DR. SOLOWAY: All right, I've got some rapid fire questions here, and we've got about 15 minutes, so I think I can get through most of it.

I have asked Tim Ratliff to increasingly, for all of you who go to your offices, you will find, I'm sure on a regular basis, with the Internet, with all the books out on bladder and prostate cancer, et cetera, patients are very educated. So Tim is going to be the representative, if you will, for some of these questions.

First of all, he's been around urologic circles at a couple of major institutions, and been in conferences. So he knows a heck of a lot about clinical bladder cancer. But he is going to be the patient advocate for this panel on these clinical questions.

So I'm going to start out with Dr. Herr. Harry, if a high grade TCC is under-staged, which we know it is in X percent, one of the questions that comes up is: what duration of delay is unacceptable? In other words, if you are talking about re-staging, you have a T1; maybe it's a T2. And this also really comes to bear when scheduling a patient, even with T2 disease, let's say a minimal T2, but you are going to do a cystectomy. What delay is reasonable for getting that patient to the operating room? That's something we don't really discuss very often.

DR. HERR: There is actually some historical data published in medical decision-making that would suggest that three months is probably -- you should get something done within a three month interval. That the progression rate to deeper muscle invasion and/or metastasis clearly in the under-staged tumor probably puts the patient at risk.

I personally use around six weeks, especially for re-TUR. And I don't want to hit that window of three months. And I think once you get beyond three months, you are risking a reduced survival in that patient, especially with a high risk of disease. And there is data to support that.

DR. SOLOWAY: All right, let me ask the audience, just to pull the audience -- a show of hands -- how many think that you've got to make that decision, or if it's a cystectomy, you've got to do this within six weeks is appropriate? How many would say six weeks? [A majority show of hands.]

I don't have to go further. The question occasionally comes up, if for some reason, the patient or with your scheduling, you can't get the patient to the operating room in six weeks, and let's say there is not another person to do the surgery, Harry, would you suggest based upon something you said here, that patients should get chemotherapy in the interval? Let's assume it is T2 disease. T2/T3.

DR. HERR: Well, I would not personally. It's hard to believe that you couldn't find someone to do the operation. If the operation is needed, then the operation should be done.

DR. SOLOWAY: Okay, that's a good answer.
All right, next question. We are debating now a patient, talking to them about a possible cystectomy, possible considerations of another round of intravesicle therapy. This is often a discussion we will have with patients. And in your mind and the patient's, what are the most critical factors for the patients, as the patient, he or she, sees their goal to preserve the bladder? And this also would come under bladder preservation.

So we have various discussions, be it more TUR, plus further intravesicle therapy when there is a risk involved of progression of disease, or bladder preservation versus cystectomy and diversion, which may be a neobladder. So in your mind, and then I'm going to ask Tim here particularly as the patient advocate.

So number one, is a patient's and your main concern the perioperative morbidity and mortality? Which is not insignificant. Is it the alteration in voiding pattern that may occur with any type of diversion, or leaking if it's a stoma? Is it the sexual consequences? That's certainly a major factor in the male. Or is it the possibility of upper tract disease?

So, Don, if you had to pick one in this decision-making, what do you think is most important for the patient, if you are physician looking at it? They are all important. Is there one that is a most for the patient, do you think?

DR. LAMM: I think what is most important is what's important to the patient. Obviously, survival is what we are looking for, but this is why you need to talk to your patient and find out what they want. And then you influence that decision based on data and your own opinions.

DR. SOLOWAY: So one of these doesn't stick out at you? Most of my patients are really worried about this, the operation and possible mortality. It's a conversation.
Tim, what are your perceptions, being the patient advocate, if you will?

DR. RATLIFF: I think it's tumor-free survival. So am I going to undergo all of this surgery and all of this trauma, and all the problems that you just listed, and still die at the same time? So is it going to really make a difference? Is it worth my effort? Or is the disease already spread beyond the bladder? Is it active in the lymph nodes, and it's going to progress no matter what?

DR. SOLOWAY: Now, you as the clinician may not know the answer to that. And then it's going to bring in your bias, therefore, whether you think an operation versus bladder preservation, let's say with chemotherapy and radiation are most important.

DR. RATLIFF: Right, but what I would want you to do is convince me that the data that exists out there now would support me having surgery. So with my particular cancer, my particular stage, what are the numbers that would indicate that surgery is going to benefit me?

DR. SOLOWAY: Harry?

DR. HERR: Well, my patients ask me, what's the chance that I can preserve my bladder? In other words, what's the percent of relapse? And half are going to relapse, 60 percent. A third of them are going to be invasive. And then they are going to ask, well, what's the chance if I preserve my bladder, I'll get a new tumor? And that's over 50 percent.

And then they are going to say, what's the chance that that new tumor -- and this is the key question -- is going to kill me? And we have actually looked at that and published it, and it's about 20 percent. And that's what I tell patients. That if we preserve the bladder, and we follow them 15-20 years, the new tumor will develop, and that the mortality of that new tumor will be around 15-20 percent.

DR. SOLOWAY: And, Harry, just if I can just -- again, this is something that may take some thought, and all patients are different, but of these four things, let's say the patient is contemplating again, bladder preservation versus cystectomy-- what do you think impacts his major concern of going to cystectomy is?

Let's say the likelihood of cure is about the same. He's got a T2, not a big T2 tumor. So he might do well with bladder preservation with chemotherapy-radiation therapy.

DR. HERR: Urinary function. That's the predominant issue.

DR. SOLOWAY: They are not as much worried about the mortality and morbidity of the surgery itself?

DR. HERR: Not in this day and age. Not when presented and given the current figures, no.

DR. SOLOWAY: Okay. Dr. O'Donnell, just straightforward, for a patient who has failed BCG -- and you might tweak some of this from your trial -- initial course of BCG. He still has high grade Ta, CAS, or T1. Are you less likely to suggest cystectomy if a patient is older, or particularly with co-morbidity? Is there a bias toward further rounds of intravesicle therapy? And how big is that bias, do you think?

DR. O'DONNELL: I think clearly that high risk patients, by the criteria you are going to use to define that for surgical mortality and morbidity have to play a role in the equation. And so you have discussions with patients of risks of one thing or another.

They ultimately do want you to make a decision based on their individual situation. And they appreciate that when you show them their x-rays and you talk to them specifically about their disease. So that's really the approach that I take.

And in terms of recommending alternatives to cystectomy, I think the discussion must begin at what is the safest approach, and what are your interests here? So for instance, the safest approach in most patients, the absolute approach to having the best chance of curing the cancer is probably a cystectomy. But different people have different margins of risk that they will accept though.

For instance, when you say well, what's the difference between a trial of advanced immunotherapy versus cystectomy? And it may be a 5 percent tangible risk difference. And many people will say, I can accept that risk. Life is full of risks, and people are used to this, especially at the age that they are presenting, at the median age of 70 years old. They have accepted the idea that they are going to die some time in the future.

So they will have different parameters, and that will be a set point that will depend on how they are feeling their own health is, and what their age is, and what their expectations are.

And so I think that's really the crux of it. Be honest. Tell them that cystectomy is the safest, and the most guaranteed way to get rid of the cancer, but that alternatives may put you at a certain margin. It's a relatively small period of time in which you are undergoing that trial or that treatment.

DR. SOLOWAY: Mike, let me follow-up. A man has high level TCC. You are contemplating a radical cystectomy with an orthotopic neobladder. Do you always, and under what circumstances do you biopsy the prostatic urethra not at the time of surgery, but this is at the time of the endoscopy?

DR. O'DONNELL: If it's a patient that I have been following through, I make it a point at the time when I do my restaging evaluations, to do biopsies of the prostatic urethra. I like to know while I'm there, what my chances of being able to do it an orthotopic neobladder. I like to tell the patient ahead of time, yes, we checked this, and it's unlikely we won't be able to do the procedure.

However, there are certain circumstances, for instance when a patient is referred to you. It's been 6-8 weeks since they have had their T2, T3 disease diagnosed. You don't want to put them through any extra time and delay and so forth. And you know that the data shows you that if you do a frozen section margin at the time of cystectomy, they are pretty reliable.

Now, I have personally been burned a couple of times where the margin has been "negative," and the final margin says there has been severe dysplastic CIS elements within intraurethral ducts.

DR. SOLOWAY: So let's say you have 100 patients that are in this situation. You are doing an endoscopy. How often are you biopsying a prostatic urethra?

DR. O'DONNELL: If they have high-grade aggressive disease grade 3, T1, CIS, almost all the time.

DR. SOLOWAY: So almost all the time.
Harry?

DR. HERR: No, we have often biopsied it previously, looking for disease in that site, but we don't use that as a criteria, whether or not to do orthotopic diversion. Nor do we do frozen sections at surgery. I don't think there is any evidence to show the prostatic involvement puts that patient at more risk than not.

DR. SOLOWAY: And you are not doing frozen sections at the time of surgery? If you plan to do an orthotopic neobladder, you are going to do it based --

DR. HERR: If it is technically feasible, yes.

DR. SOLOWAY: All right, interesting.
Don, frozen sections?

DR. LAMM: Yes, I do look at it. But I would compliment Harry on his consistency, because he does the same thing with ureters.

DR. SOLOWAY: All right, this is the audience. How many of you do frozen sections at the time of -- how many do not? Interesting, 50-50. Fifty percent of you do not do frozen sections at the time of an orthotopic neobladder. Interesting.

Do you do frozen sections? Don, you preempted my question here of the ureter. So you have a patient with a unifocal T1 to T3 tumor. Do you think it's necessary to do frozen sections of the ureters, no CIS in the bladder?

Don?

DR. LAMM: Now that I'm at the Mayo Clinic, they are automatic. I don't even have to think about it. But yes, I accept Harry's data. It is true. But you've got one chance.

DR. SOLOWAY: So the answer is it's not necessary, but you do it routinely?
Mike?

DR. O'DONNELL: I do it, and I do it at a time in the operation when I know I'll get the results back, and it won't change the speed or the approach or anything else I'm doing in the operation.

DR. SOLOWAY: So the answer is yes, you do it routinely?

DR. O'DONNELL: Yes, and I also do it because we have therapies that can be topically applied to the upper tract that can eliminate --

DR. SOLOWAY: The bottom line is the answer is yes.
Harry, no, you don't do it?

DR. HERR: No.

DR. SOLOWAY: And even up here I don't do it routinely, particularly if there is no CIS.

How many in the audience always do frozen sections of the ureters? How many do not?

Clearly, the majority do continue to do them. Harry, you and I are in the minority on this one.

All right, now, next question. You have just completely -- so, you do a good endoscopic resection, resected several bladder tumors. They can be primary or new tumors. They appear endoscopically to be high grade Ta or T1. Will you order intravesical chemotherapy such as mitomycin in the recovery room? Dr. Lamm, one dose?

DR. LAMM: Absolutely.

DR. SOLOWAY: Mike O'Donnell?

DR. O'DONNELL: Yes, actually in the operating room.

DR. SOLOWAY: Tim, you are the patient's advocate. You are in the recovery room. Are you going to say did you give that fellow mitomycin-C?

DR. RATLIFF: I'd want it.

DR. SOLOWAY: Harry, are you going to be the odd many out?

DR. HERR: We generally don't do it, but I accept the data.

DR. SOLOWAY: How many are going to give intravesicle mitomycin-C based on the trials? Okay. Harry, you're getting older and older these days. It's tough to change.

All right, now second TUR. Harry, I've got some rapid-fire questions for you here. Within a few weeks of the initial or index TUR, certainly it delays treatment like BCG, or cystectomy, and it adds cost, morbidity, et cetera. There is a downside to a second TUR. That is, taking the patient back to restage the patient. So I'm going to give you very specific scenarios.

Number one, you have a patient with; it could be one, two, or three tumors; none of them are large. This is the first tumor in this particular patient. He's got high grade T1, no CIS. You've done a "complete" resection. There is muscle in the specimen. It's a very common scenario.

First, Don Lamm, do we have to do a second TUR before you start BCG in this patient?

DR. LAMM: No, you don't. You give them the initial chemotherapy, and then you give them the BCG, and you biopsy them at three months or six months.

DR. SOLOWAY: Okay. Mike O'Donnell?

DR. O'DONNELL: I do the same thing.

DR. SOLOWAY: Same, no second TUR?

DR. O'DONNELL: If I've done the first, and I feel good about it, and again, just like you can tell that a lot of tumors are Ta, you can also tell when you've got a more aggressive T1 or not.

DR. SOLOWAY: Harry?

DR. HERR: Not if I had done a small tumor in the setting myself.

DR. SOLOWAY: That's what we are talking about, yes.

DR. HERR: Yes, if it had been done elsewhere, I would have done it.

DR. SOLOWAY: Okay, fair enough. So we have uniformity here that this patient doesn't need a second TUR.
Now, only the different scenario here is the patient has some CIS in another area of the bladder. You did a cold cup biopsy within a little erythematous patch. Don, anything different here?

DR. LAMM: No.

DR. SOLOWAY: Any of the panelists? Okay, so no second TUR for this group.
All right, now, the next case, the patient has not had prior BCG. You have adequate uninvolved lamina propria, but no muscle, so we are just going to say T1 microfocus, T1A if you want to say it, millimeter of invasion, and you don't have muscle. Do you have to do a second TUR?

Don?

DR. LAMM: Not if I did the TUR. Obviously, if somebody else did it, I would.

DR. SOLOWAY: Okay, so you would be happy without muscle.
Mike?

DR. O'DONNELL: I feel the same way.

DR. SOLOWAY: Okay. Harry?

DR. HERR: No, I would repeat the TUR.

DR. SOLOWAY: All right, this is a little tougher. How many in the audience believe this patient, just because there was no muscle there, you have to go back and do another TUR, even if you did the first one? How many think we can go ahead with BCG? That's pretty close, 50-50. So there it's not as clear.

The next case, outside pathology, high grade TCC into muscle. Probably, you are never quite sure if it's muscular, it's appropriate. Your TUR resection site indicates CIS plus high grade focal Ta. So you've done, Harry, just like you said, the patient was outside of your institution. You re-resect, but there is no muscle involvement.

You have lamina propria, muscularis propria, and there is no tumor there. So it's a high grade Ta tumor. What is your treatment?

Don?

DR. LAMM: I would recommend cystectomy, but I would inform the patient about alternatives.

DR. SOLOWAY: Okay, Tim, what would you want?

DR. RATLIFF: I think I would try a series of BCG and interferon first.

DR. SOLOWAY: Okay. Mike?

DR. O'DONNELL: If this patient had documented muscle invasion at one point?

DR. SOLOWAY: The outside slide is yes, but your re-resection is a pretty good resection. There is certainly no tumor, even beyond the mucosa--

DR. O'DONNELL: I would go for cystectomy, actually.

DR. SOLOWAY: Okay. Harry?

DR. HERR: I think you have either option here. And here the patient, as Mike mentioned, comes into play here. But I think conservative management in this setting is safe.

DR. SOLOWAY: And you have published, I think, pretty conclusive evidence, which has influenced me.

All right, let's poll that one out to the audience. Again, the scenario is your TUR, there is no invasion. Outside slides show an area of invasion; bi-manual, totally normal metastatic work-up, negative. How many think that patient should go on to have a cystectomy?

How many think you can go ahead and give that patient a short trial, whatever intravesicle therapy? Again, that's a tough one. So that's why these are tens, these high-grade patients.

So we have some, I think uniformity of opinion about second TUR. It's not necessary for all patients. We still have some divisions, and that's the reason for clinical trials.

So, I think we're on schedule Marston. Thanks to the panel, an excellent start off for the program this morning.

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