DR. CRAWFORD: I want to applaud both of you guys for being on time.

Thoughts I have are that unfortunately, we don't have a randomized clinical trial to address this issue. I think both of you said that. The other thing is I think we have learned from RTOG studies 86-10 and from also Ed's study that these studies are studies that take a long time. They are not five-year studies. The difference emerged at eight years and ten years.

The controversy I think also involves when to pull the trigger in the way of hormonal therapy. And so there are a couple of concluding things I want to say. Regarding radical prostatectomy, as we have all heard, we are way behind the radiation oncologists in defining the benefit of combining hormonal therapy with radical prostatectomy.

We have seen that the adjuvant trials with radiation show a benefit. We know this from other studies in other tumors in breast and colorectal that adjuvant is better. I think that we need to even look at chemotherapy earlier in high-risk cohorts following radical prostatectomy.

And I want to make a plea to this audience on behalf of ECOG and SWOG and CALGB that are involved in this study, I think this is one of the more important studies ongoing in urologic oncology right now. And that is taking patients who are at high risk after radical prostatectomy with these features, and randomizing them to hormonal therapy or hormonal and chemotherapy.

This is a composite slide I just did of data from BOLA, and data from RTOG, and superimposing that, a study of hormonal therapy from SWOG. Actually, these are reversed. This was Ike Powell's paper that just came out. And this is not a randomized trial, but it's a phase II trial that shows that four months of hormonal therapy in radical prostatectomy actually do pretty good too in treating these patients.

Why put patients on SWOG 99-21, the inter-group study? People brag about the positive margin rates going down. Mine are going up. And one of the reasons is I'm going after high risk patients to put on this study, because I think it's an important study.

What is the advantage of surgery over referring this patient for radiation and hormones? I think one is you determine the lymph node status. And Ed has very clearly shown that if you microscopic lymph node disease, I think that that in fact long-term hormonal therapy is a benefit.

Not everybody with high risk features is going to have extracapsullary disease or seminal vesical invasion. So you may spare some patients adjuvant therapy afterwards.

Local control -- I think we can make an argument that local control with surgery is as good, if not better than radiation to some degree. Most of us do a lot of radical prostatectomies. There should be a low morbidity. Incontinence should be rare. And I think we need to do this study to address the issue. The radiation studies show a benefit when you combine it. We need to look at it with surgery, and see if the same thing is true.

So I think the other thing is, and let me just ask the panel this, and if anybody has any questions, please come up to the microphone. I think both of our panelists were kind of pro early rather than late. Ed, let's say a guy is failing a radical prostatectomy, and both of you showed Chris' data about defining a failure above .04. At what level do you pull the trigger?

DR. MESSING: For hormones or for any treatment?

DR. CRAWFORD: For hormones. Mary Gospodarowicz isn't going to like this, but anyway I don't know that there is any study that proves that adjuvant radiation improves survival rate. Local control and things like that, SWOG started a study in 1988-94. And there will be some criticism of that study, but it was closed in three years.

It's been closed for a decade, and we are not reporting any results. To me, that means that there is not a difference that is emerging, or else our data safety monitoring committee would tell us that adjuvant radiation after radical prostatectomy, and it made a difference versus some delayed therapy.

So getting back to the question. A guy has radical. Let's assume you don't choose radiation. His PSA goes up afterwards within a year and a half. It is 0.5. What do you tell that patient, or what do you do?

DR. MESSING: Again, I use a lot of the Pound criteria, but I think if within a year and a half the PSA is going up, particularly if he was a high grade tumor patient, I would wait, and I'd see what another PSA is. But if it is over 0.2 or 0.3, I would pull the plug on that guy, because that's meeting the Pound criteria of someone who is sure to -- not sure, but has a high chance of failing very, very quickly.

If alternatively, it was a lower Gleason grade, negative margins, that the doubling time wasn't that great, I would still consider radiation. So again, but I would do it early, because I believe that what my study showed, and what exactly that Marty's experiment in his lab showed, and several other experiments have shown is that with tiny quantities of cancer, that endocrine therapy is not only better, but is a real home run.

You know I was trying to show in my talk that there a lot of people who don't need it. And you will be treating a lot of people -- I don't believe it's 50 percent, but you will be treating a lot of the people who will fail, ostensibly fail after prostatectomy if their PSA is detectable, unnecessarily, because they may not have cancer. And their PSAs are going to go down with hormonal therapy. They will probably go down with radiation therapy, because radiation shrinks a normal prostate.

DR. CRAWFORD: So I hear you say that with high grade cancers, if they fail at 0.5, you will pull the trigger?

DR. MESSING: Or earlier.

DR. CRAWFORD: Marty, that was great work with the Shionogi tumor model. I'm impressed. I'm always impressed with you. I think that is another interesting thing. Do you want to comment on that, what your feelings are to the same question?

DR. GLEAVE: I think that we are up here arguing the same thing. I usually like to wait to get a trend line for PSA. If you are going at 0.2, 0.3, I'll wait, and get an idea of what the doubling time is. That's an important factor down the road, also for data gathering. So if we are going to pull the plug at 0.2-0.3 in all patients, you will never get an idea of what the doubling time is.

So I will bring them back in and get an idea, and probably not pull the plug until 0.6-0.8, somewhere around there, if they have high risk features. If they low risk features, I will just watch it go up for a longer period of time.

I'm surprised, I do see some people who are being told that at levels of 0.06, 0.08, that you are going to fail. That is not necessarily true either. And I think that a lot of reassurance has to be applied to those patients.

DR. CRAWFORD: So you would rather put a lot of credence in at least the doubling time. But you don't let the PSA get to 3 or 4 or 5? It's an early doubling time, right?

DR. MESSING: Again, for the high risk patients.

DR. CRAWFORD: Okay, let me just ask you this. What does pulling the trigger mean? What do you give a patient? Do you give them combined androgen-block A? Do you give them monotherapy? Do you give them high dose casodex 150?

DR. MESSING: I have not been able to use for most of the patients I have. I have tried, but I can't fight with my insurance companies giving them high dose anti-androgens. It's just something that is prohibitively expensive for most of the people I know. If I could, I would.

So I have been using standard LH-RH agonists. I pre-treat them a month, a couple of weeks with anti-androgens first, and then LH-RH.

DR. CRAWFORD: Marty?

DR. GLEAVE: Same thing, a short course of lead in anti-androgen, and then come in with an LH-RH. Do you treat then adjuvantly, say for two years, or do you treat on an intermittent basis?

DR. CRAWFORD: Let me ask both of you, so how long do you do it for? The Bolla study three years, and I assume a lot of that was high-risk patients, and probably had micro metastatic disease. And I think you both said that. It's a systemic treatment. Do you do it for one year? Three years? Or do it for life, like in the --

DR. MESSING: Well, again, the Bolla study was adjuvant as opposed to salvage.

DR. CRAWFORD: I understand that, but I think a lot of those people did have microscopic disease, or things like that. So there is a crossover. So if a guy has a rising PSA, and you pull the trigger at 0.5, how long do you treat? Do you go forever?

DR. MESSING: Unless there is a reason not to, or unless they want intermittent therapy, I tell them forever. I don't know data to say in this scenario that stopping it is the right thing.

DR. CRAWFORD: And then you get into the argument about all the long-term side of hormone therapy, and I don't think we need to dwell on those. We all know what they are. And there are ways to abate them.

Marty, what do you do?

DR. GLEAVE: Forever is a long time in these guys. And so one of the reasons I can pull the trigger or feel comfortable pulling the trigger earlier is that I don't tell them it's forever. It's either two years of adjuvant, or for the most part we treat intermittently. So that's nine months.

DR. CRAWFORD: I think, and I don't either, and I don't know if it's right, but I pick two or three years too and then stop it, because they've got an end in sight. I think your intermittent therapy study for rising PSAs after radiation is interesting. I just don't see intermittent therapy applying here. If I'm going to treat them, I want to wipe it out for as long as I can and then stop it. To me, intermittent therapy is a couple, two to three years, and then stopping it.

Dr. Dawson, you have a question?

DR. DAWSON: Yes. Both of you said the same thing, and I'm trying to have someone explain this to me, that you give an anti-androgen first. What's the flare you are trying to block in a patient who doesn't have a prostate, who has just got a rising PSA?

DR. CRAWFORD: Good point.

DR. MESSING: I concur it's a good point, but he does have tumor cells. They will call as a surgeon, testosterone. I have no idea what that means, and I sort of carried it over from my treatment of people with more advanced disease. And you bring a good point up, so I won't argue.

DR. WARD: John Ward from Mayo Clinic.

I have had the opportunity to actually take Chris Amling's work and work a little bit further with it. And there are two points that both of you made that I would just like to expound on, that are back on our poster that hopefully will be coming out in press sometime soon.

The first is I don't think we can stop looking at patients, or use that two year cut off mark from the Pound paper. What we have found is that certainly people continue to have PSA recurrences 10-15 years down the road. But those PSA recurrences after even five years, are just a significant based on the doubling time, as PSA recurrences that recur within two years. If you have a PSA doubling time of less than 12 months, if it occurred after 5 years, they are still at high risk for developing clinical disease.

The second point is that a patient with a low Gleason grade, a Gleason 5 or 6 patient who has a significant doubling time again, is at significant risk for developing clinical disease recurrence. So I think we are going to see a change and a shift away from just an absolute PSA value, to depending on the PSA doubling time, as you have mentioned.

DR. MESSING: I think that is well taken, but I think at least my inference from that, and from the radiation therapy data where virtually everyone failed is that if you have the rapid recurrence, it is likely that you had a large volume of disease outside the field of the prostate. So that these people almost certainly have metastases. Now, that may be wrong. It may be a volume of cancer or whatever else.

And I think the person who fails later, and I think the Pound data show it, and there are other indirect data that showed it. I wrote a paper many years ago that showed it, that if you fail later, the likelihood of responding to salvage treatment is better. Now, I don't know if you are 5 years out and your PSA doubling time is under 10 months, whether you are more likely to fail radiation. You probably are, but still your chances are much better than if you fail at 5 months out.

DR. CRAWFORD: Thanks, Ed.

Well, let it be known that our group made up the time and we're done in 15 seconds before 11:15 am. Congratulations to both of you.

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