SLIDES & TRANSCRIPTS
Friday, December 5, 2003

Prostate Cancer Prevention Studies

Peter Greenwald, M.D., Dr. P.H.
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Actually I am delighted to see that the urologic oncologists are in the lead in expanding the scope of oncology to include prevention, and I think that will change over time as we get more understanding.

In the early 1980s a number of epidemiologists were suggesting that beta-carotene might be protective against cancer. They had done a number of studies and usually an index of beta-carotene derived from vegetable intake and there was close to a consensus at that time amongst the epidemiologists.

The industry, the vitamin industry and then the food industry took that information and taught the public the word "beta-carotene," implying it would protect against cancer, and made a number of products internationally, in the US as well as in other countries, and these are some examples.  

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Based on the epidemiologic data we got together with some scientists in Finland and set up a study called the ATBC, the alpha-tocopherol-beta-carotene study where 29,000 men were randomized to get either beta-carotene, the left hand column, placebo for beta-carotene, vitamin E, the upper row or placebo for vitamin E, and

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to our surprise the result was the opposite of the hypothesis, that is after several years of no difference it turned out that the men on beta-carotene; there were all heavy smokers, the smokers on beta-carotene got more not less lung cancer, and I will round off the numbers but those on placebo for beta-carotene developed about five lung cancers per 1000 men per year and those on beta-carotene got about 6 lung cancers per 1000 men per year. The actual increase was 16 percent. What I described was 20 percent.

No matter how astute an epidemiologist is or how astute a clinician is I don't believe that you could see that difference without a very large, very well-conducted double-blind randomized trial.

So, that helped make the case for doing randomized trials in this sort of situation

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but another very interesting end point was the secondary end point of what happened in other cancers.

Remember there were 29,000 men. So, 14,500 got vitamin E. These are the other cancers related to vitamin E, and of the 14,500 who took vitamin E, 99 developed clinical cancer of the prostate during the course of the trial and of the 14,500 who took placebo for vitamin E 147 developed clinical cancer of the prostate during the course of the trial.

So, we had a one-third reduction in the incidence rate of prostate cancer in this well-designed double blind randomized trial of 29,000 men and we took this as a lead.

Since it was a secondary end point we did not take it as definitive but as a lead that needed to be confirmed or refuted in another large-scale clinical trial.

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At about the same time Larry Clark who worked at the University of Arizona was doing a study to see if selenium could prevent cancers of the skin. So, he randomized about 1300 people, three-quarters men, one-quarter women to take selenized yeast and the control group got yeast that had no selenium in it.

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The result was quite interesting.

The main end point, and that is what the trial was powered for was no difference in squamous cancer or basal cell, if anything a slightly higher rate, but you see if you add these up, for example, in basal cell there are over 700 cancers. So, this trial of 1300 was powered where you could tell differences when you got 700 cancers.

Prostate was quite interesting, again a secondary end point. The numbers are very small but if you subtract this from 100 you can see there was a 63 percent reduction in cancer of the prostate, clinical cancer of the prostate in the men who took selenized yeast as compared to those who took yeast without selenium.

I was quite skeptical at this point because the numbers were really small and I would say not definitive  

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but there were some epidemiological data that were supportive. There is a Harvard group doing a prospective study of health professionals. These are dentists, podiatrists, not physicians and there is a way of measuring selenium in toenails, an atomic absorption method that is very accurate that tells you a level about 4 or 5 months before the large toenail is cut.

Well, dividing this population of almost 34,000 men into five groups from lowest to highest you can see that the group with the highest level of selenium, again, subtract from 100, had 65 percent lower rate of cancer of the prostate.

So, you have an epidemiological study consistent with the clinical trial results of about a two-thirds reduction.

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There was another interesting study done in Baltimore by a Hopkins group where they were doing a longitudinal follow-up on a study of aging and they had serum levels of selenium and they found the same thing, divided highest to lowest quartile, I am sorry, lowest to highest quartile, those with the most selenium had subtract from 100 a 76 percent lower rate of cancer of the prostate and I have aa rule of thumb. I have a doctorate in epidemiology as well as being a physician and I know there are some biases like the beta-carotene study, but I think when you see an expert group from Harvard and an expert group from Hopkins coming out with the same results you are likely to be on the right track.

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So, we felt putting this together with the clinical trial really provided a good rationale for doing the Select trial and there are many other data based on animal laboratory experiments.

So, the Select trial is well under way with some of the leaders of the trial here and it compares selenium or vitamin E to placebo to see if it will prevent clinical cancer of the prostate and accrual is going very well thanks to many of you. It is over 27,000 now I think, and so we have a good rationale but we also have a need to get a better basic understanding of how these elements work.

So, when we have the amount of human data that were available we think we have to move ahead with good judgment but at the same time fill out the picture.

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One study doing that is led by Anita Sabichi working with the Southwest Oncology Group and this is a study of men with high-grade PIN with both a clinical end point and looking at a number of markers and I believe the accrual is something over 250 at this point and picking up pretty well.

So, complementing Select is a study to see if progression of high-grade PIN to clinical cancer is possible

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and there is another sort of approach. This is a pre-prostatectomy model where men who were scheduled for prostatectomy at 2 to 4 weeks, well, 14 to 31 days after they started the trial were put on selenium methionine for observation and from the study it was possible to tell that there were higher tissue levels. So, we knew that the selenium was getting into the prostate, no difference in seminal vessels and the pre- and post-study PSA was unchanged which is quite interesting since that can come into play in the diagnosis of prostate cancer. I didn't say mortality you notice.

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This type of model, a pre-prostatectomy method of study is being used fairly commonly now and it is very, very helpful in helping us to understand the various agents that might be useful in prevention of cancer of the prostate and understanding the biological effect.

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For example, the study of sulindac which induces apoptosis, it is an NSAID but it does not inhibit cyclo-oxygenase and there is a study at the Mayo Clinic. There is a study of celecoxib, genistein, toremifene which may reduce androgen development in Pittsburgh ; hectorol which is a vitamin B analog that has a differentiating effect without causing hypercalcemia and there are a lot of the studies that are favorable to milk and vitamin D. It is done in Wisconsin where they have a group that is very expert in studying these things, the study of lycopene and so forth.

So what we are looking for are ways of doing Phase II trials that will give us insight into these agents so when we get into the large expensive long-term ones we will be doing it with a very sound footing coming out of a combination of biological and clinical studies as well as basic laboratory studies.

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There are a number of other populations that would be useful and are being studied and these are just some examples.

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Now, let me turn to the prostate cancer prevention trial. I am sure you are all aware of the mechanism of action of finasteride and the leaders of this trial are here and many others of you I am sure took part.

In 1992, with these leaders we decided that the prostate cancer prevention trial was merited for the following reasons. Prostate cancer was known to be linked to male hormones and particularly the potent male hormone DHT in the prostate. Men with inherited deficiency don't get prostate cancer. Finasteride inhibits the growth of prostate cancer cells in the lab. Japanese men have less prostate cancer and lower male hormone levels while US black men have a higher prostate risk and high levels.

Finasteride has a very specific target that inhibits the enzyme responsible for the formation of DHT and in 1992, two clinical trials were completed showing the efficacy and safety of finasteride for the treatment of BTH. These results led the FDA to approve the drug for the treatment of BTH.

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With this trial the physicians and scientists who conducted the trial in the over 18,000 participants put cancer research to its most important test. Could we prevent the disease?

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One interesting aspect of the design was that the end point was period prevalence, that is it was a combination of cancers diagnosed during the 7 years of the study plus those diagnosed at the end, at the close-out biopsy which together is something we call period prevalence.

So, it is a combination of what is clearly clinical prostate cancer. They had a rise in PSA or a rectal exam, some indication for having the test, but then at the end whether you call it a cancer or a marker of occult cancer isn't really clear at this point but both of these saw the reduction in incidence

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and the result was about a one-quarter reduction in total cancers with a reduction in both groups.

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The one point where there is some controversy, here you can see for the Gleason 5 and 6 there was a huge reduction. In the 7 to 10 it appeared to be slightly the other way, that is a higher occurrence of higher Gleason grades in those on finasteride and we don't know how to interpret that at this point.

Many pathologists and urologists I talk to say that once person is on a hormone don't read the Gleason score because it gets very confused. So, whether that is true or there are other reasons that are sort of an artefact or whether there is a real effect is not known and that is something, a reason for doing ongoing study.

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The Director of NCI, Dr. Von Eschenbach stresses the approach to cancer research in three ways, discovery, meaning basic research, development, meaning these clinical trials and delivery meaning assuring the population benefits.

One benefit of the prostate prevention trial in addition to the new knowledge that it brings is that it does all three of these things. Discovery will come about because of the biorepository and the thoughtful use of it. Many of the investigators already have a number of proposals and have research under way to bring about better biological understanding and we learn which of the occult cancers are likely to be aggressive and which are not.

Development is the trial itself and delivery in my view comes from the fact that the trial was done through the community clinical oncology program and the cooperative group system through many of you who have participated. That is it was done by a network of physicians and other health professionals throughout the United States who see it as their study. Thus, as the results come clear we are a leg up in the adoption and the diffusion of the knowledge.

When people see it as their study they understand it and that really helps with bringing the new knowledge to the people of the United States, and I will just skip to the last slide

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which is a diagram emphasizing the importance of prevention, that cancer is the dragon being fought with medieval weapons although now somewhat more modern. It is a lot easier to get the edge, to have Prince Valiant getting the edge.

The field of oncology is changing, urologic oncology as well as other aspects. It is changing to include prevention.

There are many opportunities for this and we welcome your participation in developing this expanded field.

Thank you.

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