DR. LANGE: I have been told that we have only 10 minutes, and I would like to ask a variety of questions individually, and then I would like to open it up, and I would invite the Innsbruck group and Mike Jewett. As many of you know, he had sort of a shootout not too long ago where he had Foster and Sheinfeld and the Innsbruck group come up and do cases and debate the issues; and so maybe he would like to summarize that.
The first thing I would like to ask all the people, I think Dr. Basl already gave us the answer, but let us start at this end and just go on down. You believe right now that the survival between, basically, the three options, surveillance, which as you know Larry Eignhorn is not discouraging, two courses of chemo and RPLND for high-risk disease is the same?
Joel?
DR. SHEINFELD: (Microphone was turned off.)
DR. LANGE: So, what would you say would be if I were a patient and said, "You know, I don't really want that big incision. What am I doing to my chances of survival? No, what am I doing if I watch it or get two courses of chemo? How much less survival am I going to have?
DR. SHEINFELD: (Microphone off.)
DR. LANGE: Just give me a number?
DR. SHEINFELD: (Microphone off.) An unknown number of these patients will have relapse, and you are going to lose three out of four of those patients. So, I would not give someone up-front chemotherapy. I think it is unnecessary in many cases. I think these patients are disadvantaged at the time of failure.
DR.LANGE: All right. You won't give me a number. How about George? George, I am a patient. How much less survival am I going to have if I take surveillance or two courses of chemo rather than getting the RPLND?
DR. BOSL: You are talking about only clinical stage 1?
DR.LANGE: Yes, stage 1, high risk.
DR. BOSL: Stage 1, high risk, I think that probably at 20 years if I am going to make a prediction you are going to be down between 3 and 8 percent because of myocardial infarction, leukemia and late relapses that cannot be handled.
DR. LANGE: So, my chances of dying of the cancer are how much less?
DR. BOSL: I didn't say cancer, Paul. I said --
DR. LANGE: No, I will get to the complications in a minute.
DR. BOSL: I can't separate the two, and I am not going to talk to a patient only about the potential complications, which I will definitely discuss. I am going to talk about the biology, which I do in every patient. I discuss where these tumors come from. I discuss what the downstream possibility and probability of teratoma is, what it means since they all come in with their path reports now and ask questions about it; at least my patients do. So, I don't see how you can separate a discussion of the toxicity from the management of the disease, whether a patient dies of myocardial infarction 10 years from now, which all these patients are between the ages of 30 and 42 in minority series for disease, I think is completely irrelevant. Disease-specific survival, I do not think is the proper end point.
DR. LANGE: Okay, so you have made it very clear that you think the long-term complications of chemotherapy are significant.
DR. BOSL: And they are real and proven.
DR. LANGE: All right, and so we should do whatever we can to avoid chemo. Let us move on to the type of RPLND because I guess everybody on the panel here is an RPLND person. What about laparoscopic approach?
Dr. Kavoussi, do you think that you should do a laparoscopic approach if you are going to give chemotherapy for N1 or don't you think it computes?
DR. KAVOUSSI: I think that the dissection has evolved to the point that it is the exact same dissection that one can do open, and that is a personal opinion, and, as I said, there need to be prospective studies.
We have at our institution, as I stated, been advising patients for low volume stage 2 disease not to undergo chemotherapy. But, as I said, there are still concerns that this is not a complete dissection, which I think are not invalid concerns. But, if it were my child, let us say, and I could send him out to Jim and have Jim do the retroperitoneal lymphadenectomy on him and Jim had low-volume disease, I would go ahead. And I would feel comfortable in just putting him on, just watching him after that, and not giving chemotherapy.
DR. LANGE: Right. Now, when you are in there and you find a positive node, do you think you need to go bilateral and/or can you go bilateral?
DR. KAVOUSSI: I think we need to learn from the experience of what people like the folks at Memorial and the folks in Indiana have shown us. And I think Joel showed some very nice data this afternoon that, yes, you need to go further. And he makes an argument for going bilateral.
So, the answer is can you go bilateral, and I showed you in this individual here; and there are times that you get scared because you see the ureter on the other side and not intentionally early on. So, you can do a full bilateral node dissection laparoscopically.
DR. LANGE: Okay, Joel, do you think you are going to lose this bet to Dr. Kavoussi in about 10 years, or do you think you are going to prevail?
DR. SHEINFELD: We will know when there is data, and there is no data yet. That is the issue. Film clips are nice but film clips are not data; and so we have learned the hard way that modified templates expose patients to unnecessary risks and a subset of these patients cannot be rescued. So, that is hard to translate when you see these late relapsing patients where three out of four are going to die and they started with stage 1. That is very significant, and that is a result of incomplete open [RPLND]. That is the template, open template experimentation, uncontrolled. So, these are lessons we learned the hard way in the open era and the open surgeons didn't get away with it; and I don't see any reason why the laparoscopic surgeons will get away with it.
DR. LANGE: All right, we have one more question and then I will invite at least two questions from the panel, and then we have to quit.
Dr. Bosl, if I told you that I could do boundaries, laparoscopically, just like Joel could, and I told you it looks like I can do it as well, do I need to have a prospective study or will you just take my word for it?
DR. BOSL: That certainly is a planted question. The answer is no. I don't think you can do that on the basis of Phase 2 trials. The carboplatin versus platinum data were based on large Phase 2 trials, and it subsequently [was] proven that the complete response rate is identical but the long-term relapse rate and survival rate is inferior when you use platinum. Single agent carboplatin compared to etoposide, platinum, based upon Phase 2 trials in seminoma, was shown to be inferior; and the lower dose of etoposide used in Europe for years was shown to be inferior to 500 milligrams per square meter, otherwise the identical regimen by Guy Toner in Australia.
When you test the lower bound, Phase 2 trials have wide confidence intervals around them; and Phase 2 trials are not adequate to set a new standard of care, particularly when you are dealing with something that has a cure rate as high as this. I think if you are dealing with a different disease one might make a different argument where systemic therapy is not so important. But in this disease, I think that I need to have data that the node dissections are equivalent, that the outcomes are equivalent, because the chemotherapy is going to have its independent consequences.
DR. LANGE: I don't see anybody from Innsbruck or Dr. Jewett. Do you want to comment?
PARTICIPANT: Not me, but two associates have done 121 patients with stage 1, and we started to do template dissections. And you know, at the beginning we were very fearful because I think what Dr. Sheinfeld told us I think this is totally right; and therefore, we gave two cycles of chemo. So, at the time being we can't say that we have done this in oncological efficacy, but since February 2001, we are doing both sided nerve sparing retrograde neo-lymph node dissection; and this is feasible with laparoscopic surgery. And then we will see what our, probably in about 2 years we can tell you if we are safe in terms of the efficacy in oncology. But, I think from the technical standpoint what Dr. Peschley is doing now, (and he is not primarily an endoscopic urologist; he is primarily an oncological surgeon who has gone into laparoscopic surgery) and he is doing a full and both-sided laparoscopic approach and is doing nerve sparing.
DR.BOSL: I think that large numbers in that setting, when you are not giving chemotherapy afterwards to all patients, I think is, in fact, going to be a very important piece of the data collection on this. Because part of my concerns about this is not just the completeness of the node dissection and local relapse, but it is the unequivocal presence, now proven beyond a shadow of a doubt, that myocardial infarction and other vascular complications occur to these patients in a far higher frequency than happens in the normal population. And it is that piece of it that drives me to be so concerned about how much chemotherapy I give up front, because 20 years out follow-up is not quite so good. And these patients are only going to be in their low to mid-forties, and it is that thing that really drives my concern.
DR. LANGE: Okay, I am going to turn the program over to Eric, but, Lou you have the last word.
DR. KAVOUSSI: I just had a question for George. Is that [chemotherapy complication data] cycle based?
DR. BOSL: The data come, probably, from three to four cycles per metastatic disease. But, as I showed for the leukemia, there is no lower bound. There is no absent risk, and so on my slide where I had the hypothetical I put question marks there. I don't know exactly what that number is going to, but I have no doubt but that it is going to happen to some extent. Whether it is going to be quite as high as the three to four cycles I am not sure but I think we can be reasonably assured that it will happen and it will happen even in the absence of bleomycin.
DR. LANGE: I think we can conclude this panel with my thanks to the participants by saying that chemotherapy is poison, even long term, and that RPLND is still here to stay and whether it can be laparoscopic is up in the air.
Thank you.
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