DR. KOCH: I would like to start with John , starting with something more clinical. The extended node dissection that you do is certainly quite extended I think, compared to what has been commonly done in many centers doing cystectomies. What I want to ask you is do you see this as a significant problem when we bring that type of technique to clinical trials? I think your data, and Dr. Herr's data is fairly significant and strongly suggestive that there is some therapeutic benefit to that.

DR. STEIN: As Harry had mentioned this morning, there is no good substitution for good surgery. And again, I emphasize, we don't know of the ideal limits of lymph node dissection, but at least it appears that an extended lymph node dissection is important. And the concept of lymph node density, when you take that into account, and I think it will help stratify different patients if they have a more limited dissection.

For example, if someone has 3 nodes positive and only 10 are removed, their lymph node density is significantly different than 3 nodes positive and 30 lymph nodes removed. So I think the lymph node density tries to incorporate that concept. And it may be able to be used in clinical trials to better stratify patients.

DR. KOCH: But do you see that being done with consistency when it is brought to clinical trials across different institutions?

DR. STEIN: There will be clearly some difficulties with that based on training. Even with the advent of laparoscopic approaches, now looking at doing cystectomies, because I think it is much more difficult laparoscopically to do an appropriate lymph node dissection in patients with bladder cancer.

DR. KOCH: Let's take a question from the audience.

PARTICIPANT: I have a question for John, which is the same question I wanted to ask Harry before. And that is while I would like to believe that the extended node dissection is truly influencing survival, I think if you look at that data, it could very much be construed as a stage migration effect.

If the node dissection is simply a more precise diagnostic test for nodal metastasis, you get an improvement in survival in both the node-negative and the node-positive groups, exactly like CT for renal cancer. And the question is, how can you tease out whether this is a stage migration effect, or a true survival benefit?

DR. STEIN: Well, you could look at what Harry Herr just presented earlier. I mean there was a significant difference in his. I think obviously, the concept of picking of micro metastases with an extended lymph node dissection is what we are trying to do.

PARTICIPANT: I'm going to just follow up on your question about the p53. And I'll put in a plug for Richard Cody's trial. I noticed that that trial, which is post-cystectomy adjuvant trial does not have any restrictions on the type and degree of node dissection done. Is that correct?

DR. STEIN: No. Let me just interrupt you on quick second there. We have built into the trial, that at least 15 lymph nodes must be analyzed. If 15 lymph nodes are not analyzed in those patients, they all must have an abdominal-pelvic CAT scan. So we are trying to level the field a little bit.

I will tell you, looking at every single pathology in over 320 patients, and Seth Lerner will talk about this a little bit more, but there is a significant difference in the lymph node dissection, not only in academic, but obviously in some non-academic institutions across the country.

PARTICIPANT: Right. So the questions of accrual, Seth will talk about next week. But there should be no reason for us not to be using that trial in a routine practice. I mean every urologist here who does a cystectomy should be able to enter that trial, get it through its IRB. It doesn't do anything to you. All you do is do your cystectomy, and then say if the p53 is positive or not, and send the patient on to a medical oncologist.

DR. STEIN: Well, we have encouraged that.

PARTICIPANT: It's the easiest trial in the world. And when nobody raised a hand, I was upset. So that's my plug.

DR. KOCH: It might have been your perspective. A few people raised their hand.
I have a question for Dr. deVere White. John presented a strong case for the node dissection. And my question was how do you integrate the issues in terms of molecular markers and p53 status with the surgical issues in terms of extended node dissection when you move this to clinical trials? It seems like both those variables will confound each other quite a bit, and minimize the likelihood that you have an interpretable outcome for your trial.

DR. DE VERE WHITE: Well, no, I really wouldn't think so. I mean I think that if these markers are really going to be worth anything, they have got to be able to predict what's going to happen. So I mean if an extent of a node dissection overcomes the use of markers, and I don't think there is going to be one marker. It's going to be a panel of some number. And if a node dissection can outweigh the use of that panel of markers, then the answer is panel of markers just aren't worth it. So, I don't think that it's really an issue.

DR. KOCH: But you don't stratify your trial by the surgical technique, do you?

DR. DE VERE WHITE: All right, well, the trial that I just talked about?

DR. KOCH: Yes.

DR. DE VERE WHITE: No, the trial that we talked about is a sequential approach. And it would be based -- and Nick wouldn't like it, because it is based on neo-adjuvant chemotherapy. So just like Harry, you redo your resection, and if there is still tumor in the muscle in that resection, they again get their neo-adjuvant chemotherapy.

And instead of going to a cystectomy without any lymph node dissection, they get re-resected. And if that is positive, they then go on to their cystectomy. But if that is negative, they get to choose whether they want a cystectomy or they cystoscopy.

DR. KOCH: Let me ask you another question about that, a more clinical question. Where is your data that treating that group of patients that opts for surveillance only, that have had a complete response to chemotherapy, where is your data that that's a safe thing to do? I thought what Dr. Herr presented, I think it was earlier, would suggest that there is going to be a real high recurrence rate in that group.

DR. DE VERE WHITE: Well, obviously, if one had all of the data, then there would be no reason to do a trial. So obviously, the problem is that all of the data isn't, and that's why you need the trial.

But let's just stay in America. So let's just with Harry's figures, and really if Harry wants to get up and give them, but I mean Harry has 150 cases, and compared 10 years, what happens if you had a cystoscopy or a cystectomy. And the disease-specific survival at 10 years is the exact same in both groups. And the only difference is that half the patients with the cystoscopy still had their bladder. So I mean clearly I think that Harry has shown that it can work.

I think the other issue is that John showed that no matter how far your extended surgery goes you still don't save anyone. So the problem always one talks about is the assumption that if you have that surgery, you are saved, and therefore, you are only at risk if you don't, just is not true. If was true, we wouldn't be talking about neo-adjuvant and adjuvant chemotherapy.

So obviously, one has to prove that it is safe. And I think that if you look at it, and we put out a paper, and there are about 15 different studies out there, and if you look at both England and look at Reg Hall's study, the survival if you have a less than muscle-invasive disease, and you don't have a cystectomy, you have a 75 percent survival. And if you have muscle-invasive disease, and have a cystectomy, you had a 28 percent survival.

And those figures are very, very similar to what you see in the large inter-group national studies. So yes, there is a risk, but that's why the patient gets to choose, so he is not randomized. If the patient says, no, you just take my bladder out, I think that is fine.

But certainly, if we can reproduce Harry's data, and we can actually validate markers and find new markers, then I think we will move the field further, and should be able to do it safely. And if we can't, that's what a trial is for. We'll go back to the drawing board.

DR. KOCH: I think that is well answered.
Dr. Cardo, you gave us some data on some of the upstream and downstream events relative to p53. And we have some national trials going on with p53 at this moment. I was wondering what your prediction of the likelihood of those trials being fruitful, with knowing that it's a much more complex issue than just whether or not p53 is mutated.

DR. CORDON-CARDO: Well, I completely agree also with Dr. deVere White that a single marker may not be the answer. But as you can hear from some of our colleagues, even just to study one marker, it's becoming a very difficult task. So imagine studying four or five markers. Every time that you introduce a new marker or a new variable into the statistical equation, you will need probably around 40-60 patients more in order to make the final assessment statistically valuable.
So it is important to understand the pathway I think. Also, it's important to know our limitations. And if we can start doing one or two markers, maybe that's better than doing 20 or 30 or even 6, because accrual will take, and I don't know to the extent that people will participate.

I also would like to make the comment that several people have presented today that socially it's in different hands of having very different outcomes. And that experienced surgeons produce a much more safe outcome for the patient. Probably, we should say the same for who is performing the molecular assay.

You know, I'm a pathologist. I don't think that any of you would allow me to go into your operating rooms and take care of a prostate or a bladder, thank God. But it seems like everybody is happen to take histochemistry, molecular biology, and to do it in the afternoon.

Well, that's not what why we are here. I think that we need to realize that molecular techniques have power limitations, and people have them too. And I think that we need to trust the type of exercises that are coming with the kind of data that gets results. And I think that if we keep procrastinating to bring biology into anatomy, we are not doing our job.

DR. KOCH: Thank you.
A question from the audience?

PARTICIPANT: Yes, this is a question for Dr. Stein. I would just like for you to comment on why, from your perspective, the increased resection of negative nodes, in other words the number of negative nodes resected at the time of lymphadenectomy confirms an independent prognostic significance? And if you believe that's micro metastasis, is there anything that you have done to evaluate that?

DR. STEIN: Well, in our series, when we removed greater than 15 lymph nodes, it wasn't statistically significant. And I believe the reason for that is that 86 percent of our patients have more than 15 lymph nodes. I think we don't have enough power in our series to demonstrate that.
But if you look at the other three trials that I mentioned, or those three reports, they all suggest that there is a benefit with a higher number of lymph nodes removed.

DR. KOCH: A question for Dr. Baffa. Where do you think the Fhit gene and FEZ1 fit into all this? It's a different pathway, if I understand it. Is that correct?

DR. BAFFA: Yes, it is a completely different pathway. I put the two genes together, because we are working on those two genes, but they are completely different. I didn't have the time to show you again the data on the FEZ1 gene, and we are working very hard on that. The FEZ1 gene is involved in cell cycle regulation.

In my lab, we are working on the function of the Fhit gene right now. It seems to be involved on apoptosis, mainly in apoptosis. We don't know which pathway of apoptosis, but in the Fhit gene there are many reports studying several types of solid tumors, breast cancer, lung cancer, gastric cancers, and so on. And we are ahead. We are close to proposing a phase one clinical trial for the Fhit gene.

The FEZ1 we are still far. We need to continue animal study, and then we will see. In our department, our urologists have great expertise in prostatectomy study. Dr. Gomella with the vaccinia studies, so we are ready for that. But probably it is not the time yet.

DR. KOCH: If I understood Dr. Ratliff's talk earlier this morning, he was suggesting that there has been a lot of difficulty in terms of intervesicle gene therapy. And in terms of I think just the success rate of inducing that gene in the urothelium. Is this a problem for your genes as well?

DR. BAFFA: Yes, it's going to be a problem. And that's why the animal model then is going to be different than the human. The receptors are different. The capability of the different vectors to transfuse is different in humans, but we need to do the animal study. There can be no doubt.

One of the advantages is that in mice we can use a non-viral vector. But we need to test it, and we need to do all the experiments in making sure that we are working in the right direction.

I can tell you we are working with the T24 cell lines, and using the adenovirals. In the Fhit we didn't see any changes. And then we realized that those cells didn't have the receptor for the adenovirus. So we were not infecting the cells. This is a small thing, but that's the way. Absolutely, I agree with everything that was said this morning.

DR. KOCH: Okay, then one last question. The title of our session today was, "Molecular Genetics of Bladder Cancer, Ready for Prime Time?" So what I want to ask the panelists, we'll just run through you, and ask you are we ready to be using this in standard clinical practice, or does it await further clinical trials? Ralph?

DR. DE VERE WHITE: No, I think the answer is regrettably we are not ready to use it in clinical practice. We clearly are ready for prime time to go and properly evaluate these, just like Carlos said, because we should be able to have them in prime time.

DR. KOCH: You don't think there is enough data on p53 to be using it clinically or on a regular basis right now?

DR. DE VERE WHITE: In an individual patient, absolutely not.

DR. KOCH: Dr. Cardo?

DR. CORDON-CARDO: I completely agree. I think that we need these multi-institutional clinical trials prospectively that will bring the potential power of these markers into play. We have done that well in other diseases. I mean it's impossible to think performing a root analysis on a breast cancer without doing estrogen receptor, progesterone receptor validates, even if we have to do analysis, because they drive therapeutic endpoints.

I think that we need to start looking at these markers, not just as biological tools, but also as markers that can help all of us to select the better therapy for those patients that deserve a more aggressive intervention. And maybe that would be the way that we all would start using, not just because we bring some biology and also predictive nature, but because we are going to be more skillful in giving each patient a better chance for cure by selecting the right therapeutic approaches.

As Dr. Harry Herr knows, some of the bladders, if you leave them instead or if you take them out, survival is the same. So we need to identify the group of patients that will clearly benefit from these more aggressive interventions.

DR. KOCH: Okay, John, you've been a big proponent of p53. Do you use it in your clinical practice outside of a trial setting?

DR. STEIN: I will use it, but I use it knowing that the p53 is done by someone who is skilled, as Carlos has mentioned earlier, at an institution that has a standard. And I think if you are going to use that, you should have someone who is well equipped and well capable of evaluating that.

And I echo both what Carlos and Dr. deVere White had mentioned, that it's not going to be one marker, it's going to be a multitude of markers.

DR. KOCH: Raffaelle?

DR. BAFFA: Yes, I agree with them. But I would like to say that we also need to identify in our lives, new markers. We have different markers, diagnostic markers, prognostic markers, markers of response to different drugs, and so on. So we have to work for identifying new markers also. I wouldn't use p53 right now.

DR. KOCH: Well, the message would seem pretty clear both from the audience, and from the panel that we have to do these clinical trials to evaluate the significance of the currently available markers, as well as to identify new markers, and how these markers interrelate with each other.

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