DR. PLATZ: It is time for the discussion panel. We will spend about 20 minutes discussing the issues that have been raised during the presenting talks as well as any issues that you would like to raise related to these cancer sites.
PARTICIPANT: For Dr. Schwartz, that was a great talk. Let me just ask you, have you looked at some of the long-term biorepositories? For example, in DOD there is this huge biorepository where people give blood for other reasons periodically and they can be linked with the risk of subsequent diseases and it is certainly a target population that has a high prevalence of young individuals. Have you any plans to look at those?
DR. SCHWARTZ: I was hoping to stir that very pot at this meeting.
PARTICIPANT: I think perhaps some of the people are here in the audience.
DR. SCHWARTZ: There are a number of opportunities. I wanted to point out that many epidemiologists have referred to testicular cancer as the epidemiologist's nightmare and the reason for that is speaking of testicular cancer whatever agent causes testicular cancer probably starts in utero or in the perinatal period and the reason for that is the initial lesion in testicular cancer, carcinoma in situ of the testicles can be found in fetuses as early as 30 weeks. So, the general rule is that it is very hard to ask a fetus a question and even if he could answer it is very clearly a problem to get because there are studies that ask mothers about their exposures but again exposures that occurred 20 to 30 years ago are hard to reliably get at. The nice thing about ochratoxin is that it is a substance for which purified monoclonal antibodies are available and if there were a possibility of blood from individuals who subsequently develop testis cancer those would be very, very valuable and I would love to talk to anybody who might want to explore that.
PARTICIPANT: I had a couple of questions but first for Dr. Chow, you had mentioned, and this was not the major part of your talk but that with smoking cessation the risk of developing renal cell cancer only declines very, very slowly if at all and then said that for other smoking-related cancers there is a precipitous drop relatively speaking and you mentioned transitional cell cancer in that and my understanding at least is that for bladder cancer like renal cancer the drop for people who stop smoking is quite gradual, taking 10 or 20 years while for lung and esophageal and head and neck cancers it is much more rapid. Could you just explain that to me?
DR. CHOW: Yes, for squamous cell and transitional cell just as you said the risk appears quite substantially almost immediately after they stop smoking actually.
PARTICIPANT: I don't believe that is true for transitional cells. So, you probably have data on it and I have just quoted other people who have digested it, but that has been sort of the party line in urology that it is a much slower drop for the bladder cancer.
DR. CHOW: Actually for some of the epi studies the risk seems to have reduced a lot more, like for renal pelvis cancer the risk is reduced more than renal cell cancer.
PARTICIPANT: But also the risk is much higher, that is the risk for a smoker to get urothelial cancer is four or five times the risk of a person who has never smoked and you, yourself, mentioned that it is only one and one-half to two times even for someone who smokes a like a chimney to get renal cancer. So, the magnitude of the changes is different. Again, this isn't a big deal but I wanted to clarify that.
DR. CHOW: I did not mean that the risk will be dropped to totally zero. I mean when compared to renal cell cancer, the risk even among former smokers for say renal pelvis cancer would still be a lot higher. So, it is not reduced to totally zero or none, but it is just that the rate of decrease is sooner than for renal cell cancer.
PARTICIPANT: Yes, that certainly may be true. The other question just deals with what Gary was talking about in what I thought was a fabulous hypothesis, but my question is there are epidemiological data for populations that in the United States ostensibly especially 30 or 40 years ago where pork consumption was very, very low in Jewish populations and maybe Muslim populations, are the risks in those populations in the US different than other Caucasian populations and could you assume there would be some for them as well where the mothers may not have had pork exposure at all?
DR. SCHWARTZ: That is a very good question. Thank you for asking it. I tried to find out whether data for the US exists on that question the best place to go I would think would be something like the serocancer registry in Connecticut where there are a significant number of persons of Jewish origin in the Northeastern United States . The data have never been analyzed. No one has posed the question of ethnicity or religious practice in that regard.
I'd like to point out that there are some very nice data from the Army that relate to the issue of Muslims, who also abstain, from pork and Balkan endemic nephropathy, which is an epidemiologic challenge that is fascinating. One of the interesting things about Balkan endemic nephropathy or BEN, is that the geographic location of it is very clearly excludes areas that have been traditionally inhabited by Muslims. So the data for Balkan nephropathy are consistent with that. That is an excellent question.
PARTICIPANT: I had a question for Dr. Brawley and I thought it was a great summary of the epidemiology of prostate cancer, but it concerned me that you showed the Tyrol data which I agree supports the concept that something good is happening but you didn't show the recent publication by Louyow and Albertson comparing Connecticut to Seattle which showed the identical fall in mortality in both regions with dramatic differences in screening rates and intervention rates. So, is this selective use of statistics to make your point?
DR. BRAWLEY: This is the first time I have ever been accused of doing that one in this direction. Actually I was the first to publish in 1996, the difference between Washington and Connecticut , and Grace came up and completed the job and did it much better. I just had 15 minutes is the problem, and I wanted to show arguments for and arguments against and try to be balanced.
PARTICIPANT: Otis, we haven't still convinced the rest of the world, the non-urologic world that prostate cancer screening is a beneficial thing in terms of mortality. Given the data that we have, the data that will come out soon from PCPT looking at the sensitivity and specificity of PSA for men at low risk, under four, how is that going to impact on our perception by others in the world and where are we going to be 5 years from now as far as screening goes?
DR. BRAWLEY: If I look in my crystal ball my prediction is 5 years from now we are not going to progress and we are not going to digress. I think that 5 years from now screening for those of us with epidemiologic training is going to be something that we are afraid of. Screening for the treaters to see the patients is going to be something that we are going to be proponents of and I am not optimistic that PLCO or that the European trials are going to actually change anything.
(Comment off microphone.)
DR. BRAWLEY: I agree that those are the gold standards that are going to give us a clear answer or I hope they give us a clear answer. I am worried about contamination in both. So, I hope they give us a clear answer. My suspicion is no matter how clear the answer is that the pro screeners will cloud the issue and if the answer is in favor of screening the anti-screeners will cloud the issue with the question of over diagnosis and I really believe that there is an inherent prejudice among people in the United States going back to the 1920s and the old campaigns about early detection. There is this prejudice that early detection works and to convince people that early detection would not work I mean it really is a prejudice in the true sense of the word "prejudice." I don't think it is going to be possible to overcome in this country.
DR. PLATZ: That is a little bit pessimistic. What can we do to try to bring together two sides? Is it just a matter of getting both sides into the same room and brainstorming to understand the viewpoints of each side? I don't think we should just throw our hands up in the air and say, "Well, it is a difference in opinion."
DR. BRAWLEY: I honestly don't know. I am very pessimistic.
PARTICIPANT: A different topic, Dr. Chow, first a comment, as far as kidney cancer goes, our data, the data from Mac Walther and our group would suggest and looking at studies longitudinally and I am interested to know what Mike Jewett thinks about this; we estimate that from the time, just to take clear cell kidney cancer, at the time of the second hit, the time the cancer cell starts to grow, in most cases from hereditary but it is the same gene and we think the growth rates are the same and sporadic; we have 15 years of data on this as you can imagine on following people with these tumors, and we estimate that it takes from the time the second hit happens the cell starts to grow and between the time that happens and we can detect it clinically, CT, ultrasound, we say 2 centimeters we estimate give or take that is in the ballpark of 25 years. So, if that does apply to sporadic and I suggest it would and have no reason to think it wouldn't, therefore, your epidemiologic data with smoking and all, I would say there would be potentially a long, possibly a long lead in, and we know we have seen recurrences very, very late, sometimes 20 and 30 years, but I have another question for you and that is on for example your smoking data or the hypertension data you would say kidney cancer is maybe actually not kidney cancer; it is maybe five diseases or so. Where are we with understanding the different histologic relationships with any of these etiologic factors like clear versus papillary?
DR. CHOW: Actually not much. None of the previous epidemiologic studies has a consistent review of the histology and the genetic subtypes of tumors. So, basically we have no data on risk factor by subtype in some epidemiologic studies but what we are hoping to do is in our new studies, one is in Europe, one is in the US that involve you and Marina Morano and Burt Sebach and we can share on those.
PARTICIPANT: Another thing we are very interested in, we have been struck by although we have a very selected referral pattern, and we understand that, we have been struck by the patients of African-American descent that have come into our hands for whatever reason who tend to have a different histologic pattern, tend to be more type 2 papillary, tend to be more collecting, and now maybe that is just a bias. We want to look at that more systematically.
Have you any experience with it?
DR. CHOW: Again, none. In fact, it is kind of discouraging to say that in epi studies in none of the previous epi studies we have included sufficient number of African Americans to even look at risk factors among this group let along subtype of tumors.
PARTICIPANT: I was going to ask a much simpler question to you, Dr. Chow. If the increasing incidence of renal cell carcinoma is largely the detection of early stage, smaller, presumably incidental tumors and they have a slow growth rate what do you predict the time lag would be before we see an impact of the increased use of surgical treatment for these incidentally detected tumors on the mortality from the disease?
DR. CHOW: Actually what I didn't show is the mortality pattern. The mortality pattern has already kind of leveled for the past few years probably due to earlier diagnosis of some of the cancers and also better treatment.
PARTICIPANT: But if what Marston is saying is true it may be 20 years or longer before we see that impact. Would you agree with that?
DR. CHOW: In terms of?
PARTICIPANT: If you look at the frequency of surgery for renal cell carcinoma that is increasing and these are largely for these small lesions. When will we see that translate into a decreased mortality?
DR. CHOW: The survival pattern for the early stage tumors is very different than late stage tumors and a large proportion of the increase has been in the early stage tumors which I presume the survival is much better. So, the mortality hasn't actually, I mean it was increasing but until recently for the past few years it has started to level.
PARTICIPANT: I have a quick question for Dr. Schwartz. How does your hypothesis relate to the knowledge about genetic susceptibility to germ cell tumors with the described linkage studies?
DR. SCHWARTZ: First, let me point out that I think that most of the epidemiologic literature has to be interpreted as indicating that testicular cancer is primarily a disease that is environmentally acquired which is not to say that there aren't risk factors for any cancer but it is difficult to explain how things like risk for testis cancer increases 2 percent each year with a doubling in rates for every 20 years. Countries that are actually quite similar in Scandinavia which are connected by a bridge, Denmark and Norway for instance, the risk is 50 percent on the Norwegian side of that bridge and my feeling is that there will likely be genetic susceptibility to testicular cancer in some small groups of individuals. I think our ability to home in on that would be much, much stronger if we knew genetic susceptibility to apply. So, for instance we have known for years that testis cancer is very rare among blacks. I mean that is not a socioeconomic status issue because it is rare among blacks regardless of their SES status.
My feeling is that blacks and whites differ on a number of things as you mentioned including the ability to actually remove DNA lesions and I think that one of the ways that the hypothesis might advance the studies that we are discussing is to focus a little bit. For example I think studies on GST polymorphisms in blacks and whites with respect to testis cancer would be highly informative because those vary dramatically between racial groups and those individuals vary in their ability to correct DNA adducts.
PARTICIPANT: I would like to ask Dr. Brawley a question on the issue of disparity. Our institution has been able to show that early detection by early testing has eliminated the disparity in those men who have prostate cancer between African Americans and Caucasians. Other institutions have shown the same thing, too.
I am sure that it is important to reduce this disparity, and I am sure you will agree with that. Should we do testing or encourage testing, and I don't want to use the word "screening" among this high-risk group in order to eliminate disparity? What is your opinion on that?
DR. BRAWLEY: My opinion really hasn't changed and that is I was actually one of the group at the ACS who supported what I considered the real American Cancer Society recommendation which is that people should be informed of the potential risks and the potential benefits and should be encouraged to make an informed decision. That is not a statement for screening, but it is also not a statement against screening.
Those of us in epidemiology are fortunate enough to look at data in lung cancer and neuroblastoma and a few other diseases where screening is actually net harmful are willing to admit that screening for prostate cancer may be net helpful for a group. That is the only, by the way I actually suspect that in the paper review that screening may actually be net harmful to blacks more so than it was to whites in terms of over diagnosis at least and so since there are so many open questions and I have actually written letters and been very public. I think any man who wants to be screened ought to have the opportunity to be screened. No insurance should deprive an individual of the opportunity to be screened and no doctor should deprive an individual of the opportunity to be screened.
That being said, don't bring that needle near me because I don't plan on being screened.
PARTICIPANT: Dr. Brawley's pessimism I think is a consequence of surviving many of the wars over the last 50 years.
A question for Dr. Moore, can you give us some background information on arsenic exposure in the United States and what are the sources and are there particular groups that are likely to be more exposed?
DR. MOORE: There are actually quite a few people exposed in the United States . Above the current maximum contaminant level there are about 300,000 people and most of those people are not in large cities or towns. It is mostly people who have private wells, small public water supplies which are not screened the same way that large public water supplies are in New Mexico for instance and most of the exposures in the United States take place in New Hampshire and Maine . Fallon , Nevada , is a very important town. They have had water at 100 micrograms per liter and although EPA has said to lower the level they just don't have the money to do it because it is very expensive and they need reverse osmosis filtration to remove the arsenic from the water. So, that is why this is also a very important political controversy.
(Comment off microphone.)
DR. MOORE: It is just naturally occurring. A lot of times it occurs in areas that look a lot like Nevada that are dry areas where they do a lot of copper mining but not always and so in the United States I would say most of the exposure of people that you would consider exposed would be between 25, since now 10 micrograms per liter is our goal and it has been recommended by IARC 10 micrograms per liter for the last 15 years. There is lower exposure in other countries but there also appears to be a lot of genetic or nutritional susceptibility issues because there are people in Calcutta ; there is a huge exposure. There are millions of people who are exposed from drinking water in private dug wells that were dug during the green revolution by UNICEF, but they are exposed to a level that perhaps if people were exposed in this country or even the people I studied in Chile , they have no symptoms. So, it is very interesting.
DR. PLATZ: Two more questions, since we are over the time already.
PARTICIPANT: I just wanted to follow up with Dr. Schwartz on the issue of genetic interaction with the ochratoxin. When the ochratoxin Balkan nephropathy TCC story broke, and I recall the peak of this was about 12 years ago, there was actually an NIH consensus conference on this, the concept then was that there was a group of slow acetylators of the ochratoxin, and they were the ones who were susceptible, and I haven't heard much about that since, and I just wonder is that a genetic heterogeneity of acetylation rate of the toxin also important in testicular cancer?
DR. SCHWARTZ: That is a great question. You are absolutely right. There was an interest in the fast, slow acetylator phenotype which seems to have died out. I haven't seen anything on it since but that would be a natural place to go. Obviously these people are very highly exposed in the Balkans. The food in the Balkans particularly stored vegetables has astronomically high levels of ochratoxin and clearly not everyone exposed to ochratoxin will develop cancer. So, there has got to be something about persons who have the disease, where some genetic factor interacts with exposure. Certainly probably the first place to look is the slow/fast acetylator phenotype.
DR. PLATZ: We are actually out of time.
Thank you. Thanks to the speakers for their comments.
(Applause.)
DR. KLEIN: I would like to introduce our next speaker, Dr. Peter Greenwald, the Director of the Division of Cancer Prevention who is going to talk to us about chemoprevention of prostate cancer, and, Peter I am going to issue a challenge to you. We have a big randomized trial that NCI supported that shows that we have a relatively non-toxic agent that prevents prostate cancer; yet no one wants to take it. Why is that, and what can we do about it?
Agenda Item: Prostate Cancer Prevention Studies - Peter Greenwald, M.D., DR.PH.
DR. GREENWALD:
(Applause.)
DR. KLEIN; Given the fact that the publication of the PCPT results was probably one of the most important events in urology in the last decade and the controversy surrounding the results I thought we would take a few minutes and hear from audience members and from Peter on the discussion on what we ought to be advising individuals.
Let me just ask for a show of hands. How many urologists in the audience are recommending finasteride to patients who ask how they can prevent prostate cancer?
(There was a show of hands.)
DR. KLEIN: A few, not many, okay. So, let us hear about what your reluctance is in this background and I throw this perspective which I think is an accurate one but which I throw out for discussion. Taking preventive agent is always about a risk/benefit analysis and so if for taking hormones in women postmenopause it seems like the risk of other kinds of cancers outweigh the benefits that you might get from osteoporosis, but I think the equation adds up differently for finasteride.
It is very clear. No one has challenged the primary finding that 25 percent fewer men got prostate cancer. The sexual side effects were known and really are pretty minor and if you look at what happened with sexual side effects in the placebo arm they are almost the same.
When you add up the fact that if you take finasteride you are 25 percent less likely to get cancer, you have a significant reduction on urinary symptoms that are associated with aging and a significant reduction in the risk of undergoing surgery for BPH and if you recognize based on the capsure database that 95 percent of men with newly diagnosed prostate cancer choose treatment, the other thing that finasteride prevents is treatment-related side effects and it seems to me when you add it up all that way and throw in the fact that perhaps at least some of the high-grade cancers might actually be histologic artifacts, it seems to me that this is on balance a very positive starting point.
We need to understand a little bit more about whether these high-grade cancers are real because there are some biologic hypotheses to suggest that they might be, but I am a little surprised that we are not stampeding and heralding to the world, "Hey, as urologists we did this great trial. We can prevent prostate cancer, and the benefits clearly outweigh the risks."
I would like to hear some discussion on that.
DR. GREENWALD: I agree with your assessment except for one thing. I would like the Food and Drug Administration to approve it for this purpose before we would recommend it.
DR. KLEIN: We are serving as advisers to FDA and as advisers to FDA that is what you would recommend?
DR. GREENWALD: It is up to the drug company to bring it forward, and I think taking a preventive drug is not an emergency. So, I think I would like to see the process play out, but I think the case they are making is sound.
Also, we will be getting more information with follow-up in men. So, those who are uncomfortable about that Gleason finding will have more information in the future as the studies go forward.
David?
PARTICIPANT: I am very concerned that finasteride masks PSA. The fact that doubling of PSA on finasteride is not an appropriate formula is evidenced by this study where at 3 years you had to readjust the PSA value, and I am concerned that the longer these patients are on finasteride this ratio may need to be readjusted even further, and that has not yet been worked out.
The studies of Jerry Andriol and really the leaders in this field who did develop the doubling formula did it on very short term basis and we are committing patients to take finasteride for a very long period of time.
DR. KLEIN: That is something that we learned about finasteride is the longer you stay on it, that double factor probably has to go higher, but, Ian correct me if I am wrong, didn't it plateau by the end of the study at 2.3 and what do you know about PSA kinetics during the course of the trial and does PSA velocity stay the same and would that still be a good surrogate for needing a biopsy?
DR. THOMPSON: I do not know about the kinetics over a longer period of time. Again, remember that they were being adjusted to have an equivalent number of biopsies in both arms. Unless you actually conduct the study again and go for 20 years you will not know the answer to that.
I think the principal issue with regard to Gabe's point is that 98 percent plus of the men were diagnosed, if you were following them and doing precisely what was recommended were diagnosed T1, T2 clinical.
DR. GREENWALD: I am not sure we would have a reason to recommend for more than 7 years based on the trial which was 7 years.
The other question I often get is what about petesha(?) does 1 milligram have almost the same effect on PSA as 5 milligrams and there are younger men taking it for a long time and we don't have a definitive trial of this sort. So, I would be interested in how you fellows are answering that question.
DR. KLEIN: It is more expensive.
PARTICIPANT: You know when you asked the question I raised my hand. I have no trouble recommending finasteride for some of my middle-aged men who already have BPH symptoms, high AUA scores but I really have problems. We have a lot of younger higher risk African-American men in the military and I really struggle with whether I should be recommending this for some of the patients who potentially may benefit the most whereas I have least trouble with some of the average risk white guys who probably might not need it anyway.
DR. KLEIN: The risk reduction in PCPT was the same for all risk groups. It was 25 percent and that was not statistically different amongst groups, and I think I have heard many people express that but I really wonder if that is correct. I mean it is our perception. The epidemiology is that black men are more likely to get prostate cancer, but really on a percentage basis, an epidemiologic basis no more likely to benefit.
DR. THOMPSON: Eric, may I introduce the next speaker, Dr. Walsh who if I can just say is going to be the Huggins Award winner after lunch but just to put things in perspective was one of the first describers of 5-alpha-reductase deficiency.
DR. WALSH: I don't think anyone knows the answer but let me just raise a few questions that I have in mind. First of all, I have always been a little annoyed about the rationale. First of all, as Ian said you know in the 5-alpha-reductase deficiency the patients don't develop prostate cancer but that is because they don't have a prostate.
Women don't develop prostate cancer either. So, I think that is sort of a straw man. Secondly, prostate cancers don't make much 5-alpha-reductase.
No. 3, when you treat people with advanced prostate cancer with Proscar you don't really get an effect and No. 4, there are animal models that show finasteride really doesn't, animal models of prostate cancer that finasteride doesn't do anything.
So, on the other side of the rationale there are a number of reasons to question whether finasteride actually has a therapeutic effect on cancer.
The next point that as I looked at the studies and I think many people may not understand is that there were, and I would like to focus on the for-cause biopsies because I think that is in the steady state as we would be using it clinically is where we are and in the for-cause biopsies there were fewer men on finasteride who agreed to undergo a biopsy because their PSA was elevated or they had a rectal exam and so the numbers that we see are exaggerated because if you look at the percent of people who underwent a biopsy it is actually a 10 percent reduction in cancer, the number of cancers in the for-cause biopsies in patients who were on placebo versus finasteride.
So, it is not a 25 percent reduction. It is really a 10 percent reduction if we were using it in practice. So, we are trying to reduce something by 10 percent with the question and I don't know the answer either to whether these tumors are more aggressive or not, long-term data on what radical prostatectomy showed in those patients, follow-up and things like that.
So, those are the questions that I have about the study. The final point I would like you to comment on is the shocking number of cancers that occur, you know, positive biopsy rates of 25 percent suggesting that many of these cancers may have been very insignificant cancers and that we really are not having an effect on the real significant ones.
So, that is really my question, but you can also throw darts at all my other comments.
DR. GREENWALD: On the first one you know when we start a clinical trial we almost always have to make a judgment of when do we have equipoise, that is when is there enough evidence that you with good judgment want to move ahead, but you don't really know the answer. I gather you wouldn't have started the trial from what you were saying. We did, and I take your point on the genetic condition, but we have a trial now with an exciting result that we would have started and you wouldn't have started as I understand it.
I am not quite sure about your second point. I have to think about the rate and the cancers that develop during the course of the trial. I agree that those are the ones that with our current knowledge would be extremely important to look at right now.
On the third point, is 25 percent high, well, it is not high compared to autopsy rates of occult cancer. So, I was not surprised at the high rate but we do have the dilemma of having to understand the significance of the cancers that were found and one thing unique about the study is we now have the biopsy material. There are some very exciting technologies that may give us a way of getting a handle on understanding that and one of the most important things we can do is try to figure out the meaning of that. I appreciate your comments.
DR. KLEIN: Mike, let me just make a comment? One way to look at this I think is that we have to refine what we mean by insignificant cancers because it is a little fuzzy, and I think we need to make a distinction between biologically significant cancers, ones that are destined to kill the host and clinically relevant cancers and we don't have good ways of knowing who has a biologically significant cancer. I agree with that comment completely.
On the other hand again the database shows that 95 percent of newly diagnosed men in the most recent period analyzed which was I think 1999 to 2001, who have a grade 6 cancer most of which probably aren't biologically significant choose therapy and so that is a clinically relevant cancer and one could make the argument that finasteride at whatever level whether it is 10 percent or 25 percent or maybe even higher since the finasteride glands were over sampled because they were smaller than the non-finasteride glands at some level we are not only preventing the cancers but we are preventing everything that goes on with treatment and all the potential treatment-related side effects and so again you could add that if you wanted to.
Take the case that this is a very positive trial, minimize the negatives and that would be a way to do it.
Howard?
PARTICIPANT: I yield the floor.
PARTICIPANT: If I may I want to point out Dr. Walsh is perfectly correct. The reduction in for-cause cases was 10 percent, but we should also recognize that was a statistically significant difference and that the rate of diagnosis in the for-cause group was 6 percent which is exactly what one would expect from the SEER data. So that group I think is really where to look for proof of principle that we are significantly decreasing the kinds of cancers that we are finding in practice.
DR. KLEIN: Okay, and we have to limit the comments to the remaining three individuals standing.
Mike?
PARTICIPANT: I was a little bit confused in trying to interpret the results of the study because at the very end when you started to biopsy people there was a sudden increase in the number of positives on those who had had finasteride and yet I don't think that that was really reviewed in the interpretation of the results.
The second aspect of it is if I don't understand the biology of the disease that we are treating here is the finasteride more effective in those cancers that are likely to be clinically insignificant, and I guess this was said in several ways by other commenters, and if we are trying to address the issue of prostate cancer, the genesis of that seems to be more of a molecular genetic genesis rather than an epigenetic type of thing. Should we then think if this is to be effective of earlier treatment to be more effective in ultimate expression of disease?
DR. THOMPSON: The reason for the change in the number of biopsies at the end was because these biopsies were for cause, an abnormal DRE or an abnormal PSA and because the men were reaching the end of the study and were going to go off the study at the 7-year mark there were more men who had been told previously that we recommend a biopsy who acceded to a prostate biopsy. I think your next question with regard to is it more effective or not and which tumors I don't think we know the answer to it. The final answer, if you don't mind, Peter there are molecular studies that are looking specifically at that.
DR. BRAWLEY: I would like to point out that in the for-cause biopsies those with the positive DRE or positive PSA over the 7 years it was more than 12 percent of men were diagnosed with prostate cancer. So, this is in keeping with your comment, Dr. Klein.
Biologically significant, clinically significant and detectable and screening are all three different things and we need to work hard to try to figure out what things truly are of risk to the individual's health, and my last point is again look at the placebo arm of this trial. Six percent of the men in the placebo arm had high-grade disease and the one thing that epidemiology can currently tell us is 3 to 4 percent of all men in the placebo arm are destined to die from prostate cancer.
So, this study actually questions even whether Gleason grade is predictive of the biologic behavior of the prostate cancer as it concerns the life of the individual.
DR. KLEIN: Dr. Schellhammer, as always the last word.
DR. SCHELLHAMMER: Not at all but just a brief comment with regard to visceral reaction. When you gave your discussion it was very convincing but I will say that what the public has heard I think overwhelmingly has been the reverse of that, namely, negative comments. So, the number of hands that go up may be reduced by the fact of that concern, but I would like to ask Dr. Greenwald, with getting off the PCPT trial vitamin E in the ADTC study was given in a 50 international unit dose and Select has 400. There are different isoforms. Selenium I understand now too little may be not good but too much may be equally inappropriate. So, how when the Select trial sorts out are these differentials going to be addressed because I can see the same discussion being brought up 3 years from now.
DR. GREENWALD: Right, there were workshops and committees debating and discussing that before we came up with a dose and the conclusion was the dose that biologically we would be sure would be effective and we would know exactly what was being given, but I mean in most of these studies you can only really do one dose unless you have a much larger study.
DR. KLEIN: Okay, thank you, Peter.
TOP
