient with a PS of two headed towards one. Those are totally different patients. And it s hard on the first visit to necessarily get a sense of that. So, in a patient like this I mean, I don t do much HCC, but I think it s very applicable to this case and patients we see with pancreatic cancer. We don t just pull the trigger as soon as we see somebody for the first time. We may say, We re going to do a little more workup, or, I want to see what s going on with your bilirubin over the next week, or, see how we do with pain control. And in a week, you can tell. Is the patient going north? Is the patient going south? Because if this patient is two going toward three, I think your enthusiasm for anything would be going south. If they are, as Lowell suggests, getting better, then I think you can start to say, Okay. Let s roll up our sleeves here. Let s not go crazy, but let s see how half-dose BID goes for a couple of weeks or a month, and then we ll take it from there. DR ENZINGER: Yes, I essentially have the same comment. I think that particularly with hepatocellular carcinoma, there is a subgroup of cancers that actually can have a relatively indolent course. And I ve had a few patients, particularly years ago, when we didn t have the options that we have now, who elected not to get any therapy and had very, very slow growth of their tumors. Now, you said that this gentleman is starting to get some abdominal discomfort. And initially I thought that this was purely an incidental finding. But if he is beginning to become symptomatic, then I can see how one would start with therapy. But if this had truly been an incidental finding, I see no rush to start any sort of treatment, and I probably, as Bob was saying, I would probably just observe the patient for a little bit to get a better sense of is this patient having any symptoms from his cancer? And what is sort of the pace of this disease? I want to get David s take on this in a second, but first, what do you think, Peter, about the strategy of, quote, temporizing with sorafenib? DR ENZINGER: I think if the patient is becoming symptomatic, I think that starting some sort of therapy is not unreasonable. I think that one needs to have a conversation with the patient and probably, if this gentleman needs to have if the patient is willing to have a resection, you re going to have to do an extensive cardiac workup and specifically look at all the comorbidities. I think a surgery like this has to be done at a tertiary care referral center, someplace where there are hundreds of hepatectomies performed per year. This is not something that should be done in the community by any means. Alan, what are your thoughts? And also, do you see, like, slow-growing HCCs? Yes. Absolutely. This is if this fellow had hep-c or hep-b, I might take it as a more ominous prognosis. But assuming this fellow hasn t had a CT scan before, this could have been there for a couple of years. I think it s a classic medical school pearl that pneumonia can cause diarrhea and abdominal pain. So, if his performance status is getting better, I actually wouldn t. We re not going to cure him. And truth be said, the benefit to sorafenib is incremental. So, if he s getting better, I wouldn t have touched him. I would have repeated his scan in two or three months, allowing that if he 3

4 started to deteriorate, I might have moved it up, but not really thinking we ve missed a golden opportunity to make a big difference. Alan, you d say the same thing if he s 82? DR CUNNINGHAM: I would say the same thing if he was 62. Now, that doesn t mean that the 62-year-old would listen to me. Doesn t mean a 92-year-old would listen to you, either, but... If you look at a series from Barcelona back about 20 years ago, they looked at the control arm of two randomized studies that treated patients with localized HCC, placebo arms. The median survival in those patients was 16 months. Those are essentially incidental HCCs that are found early. So I would definitely think twice about treating this patient. There s also a mixed histology tumor, sort of cholangio-hcc, which is particularly indolent. You won t pick that up on the average FNA. So I actually not only I would have certainly cautioned him about sorafenib. If I started it, I would have started low, as you did, but I probably would have recommended against treatment. David, any thoughts about this case? And then I want to go on to another case, but any thoughts about this at this point? Yes. I mean, our policy would be that all new cases of patients with malignant disease are discussed in a multidisciplinary setting. So it wouldn t just be an oncologist that determines what happens here. The patient would be discussed with the liver surgeons, the gastroenterologists, et cetera, and you d work out a risk-benefit. I mean, we ve never operated on anybody in this age group, so I think the surgeons would say no, because we d probably kill him. I think the thing about chemotherapy in elderly patients as well is that we often make these patients worse. And if they get toxicity, they take a long time to recover from it. So I d really like to have your I mean, we re talking here about disease where the benefits of chemotherapy are actually modest/ marginal. It s a worthwhile treatment for patients who are fit and well and who will have the ability to recover from toxicity, but I would be quite anxious that we could end up making this patient worse, and I d certainly go along with the idea of, even if the patient was keen to consider chemotherapy, just say, Let s watch and wait and see what happens. So just a couple of points about HCC, Ghassan, in general, in terms of we were chatting this afternoon about what s new. And actually there s a paper being presented here, data from the SHARP trial you can go to the next slide looking at I think there s data before, looking at Child s A versus B. Now this is looking at liver function tests and sorafenib on the SHARP trial, and it looks like, at least from what we could see there in the abstract, that the relative risk reduction is pretty similar. Any thoughts about this and similar kinds of data sets? Sure. I mean, this has to be interpreted very carefully, because remember that the SHARP trial, the population, is Child-Pugh A. So even though here we re talking about normal ALT and AST and up to moderately elevated, these are all Child s A patients. And this is really what we ve known since 1973 as being referenced to cirrhosis. So here what the investigators are going to present is that regardless of the elevation of the ALT/AST or the alpha-fetoprotein, ultimately everybody benefited the same. Another important aspect here is that there are a lot of what we call instruments to evaluate cirrhosis up to fibrosis, and we know very well that ALT/AST, alone or naked, wouldn t be enough to kind of interpret clearly what the liver functionality is about. So I think it s definitely a nice observation, but I wouldn t necessarily see out of it any change in our understanding that patients with more advanced cirrhosis might need a dose adjustment or even not recommended to have or to take sorafenib. So, Alan, we asked some questions in our poll of the audience related to this issue of dosing of sorafenib, and this also relates to this man, who s older. So we said, in general, what s your first-line approach of a 60-year-old patient who s going to receive systemic therapy in Child-Pugh A? So most people would use standard-dose sorafenib. Then next we asked the same thing or we asked Child s Pugh B. And most people, although a third would still use standard dose, two thirds would reduce it. And then the next thing we asked was, Okay. What about Child s Pugh A, but 80 years old? And again, most people reduced the dose, but there s a significant number who use the standard dose. Is there one more there? Let me see. Yes. I guess that was it. 4

5 DR CUNNINGHAM: What are your thoughts about these oh, 80-year-old Child-Pugh yes. We have that. Okay. So that s a very good question. Obviously, the SHARP trial, there s very little data on dose adjustment. The New England Journal restricts the size of the number of words, and we don t have that information. They used 400 BID. So that s the standard. In practice, I can tell you, at least in San Francisco, almost nobody tolerates 400 BID, be it the Olympic athlete or the 80-year-old. And there s evolving data and belief, even from people in Bayer/ Onyx, that we may be better off starting with a lower dose and working our way up. It would be nice to have data to tell us that that s equivalent. Ghassan, do you agree? In New York, do you see the same thing? I have to say that some people still do tolerate the full dose. And obviously, these are the Child s Pugh A patients with a good performance. But they need a very close monitoring to make sure they keep tolerating that dose, because those side effects can really be very subtle, but if you miss them, definitely you will see that patients are not tolerating the therapy. Interesting point here about the Child s Pugh B, that patients with worse liver function will probably, based on data published from our Phase II, as well as from a study that Alan and I were partners on with other colleagues from CALGB, that showed different recommendations for patients with different levels of liver dysfunction, as based on bilirubin. Add to this, in regard to the age, there s data from the RCC that shows that age wouldn t matter. And I think here, again, as Alan said, this is physiologic age is not really age as we know it by number. So I would say here, if the patient really is doing clinically well and, of course, considering what Peter and others recommended, to kind of watch them for a bit, see if really this cancer is evolving as cancer and the performance truly is still good functionality, in Child s Pugh A, I think a full dose could be justified still. So, David, what do you think about this? I mean, I just when people talk about physiologic age versus real age, but 92 is, in and of itself I m not sure how many 92-year-olds really physiologically I don t know. When you use sorafenib, do you start at the standard dose, and in what situations will you use less? To be honest with you, I don t really treat much HCC, Neil. So, I mean, I tend to treat younger patients with the standard dose. I ve not treated any octogenarians with it. It s not a big part of our clinical practice. So, Alan, just to clarify, you have a healthy 60-year-old. What dose are you going to use? I think the standard is 400 BID, and occasionally patients tolerate it. We have nurses calling twice a week. One of the mistakes, the dangers and, of course, there are hepatologists, interventional radiologists and others who are prescribing Sorafenib one of the mistakes you make is you give them a pill and they think that it s okay, and they take if anything, they tend to take too much of it. They don t call when they have toxicity. So I think the standard is 400 BID, but I m concerned that we may be moving forward with a drug that we re not using the exact right regimen. Again, hard to know. And I think that this would be the standard. My own instinct in an older 92-year-old who may not be symptomatic would I be sure I would like to if he wants treatment, the last thing I d want to do is make him real sick. Ghassan, anything new in terms of mechanism of action of sorafenib? Obviously, it s a TKI, but it affects a number of systems in addition to VEGF. I was actually we were doing an interview on AML I did not know this. Probably everybody in the audience knows it. I don t know. Lowell, do you know that sorafenib is used in Flt3-positive AML? Actually, I don t. I d never heard that before. It inhibits Flt Alan, you ve heard that. It s one of the agents being tested for AML. Interesting. But, anyhow, Ghassan, what about the mechanism going on here? Is it the vascular angiogenic mechanism or one of these other pathways? Clearly, this is a multitargeted molecule, actually, and the antiangiogenic component clearly is evident, based on what you are seeing, for example, from the SHARP data and from the Phase II. In addition to this, of course, the anti-raf, what we just heard, PDGF. It definitely has multiple targets, but if anything, what s fascinating us nowadays is the fact that it might impact the fibrosis of the liver, and 5

6 there is some preclinical data on that. And, also, the other one is it might be an antiviral therapy, and this is again, there are some publications about affecting HCV titers, and that s something being looked at. 6