Prostate Health Conference 2010

M. D. Anderson Cancer Center
Date: November 2010

>> We now begin the Prostate Health Conference, Protect Your Prostate: Get the Facts.  Please welcome the Chairman of the conference, Dr. John Davis.

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[ Applause ]

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>> All right.  Thanks, everybody.  Just a show of hands, who's been to this conference before?  So, it's some, and then who is first time in the door?  So, a nice mixture.  I welcome everyone.  This is our largest attendance, so thanks to all for coming.  We want to start with some acknowledgments.  We do have some funding that got used to organize the conference from the Oilmen's Fund as you see.  And then this is basically a large group effort.  Obviously, as one of the--as the Chairman and one of the physicians, I can provide content and I can arm wrestle some of my fabulous colleagues to give up a Saturday morning to talk to you here.  But there's a whole team behind that that actually does all the signs and the organizing and several meetings.  And you see this list of folks in the Genitourinary Center that have helped with registration, and we appreciate everybody and Colleen especially for organizing everything. 

So, the way I'll introduce it is as follows.  Just for the most part, everyone I would assume is here 'cause you want to live a long and a prosperous and healthy life.  Intermixed in that, we know that there's about 1 in 6 depending on the figures you read, 1 in 6 lifetime risk of being diagnosed with prostate cancer.  Again, that's lifetime not year to year.  But only 1 in 40 risk of dying of prostate cancer.  So, there's a bit of a split there.  So, one of the questions that comes up in my clinic all the time is who exactly dies of prostate cancer, how does that happen?  And my best explanation is it really requires two things, and you’ve got to have both of them.  First of all, you have to develop the lethal variant of prostate cancer, and not everybody gets that.  And number two is you really have to live a long time in most cases.  So, there's a lot of people out there that either don't live a long time right after they're diagnosed or they never get the lethal variant, and so that's why you have that big difference in figures about getting adverse as dying of it. 

So--and this just shows an example of how we classify and predict prostate cancer.  We have a grading system.  And there are five different grades.  And what you can see up here is there's a couple of older low grades that were used when men commonly had surgery for benign prostate cancer, or sorry, for benign prostate conditions.  Most commonly men either have a Gleason 3 pattern or 4 pattern or 5 pattern, and we have a system that combines these two.  And there's a massive difference between having Gleason 3 pattern versus 5 pattern.  But even beyond that, it's--there's a wide range of how these tumors might behave over time.  Meanwhile, men live many years and they still have to pay attention to their weight, to their cholesterol, to their hypertension.  So, in essence, prostate cancer is a specific disease to think about, but it's because it's so slow-growing, we still have to look at the big picture of health. 

So, that's kind of the theme of this year's meeting.  We brought in some experts to help us with this.  Dr. Sunil Sahai is an Internal Medicine doctor, and his main charge is to talk about health maintenance within prostate cancer.  And so he's kind of the “how do you live a long time” expert speaker.  Dr. Sahai is, of course again, an internist.  And one of his specialty interests is, why I know him, he runs a clinic for the preoperative patients.  So, some patients get diagnosed with all types of cancer, and then all of a sudden they need a major operation, and one of his jobs is to assess their health and be sure they can get through the operation safely.  And so, he's very good at quickly assessing people's health and hopefully giving them tips on how to live healthy even after their cancer treatments. 

And then the second question of course is, you know, what is this business about a lethal variant of prostate cancer.  And so we have--we are lucky to have our Chairman of Genitourinary Medical Oncology, Chris Logothetis, speak to us about, so, the agenda of prostate cancer moving forward.  So, once we've had those two speakers and some question and answer time, my urology faculty colleague, Curtis Pettaway and I, we wrote down a series of common questions about prostate cancer screening and prevention and some of the latest studies.  And we--we're just gonna go through those questions with you and try to make best use of our time.  So, without further ado, Dr. Sunil Sahai will be our first speaker.

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[ Pause ]

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>> Good morning, everyone.  I'm Sunil Sahai.  I'm an Associate Professor of Internal Medicine at MD Anderson here at MD--here in the clinic.  And before I start talking, I have two issues with speaking.  Number one, I tend to mumble.  So, if I don't say something that you understand, please stop me and raise your hand and ask question.  Number two, I tend to pick up my speed of speaking as I go through the talk, so I'm pretty much mumbling by the end of the talk.  So I try to keep conscious of that fact as long as I don't forget to. 

The title of my talk is “Seeing the Forest for the Trees,” you know, prostate cancer with healthy lifestyle.  The reason I chose this is like I said I see patients who go the operating room before surgery, and one of my jobs is what medicines are you on, and the patient may be on a 1 or 2 medicines like high blood pressure or cholesterol medications.  They're on 40 different supplements, and going through that is a nightmare for us because we don't know what these supplements would do.  And I--some of them do work, but my job is to kinda give you a big overview what can you do simple stuff free stuff that doesn't cost hundreds of dollars off internet to do to help you live longer. 

First of all, as you all know, America is getting older.  In 1980, we only had about 11 percent of our population that was above 65.  The 2050 projected is gonna be close to 20 percent of the population will be over 65, and that's because the Baby Boomer Generation and their kids are now entering that age where they are retiring.  The unfortunate part is that America is getting sicker.  If you look at what my clinic sees, and these are the patients with prostate cancer and bladder cancer, the urologic patients out of [inaudible] back.  About--out of 500 patients, over 300 had high blood pressure, another 100 plus had diabetes, another 100 plus had heart disease of some sort, and then coronary artery disease and lipids.  So basically, when you come to MD Anderson, if you are a bladder cancer or a prostate cancer patient, more than likely, you have multiple medical comorbidities or multiple medical illnesses which are what I'm gonna focus on today.  And it's not just prostate cancer, but it's all types of cancer. 

As we get older, we get more diseases.  Prostate cancer, the stuff you hear in the news, does medical illness make a difference.  The question is if you have diabetes and prostate cancer, and you compare that to somebody who does not have diabetes and prostate cancer, who lives longer?  Does diet make a difference?  Now this is what makes the news all the time and stuff on the internet.  You know, if you eat more fiber you're gonna live longer without cancer.  If you eat more pulses and legumes and nuts and beans, things like that, we live longer.  What kind of meat you eat, does that make a difference?  Fat supplement, fat, does that make a difference?  What kind of fat do you eat?  You know, supplements, do they really make a difference?  Does weight make a difference?  If you're older, if you're fatter, does it make a difference?  And also does lifestyle make a difference?  Those are questions that we really don't have a good answer to because it's very hard to do studies on these kinds of questions.  It's very easy to do a drug study when you give somebody drug A and give somebody else a placebo or drug B and compare the side--the outcomes.  But I can't remember what I had for breakfast yesterday, and [inaudible], you know, a food diary down for a whole several years worth of information. 

So, the data trickles out and it's not very clear sometimes what the data tells us.  So, contrary to point, there is about a 15 percent lifetime risk of getting a prostate cancer diagnosis.  However, there's a 3 percent risk of death.  What that means is men who develop prostate cancer have a higher rate of dying with prostate cancer than of prostate cancer.  So, the way I put it in clinic is something else is gonna kill you, not the prostate cancer for most patients.  Fatal prostate cancer, the lethal variant, there are some associations with diabetes.  We don't know really what that means because when you run the numbers, it's not statistically significant.  That means that there's a hint that there's something going on there but we really can't prove with the math, that is something that we do really pay without--we can like fairly say that this is an issue.  Same thing with high blood pressure.  Does--does having high blood pressure increase your chance of developing a fatal variant or prostate cancer?  We think it may be true in African-Americans but we're not really sure because the data does not support itself out.  Smoking, there is an association.  If you are smoking at the time you developed prostate cancer, there's a chance of you having a fatal variant.  And also there are some hints about obesity and weight.  If you're fatter and for paradox if you're taller, then you may also have increased risk of developing prostate cancer. 

So the trials that come out.  This is what makes the news, you know.  You have--trials are done, people are given supplements, and they're seeing what is your chance of developing a type of cancer, a certain type of condition.  Well, from the two trials that came out recently, we know selenium somewhat reduces the risk and vitamin E reduces the risk.

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>> If you take those two supplements, you had a lower chance of developing a lethal variant of prostate cancer.  Same thing for beta-carotene, but paradoxically, it increases your risk of developing lung cancer.  The SELECT Trial came a little bit afterwards and then says neither selenium nor vitamin E work.  So you're kind of stuck there. 

The only good trial that’s out there, which my colleagues talk about, is the PCPT trial ,which shows finasteride actually will reduce the rate of developing cancer; however, those who do develop having the lethal variant.  So right now, you're very confused.  What do I do?  What do I take?  Do I take this pill?  Do I take this supplement?  What's being pushed on the news or Internet?  You know, that's the question we have, as physicians, what do we tell our patients?  Well, I have a little bit of easier job in the sense that I don't do the counseling for this, but I do recommend a healthy lifestyle stuff.  And what I'm about to show you right now, everything I'm gonna show you is completely free.  There is no cost for you out of pocket.  And what I--for those of you who have Internet access, I would recommend writing on these websites there in your packet--there in your handouts so you can look at them at your own leisure.  

The American Heart Association, everyone has heard about the American Heart Association.  Stop smoking, live a healthy life.  They actually came out about a year ago.  It's something called "Life's Simple 7."  Seven things that you can do to remain--reduce your chance of developing an illness that'll kill you and live longer, and I'll go through them one by one.  The website is mylifecheck.heart.org.  And the nice thing about this is that as you go through this website, you register your e-mail address and your number and your password, basically.  It keeps score of what you do, and you can go back in there as the months and years progress and see what your score does.  And I will show you my scores, what I got on the scoring system. 

First thing, get active, that's the first question I ask my patients.  What do you do on a regular basis to remain fit?  Now, by definition, prostate cancer is a disease of older men.  Older men who are past 65, tend to be retired, and those who are not working don't really have any excuse not to go for a 30-minute walk every single day unless it's 200 degrees outside.  But the recommendation they have is a 150 minutes a week of moderate exercise.  Basically, the question is how do you define moderate exercise?  Basically, you should be able to talk but not sing between breaths.  Now, granted, for some of my patients, walking to the bathroom is moderate exercise because that means you're really out of shape.  But you should be able to walk the halls of MD Anderson.  This is one of the questions I ask.  My clinic is here in the main building and the Urology Clinic is over in the Mays Clinic, and I always ask, did you walk or ride the golf cart over?  So that is one of the things we check on.  A 30-minute walk 5 days a week is not that hard to build in to your schedule if you plan it that way, and it's not a 30-minute walk where you stop and ask every neighbor how the grandkids are doing, you know.  You have to go nonstop at 100 steps a minute, and go from there.  Golf, mowing the lawn, the Wii Fit actually qualifies as moderate exercise, bicycling and swimming.  Now, most of my patients who are retired, the men love it when I actually tell their wives that you got to play golf more often.  So it'd really--even riding the cart does really help in playing the game of golf. 

Or you can do 75 minutes of exercise a week, vigorous, and that's basically you can only say a few things between breaths.  That's running, cycling, swimming, playing football, any exercise class, and lifting weights.  I'm not sure about yoga, but everything else you can probably qualify as vigorous, that's right.  So if you think about it, finding 75 minutes of your time out of a week really should not be that hard.  Now this is do as I say not really as I do because I can't find that time being a physician here at MD Anderson.  But it is--you know, we have to find the time to do it, and it really does what makes a difference in us overall. 

Control your cholesterol.  Who--I'm not gonna ask questions, but everyone has heard of cholesterol, everyone has heard of HDL good cholesterol and LDL bad cholesterol.  And a lot of my patients get it confused.  A very good way remembering it is HDL is H for high.  You want your HDL to be as high as possible.  LDL is bad.  You want your LDL to be as low as possible.  And the goals are 100 mg--the numbers are up there for you.  You have 40.  Anything less than 40 is a risk factor and less than 60 is protected.  Now, one of the issues we have in Internal Medicine is that these ratios, while a person may have a very good total blood cholesterol, the ratios of the good and the bad may be off.  For example, I can tell you in the Asian-Indian population which I am, Indian males have this problem.  Indian males have very good total cholesterols but our HDL-LDL ratios are off.  We don't have enough good HDL.  We have too much bad LDL.  So, Indian men in general are at a higher risk of developing heart disease and heart attacks than the average other person who has the same number--who doesn't have that ratio messed up.  So, it's very important that you can talk to your physician about what your particular risk factors are.  There are also familial variants where these things are thrown off and you may need medication. 

Triglycerides are another component of the cholesterol panel.  They're not cholesterol.  They're a different fat in your body.  They're required.  The nice thing about triglycerides are that's the one that responds the best to exercise and diet.  You can actually get your triglycerides checked and embarked on a one month exercise program and you can see a dramatic difference in the drop of those numbers. 

Next thing, eat better.  We all need to eat better.  Everyone in this audience is that--yes sir?

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[ Inaudible Remark ]

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>> That is a cause--that is a slightly controversial topic in medicine right now.  We--most physicians believe that you need both.  You need--even if your number is too high, you still need medication and treatment, regardless of what the ratios are.  So first thing, you look at the total number first, and then you look at the ratios afterwards.  So basically, if the total number is 300, 250, or even 240, you still need treatment, and then you worry about the ratios secondary. 

Your generation, you remember the four food groups, right?  Okay.  That doesn't exist anymore.  In 2005, the government came out with new guidelines which actually are better.  The American Heart Association has these on their website what we should be eating.  You know 4 to 5 cups of fruits and vegetables a day, fish - 2 servings a week, you know.  Fiber-rich foods.  You cut back on your sodium, cut back on your sugar and beverages, you know, increase the number of nuts and pulses you eat.  Avoid processed meats and avoid saturated fat.  Stuff you've been hearing about for years.  The problem is, is that you hear about this then you go to Denny's or you go to, you know, Pizza Hut and you take out.  I do, you know.  It's, you know, I stop by Kolache Factory on the way in to give a lecture, you know.  So, it's very hard to take this abstract concept and put it into words for what do I need to do.  What does my family need to do?  The basic message is use food as a source of nutrients rather than a dietary supplement.  As you remember, the four food groups got changed to the food pyramid.  The food pyramid got changed recently to MyPyramid, and it's at the CDC website, mypyramid.gov.  Again, you go to the CDC website, and you put in your particular risk factors, your age, your lifestyle, you're a man or a woman whatever, and it'll give you a little pyramid showing you how much grains you have to eat, how many vegetables, how many fruits, milks, meats, and beans.  And the nice thing about this, this actually has variations for people who are sick, people who have diabetes, people who are of Hispanic origin, people who are African-American and has--you can--it will give you a breakdown for what you need to eat and then it has links to a whole bunch of recipes.  I'm not sure about government recipes or anything but, you know, the--it will actually help you make that decision what you need to eat and how you can watch yourself. 

Next thing, lose weight.  Now these numbers probably don't mean a lot to you.  The way we calculate who is overweight, who is obese and morbidly obese is by a number called the BMI.  The BMI is basically your weight divided by how many--how tall you are.  The BMI of 25 or higher is considered overweight.  Obese is BMI of 30.  Morbid obesity is BMI of 35 or higher.  In order to lose weight, you need 30 minutes of exercise 5 days a week.  And the basic concept on losing weight is you need to expend more energy than you're taking in.  If you cut out 500 calories a day out of your diet and you expend--have a negative net balance of 500 calories a day, and you will lose 3500 calories in a week—500 times 7—that is one pound of fat gone from your body.  So, people who can maintain that negative balance will do very well.  Now, what does BMI mean?  It's very hard to say.  Now, I'm gonna step out here.  How many of you think I'm fat?

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How many of you think I’m just right? I’m perfectly right?

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>> You got to turn around.

>> Oh.  Turn around?

[ Laughter ]

[ Inaudible Remark ]

>> According to this calculation, I am this close to being obese.  My BMI is 29.5, and my wife is duly aware of that fact and so is my physician.  But, you know, it's such an--in America--the women in the audience, you knew--you know, the old size 6 is the new size 2, you know, how they came to the size of the dresses.  The dress hasn’t changed, but this number has changed.  We now in the United States have a very warped view of what is considered to be fat and obese, and these numbers are based on Americans of all ethnicities and all stripes.  It is not just like the old childrens’ growth chart where Scandinavian kids in Minnesota for how tall your kid was, so Asian kids got screwed in the whole process.  But this growth chart is for everybody.  It doesn't matter who you are.  Now the question I always get back is well, you know, I'm 300 pounds but I'm a linebacker.  How many of you seen--have ever seen a fit retired linebacker?  All that 300 pounds of muscle mass gets turned into fat, and that's one of the issues we have. 

Next thing, manage your blood pressure.  Normal blood pressure, everyone’s heard of 120/80.  That actually is a fallacy.  A normal blood pressure is 110/70 or anything.  And in my world, it doesn't matter how low your numbers are.  I have heard my blood pressure is too low.  There's no such thing as a low blood pressure until you faint.  Marathon runners average a 90/40 or 90/30, and they're perfectly fit.  Now, for some people, a 90/40 will make them faint, but if you are consistent in running in the 120 to 140 range for that top number, you are considered pre-hypertensive and you need to start making changes in your lifestyle.  Anything higher than that gets medication. 

Next thing we do is blood sugar, insulin resistance and prediabetes.  Everyone’s heard of diabetes.  Well, the problem is the prediabetic state.  That is brought on by obesity, being inactive, having high blood pressure, having cholesterol problems.  In the United States right now, 20 million people have diabetes, of which 6 million don't know they have diabetes, but the big number is this 57 million: 57 million, America's population is 300 million.  One in 5 people don't know they are prediabetic and the majority--I have spoken to audiences.  The majority of the people in this audience is over 60.  One in 5 of you in this room are prediabetic.  You probably don't know it.  The risk--why is diabetes so bad?  Diabetes has a higher heart disease death rate, almost 4 times, stroke rate almost 4 times.  It is the single leading cause for blindness in this country.  It is the single leading cause for kidney failure.  It is the single leading cause in neuropathy, dental diseases, and amputations.  But the good news is that if you are prediabetic and you just make lifestyle changes.  I'm not talking about medications—just lifestyle changes—you can drop your rate of developing diabetes by 60 percent.  And if you're older, over 60, it's a 70 percent drop.  And those lifestyle changes are eat right and exercise more. 

The very last thing was stopping smoking.  Smoking is still the single most important cause of preventable death in the United States.  Accounts for half a million deaths a year, and of which 135 are due to heart disease.  If you stop smoking, the benefits are within a month.  They last a lifetime. 

So this is my score.  My score is 7.4, and the ideal is 10.  So I'm actually in the green zone but not really there.  My blood cholesterol is perfect.  I married a vegetarian so that really helped.  Blood pressure needs improvement.  I'm in the 120 range for my blood pressure.  Blood sugars are pretty good.  I never smoked.  I do--my diet does need improvement and I need to, you know, control my weight.  I need to become more active.  So what--by putting your numbers in, you get a number and you can realize where--have at least some idea where you need to focus your entire lifestyle. 

Another website is called realage.com.  Now this website, one of the issues is that there's a whole bunch of advertisements down that's gonna sell you stuff, but you can do the basics for free.  Well, what it does is ask you about 30 questions about your health, your habits, your relationships, your diet, and your fitness level, and then it calculates your real age, not your chronological age.  So when I put my stuff in there, my real age is 35.  I'm actually 39.  So, you know, it makes me, you know.  So when the woman celebrates--my wife who celebrates the 8th anniversary with 27th birthday, you know, she really may be 27 in real age.  It is something you guys can look at at your own leisure.  I would highly recommend it because it actually gives you individual breakdowns of what you need to do to help live longer.  To kinda summarize everything based on the current data. 

You know, the recommended diet for prevention and management of prostate cancer, with prostate cancer comprises of diet low in fat, high in vegetables and fruits, and avoiding high energy intake, basically, avoiding more energy you take than put out, excessive meat, and high dairy products.  What basically the American Heart Association website and the government is telling you all.  In conclusion, you know, "The doctor of the future will give no medicine, but instead will interest his patients in the care of the human frame, in diet and in the cause and prevention of disease."  I like this quote not because of what it says but about who said it.  Thomas Edison in 1903.  We're not there yet, but hopefully we'll be at some point. 

Thank you very much.  Do you have any questions or hypothesis?  Yeah?

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[ Audience ]

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[ Inaudible Remark ]

^M00:26:47

>> Yes sir?

>> On the hypertension issue, what's the best time of the day to measure the blood pressure?

>> Excellent question.  So when I told my patients....I'm sorry.  Okay.

[ Inaudible Remark ]

>> Okay.  So the question is when you're monitoring high blood pressure or hypertension, what's the best time to take your blood pressure?  It's a great question because it's really not discussed in most doctors' offices.  I can tell you as an internist, 8 a.m. every morning does not help me.  I can tell you what your blood pressure will be at 8 a.m. every morning.  The best way to check your blood pressure is what I tell my patients, you need random readings throughout the day.  So one day 8:00, one day at 2:00, one day at 5:00.  What I tell my patients is, who are hypertensive, they keep a wallet in their purse--index card in their purse or their wallet, and every time they walk into a store where they see a blood pressure machine, they put their arm in it and write down the time, date, and the numbers.  You may have perfectly normal blood pressures in the morning, but as the stress of the job in the day increases, you may end up having 170/110 by the end of the day.  You're not gonna catch that if you do that once a day.  If you take random readings 2 or 3 times a week, you have a much better idea where you're at.  Are there any other questions?  Yes sir?

>> Are there any supplements that are particularly bad for the prostate for an enlarged prostate?  Or are there specific supplements that are good for the prostate?

^M00:28:18

[ Inaudible Remark ]

^M00:28:23

>> I will let Dr. Davis handle that question because I'm--it's not where--I tend to look on most supplements a bit of suspicion as an internist, so--

[ Laughter ]

>> Yes sir?

^M00:28:34

[ Inaudible Remark ]

^M00:29:04

>> My point of view for supplements in general and is that a supplement is what it is.  It's a supplement to your normal diet.  If a person in the United States has a normal healthy diet as defined by the MyPyramid.gov, you really don't need a supplement.  Now some people don't have that luxury having a normal healthy diet.  There a supplement--may help supplement what you're missing.  Personally, what I'd seen from the literature as an internist looking at the whole spectrum of disease, the only thing that really helps is a multivitamin a day.  You know, having megadoses of supplements really does not, in my opinion, make that much of a difference.  And for me it's a degree of difference.  Say, selenium buys you a 1 percent chance of risk reduction of developing prostate cancer or a 10 percent cancer risk reduction; well, going for a 30-minute walk buys you a 25 percent risk reduction of dying, you know, in general.

^M00:30:02

>> So, it's kind of choose the medicine you want to reduce your risk.  Going for a walk is free.  Some of these supplements are very, very expensive, and I don't believe the science has got into the point where it tells us, yes, take this for this particular condition.  And as for the first part of the question, I'm not sure if we were in the SELECT trial or not.  We were?  Yeah.  Yes sir?

^M00:30:29

[ Inaudible Remark ]

^M00:30:34

>> For any age group is anything below 120, so 100 to 120.  Now, the blood pressure thing is very interesting in the sense that as we get older as humans, our blood pressure goes up.  And the old way of thinking was 1 plus your age was a normal blood pressure.  So if you were 60 years old, your blood pressure of 160 over something was considered normal.  About 30 years ago, a bunch of doctors got together and did a study and said let's take our blood pressure when you're older back to when you were 20 years old, that's where the 120 came from.  By dropping your blood pressure from 160 to 120, you cut the risk of heart attacks and strokes by half.  So as humans, we are probably designed to get hypertensive as we get older.  By lowering our blood pressure with diet and exercise and medications, we cut the risk of developing these other illness which are much worse for us.  So like I said, anything below 120 is where I want it.  Now, most of my patients are shocked when I say I want them in the 110s 'cause they're so used to be in 140s and 150s by their physicians.  But the data is very clear.  If your drop your blood pressure to normal ranges, 110s and 120s, you cut the risks of heart attacks and strokes by half.  Yes sir?

^M00:31:52

[ Inaudible Remark ]

^M00:32:02

>> Right, yeah.  I mean each person is gonna be different.  Now, for some of my patients having a blood pressure of 120 or 130/70 is actually making them feel bad, and they get fatigued and tired because they are so used to living at 200/110, you know.  And I take that very slowly.  I bring them down very, very slowly.  Ideally, you know--ideally I want you as low as you can go without fainting.  That's basically how I look at it.  Yes, sir.

>> In your summary, you said to avoid high calcium.  What constitutes high calcium?

>> High calcium is more than 1500 mg a day or 3 Tums tablets or 2 glasses of milk.  Was one over there first, go.

[ Inaudible Remark ]

>> What cholesterol would be too low?  Total cholesterol?  There's no such thing.

[ Inaudible Remark ]

>> Yeah, I mean there are some intriguing data having that too low of a cholesterol might also cause problems, but I've yet to come across anybody with a cholesterol that is what I would consider unhealthy low.  Now, there are those with advanced cancer like advanced stomach cancer, advanced colon cancer whose cholesterol is way too low just because they're sick from the cancer.  But for the general person who's relatively healthy, there's no number that's too low.  Yes ma'am, right here.

^M00:33:30

[ Inaudible Remark ]

^M00:33:51

>> I'm not gonna be able to answer that question without looking at exactly his numbers.  Question is this doctor has a patient on calcium.  You know the blood calcium is low but they have heart disease and other issues.  I--without looking at the exact numbers, I couldn't give you advice.  It depends on how much the supplement is and besides to that.  Now calcium is helpful.  Most Americans who get older don't take enough calcium in, in the sense that they don't--the osteoporosis and osteopenia and that kind of prevention with calcium you need it.  The question is you don't need excessive amounts of calcium.  So 1500 mg is the standard definition.  I've seen people on 6,000 mg or, you know, 8,000 mg of calcium a day and they just pretty much, you know, chalkboards.  So 1500 mg, 3 Tums tablets a day, 3 tablets of Tums a day.  I say Tums because Tums is the cheapest thing you can buy for calcium supplements.  You can go to Sam's and you can buy a bottle of 300 for 10 bucks.  You know, if you take 3 day, it'll last you 100 days.  There are two more.  Back in the back.

^M00:34:54

[ Inaudible Remark ]

^M00:35:25

>> I will tell you that if I had found a way to prevent prostate cancer, I would be living on a private island in the Caribbean.  I would not be here.  And all of us would be the same way.  I would take--it goes back to the whole supplement talk.  There’s an entire industry of supplements out there that is able to push claims out that are not FDA approved in the sense that they don't have the rigorous backgrounds that drugs require.  That person is not gonna put that in writing for you, and that person ain't gonna be around by the time you develop prostate cancer.  And I'll let Dr. Davis and the team talk about the actual supplements in terms of what helps and what doesn't really help.  There are two more that--yes sir over here.

[ Inaudible Remark ]

>> Yes.  I mean heart rate is absolutely a big component of this.  One of the things that we like to see is a nice slow heart.  The slower your heart beats in normal activities, actually the chance of you having a major event is better.  Now, an average heart rate for most people were actually numbers between 60 to 80.  Some people live in the 50s.  Most marathon runners live with heart rates in the 40s and 50s and only freak out the nurses on the floor when they see it because our alarms are set at 60 for low heart rates.  But if a patient is not symptomatic from the slow heart rate, there's really nothing to worry about.  Yes sir?

>> What about zinc and prostate?

>> Zinc and prostate.  Dr. Davis, you have a slide on that, right?  Yeah.

>> All right.

>> Okay.  Thank you.

^M00:37:13

[ Applause ]

^M00:37:19

>> All good questions.  So our next speaker will be Dr. Logothetis, who will give us the outline of prostate cancer and its multiple dilemmas.  Chris?

^M00:37:26

[ Pause ]

^M00:37:33

>> So thank you very much and thank you for taking the time to come here.  How do I forward?

>> The keyboard is under the drawer.

>> Oh the keyboard.

[ Inaudible Remark ]

>> Okay.  So what I'm gonna try to outline for you today is the challenges that we face with this disease that is really a set of diseases called prostate cancer.  And some of the questions is, in early disease, who needs therapy, and does the mere diagnosis sort of the being labeled as having a cancer justifying an intervention based on risk?  Then we have a group of cancers with intermediately aggressive behavior where intervention is generally recommended but there are many options because there are many ways to control this disease.  And the final one is the aggressive variant, what is it, how do we treat it, and what is the promise of the future for this? 

So here is basically the challenge that one sees in prostate cancer.  Unlike other diseases such as lung cancer, kidney cancers, breast cancer, when you're diagnosed with this disease, it implies an immediate need for an intervention because that disease has get up and go and without treatment, it poses risk to the individual.  Here we have a problem with prostate cancer because of the expected 217,000, this number always changes, that are diagnosed annually.  Worst-case scenario, 130,000 will need therapy, and an estimated 32,000 patients die of the disease.  So you can see in this blue outer circle a significant majority of patients derive no logical benefit from the diagnosis because they'll do well despite this.  So, overdiagnosis is estimated some around 80,000 to 87,000 annually if you consider overdiagnosis exposing patients to the risk of what the label of cancer means and the consequence to the individual patients--anxiety, risk of intervention, complications of intervention.  So this is a real risk to patients on both sides, the side of being overdiagnosed, setting a cascade of events that drive all sorts of bad events, and the side of being diagnosed too late and losing the opportunity to be cured of the disease.

^M00:40:10

>> So, the way I've tried to get at this is describe this as a clock.  So, you're dealing with a competition between your prostate and your birth date trying to take your life, right?  And what you want to do, because we're not gonna be immortal, is to make sure that these are not malsynchronized.  They need to run in time.  So the day you have your stroke, your heart attack, everything goes wrong, your prostate can do whatever it wants.  You just don't want it to do it much before.  So if these clocks are synchronized, meaning that the progression of the prostate is aligned with the progression of your disease, whatever happens with life in general, by the human definition of disease, it's not a cancer ,because it does not pose a threat within your remaining lifetime.  So, when these clocks are aligned, your biological, your age clock, and your prostate clock is aligned, then we actually have to know it and monitor the disease to make sure that they--the synchronization doesn't go off, and we have to keep an intervention to keep them in place.  So the competition is here between emergent, dependent medical--age dependent medical problems that influences the selection therap.  A relatively high-grade cancer in somebody who is very old or very infirm does not necessarily represent a disease; however, that same illness in somebody who has a quarter of century ahead of him may represent an illness that justifies intervention.  The illness is defined by the discordance between your biological clock and your prostate clock.  So, prostate cancers of low aggressiveness and low risk may, independent of age, pose no risk.  We actually don't know the proportion of the cancers that will evolve, even given sufficient time, to an aggressive variant just because you have an expected quarter of a century life still left ahead of you and you're detected to have prostate cancer doesn't necessarily mean that prostate cancer's the one that's gonna cause a problem in you in that remaining length of time. 

So, what are the principles of therapy for this early-risk disease, and this comes to sort of the issues of personalized care.  The burden and the challenge for taking care of patients with personalized care is it’s personal that requires negotiation with patients, and you have to share in the decisions and share in the risk.  All right.  So, for low-stage low-grade candidate, monitoring for the purpose of avoiding delaying therapy is one of the options.  The problem with that is somebody asked me how do we monitor and by monitoring can you be assured that you will anticipate problems?  And the answer is absolutely no, we can't be assured.  We can reduce the risk by combining a very low risk in the properly selected patients, and we can set up a backstop by monitoring it as close as we can.  But if the honest question was, are we certain that we will not lose a window of opportunity by watchful waiting, the answer is no, we're not certain.  So, but we think we can select these patients.  We're being very cautious, and that's why we prefer to do this in our institution in a clinical protocol so we can monitor these patients and we can see if there's any trend, any changes detected early and adjust our care. 

There are patients who say it's not about the cancer, it's about me, and the notion of sitting with that uncertainty for the balance of my life and not having something done is not something that I'm prepared to consider.  A very, very perfectly respectable and understandable request in such patients, even though all of us who sit in the room wonder whether we did the patient any good, are prepared to offer them therapy as long as there's a diagnosis, there is cancer, and as long as they understand that this operation is being done almost as a preventive strategy because we can't guarantee that it's gonna get aggressive. 

Lifestyle changes you've heard about.  The best way to increase the challenge for us to develop this position is to live longer well.  We're about trying to make patients live long well—that's why we consider watching patients rather than adopting the very cautious approach and treating everybody 'cause there are consequences to intervention, but that's why you share in the obligation to live long well, so that--so you can benefit from all these interventions. 

And finally, many, many patients with cancer would love to have the dilemma that most patients with prostate cancer that have localized diseases and pick among the excellent choices to live well without side effects and have to just deal with the anxiety of the unknown.  And that's a big part, I understand, but relative to what other patients have to pick for with other diseases, that's a relatively small burden. 

Now just so you understand how we think of prostate cancer.  The traditional way of thinking of a cancer is this here is this rebellion that occurs among cells within the patient.  These cells start revolting, taking off, spread throughout the body and cause all sorts of problems.  The reality is that prostate cancer has many features of diseases such as high blood pressure, arthritis, and all these other progressive degenerative changes that occur as we get older.  It is influenced by environmental factors which you would think wouldn't influence a disease that is in open rebellion that doesn't respond to any normal cue.  The reality is prostate cancer appears to respond to its environment even after it's been established as a disease.  So if you take patients at the MD Anderson Cancer Center who had prostatectomies done and whose PSA has recurred—so it's among the group of patients who there was an attempt to cure them and the PSA came back—and you normalize them so they’re as equivalent as we can be in their prostate specimens, and you just look at them by how much weight they've gained in the preceding time quarter of a century, 20 years before being diagnosed, and you can see that those patients who had more weight gain had a much shorter time to PSA recurrence than those patients who did not have the weight gain or didn't gain weight.  So here you have a disease that appears completely equal in every way that we can measure.  And the one factor that is a dietary constituent to the weight gain seems to drive an aggressive behavior on one hand and a less aggressive behavior on the other hand.  That's why mortality for prostate cancer, cancer-specific events within patients with prostate cancer independent of any treatment appears to be worse in every category when you're overweight compared to when you're normal weight.  So this effect may be retained throughout the course of the illness and becomes very, very important.  What is unknown is how much benefit you get and how much you reverse by returning to a normal weight.  Those studies are ongoing.  We suspect it will be true.  It appears to be true in colon cancer.  Data is not yet strong there yet and it appears to be true in breast cancer to prostate cancer data, takes longer to get an answer. 

So, how do we think about this?  On each of these topics, we'll discuss a little bit of what our research efforts are and this was discussed a little earlier, how you actively prevent this disease process once it gets initiated in you. 

So the essence, the essence of a cancer, the diagnosis of a cancer is that unlike normal tissue, which responds to a prompt, you remove a hormone, you radiate it, you treat it, you operated on it by resorting to a normal behavior when it behaves abnormally.  Cancers adapt to the withdrawal of a drug, adapt to a genotoxic challenge, we call it these genes, by evolving, by changing.  They are naturally unstable.  So we wanted to test the following hypothesis, that if you challenge the prostate cancer, very early prostate cancers, there will be two categories of these cancers: those that are able to adapt and survive this challenge, and those that are unable to adapt and not survive this challenge.  Those that have the intrinsic are wired to be able to adapt or those that are potentially bad.  Those that are not wired to respond to this and find another way to survive are potentially good.  So this is the general principle that happens with cancer that we wanted to apply to very early disease. 

And this is the work of Dr. Jeri Kim.  She has been funded for this and works with Dr. John Davis about this.  We know that in patients with prostate cancer who are very early in their disease, that if you give them finasteride, a drug which blocks a specific subset of a male hormone signaling in tissue, almost 1 in 3, a little less than that, who were destined to develop cancer in a decade don't get it.  And we know within many of those prostates, there was cancer already harbored.  So this suggests that very early in the disease, there is a subset of these cancers that are unable to adapt, they're cancer “wannabes,” unable to adapt to the challenge of withdrawing modestly the male hormone, and they will never become cancers.  So the logic that Jeri did, Jeri Kim, Dr. Kim did was that there will be two categories, if we give people finasteride and then we analyze their tumor, they will either adapt or not adapt.

^M00:50:00

>> Those that will adapt have potentially lethal genetic networks and would justify an intervention.  Those that fail to adapt are not the kind that harbor the ability to get aggressive and we would continue to observe.  That study is ongoing.  If you get surgery at the MD Anderson with early disease, we recommend it.  We'd like to have you participate.  It doesn't cost you anything.  It doesn't add to your time, and your operations are exactly the same, and it will inform the development of the study. 

So this concept that we're trying to develop is what's called dynamic profiling.  Instead of getting a catalog of all the molecular events which are thousands upon thousands and their interactions is a thousand-fold more, we wanna provide a logical prioritization of what we want to look at by challenging the tumor in a very specific way that we can then interrogate the tumor on how it's responded and understand whether you have a real disease or not and then understand in the future, we hope, very soon may be even by imaging, on whether you need any intervention or not where you can simply be observed.  So we look to the day that we don't need our pathologist who's sitting in the background, Dr. Troncoso, but we actually need to do is give a drug and see if the prostate changes in some way and if it changes in a favorable way, we don't do a biopsy and we observe the patients.  If it changes in an unfavorable way, then we would justify intervention. 

So the second category of patients is where the majority of patients reside and where the majority of the dilemmas arise.  And that is that--that age-dependent illnesses occur, but you know, you're sort of a typical male with typical indiscretions but you still got a lot of miles left on those wheels, and your prostate is wound a little tighter in the sense that there is potential that the prostate cancer is gonna beat you to--to, you know, the end zone before, before, your regular indiscretions do.  And that's when we need to start thinking about an intervention because here, we're talking about a deficit in your future life that we need to anticipate, and we've concluded as a group that early intervention, trying to get this under control and in a net effect will result in a longer better life, avoid complications, and prolong your life because this disease really has a chance to cause a problem. 

Now, here's the challenge.  So here's the colon, here's the pelvis, here's the bladder, here's the prostate, and what God did is he wedged the prostate below the bladder, in front of the rectum, down in his pelvis, where all the wiring is that does everything.  He's not a surgeon, so I can talk about it this way, and the surgeon has to come back and get this out of there and not cause problems and get it all out of there.  So you can see what the challenge is.  So it's not surprising in real high-grade disease that even in the hands of the best surgeon, you often have to add radiation therapy after surgery in high-grade disease, and that results in an improvement in disease-free survival, but now we know overall survival also.  That indicates that in some patients, surgery is adequate.  In some patients, surgery is necessary but insufficient in it by itself, and in some patients, it's futile.  So, if you were to do it with calculation like sort of somebody who is developing drugs is doing, surgery alone benefits by drug criteria—it cures the only endpoint—somewhere less than 10 percent of the patients.  That's the randomized trial.  If cure were the only measure where the Swedes operated on half their patients and observed the rest, and the difference in survival, it just falls into the end was that small.  However, if another 18 percent of the patients who were operated on—and that's a separate study done here also and in Europe, United States and in Europe—that almost twice--three times as many patients are benefited because they have high-risk disease by the addition of surgery after the radiation.  So surgery is essential in almost curing the 25 percent of the patients with localized disease that can be cured.  It's an essential contributor.  It can do it by itself in less than 10 percent.  If cure were the only endpoint, that in 11 years 40 percent of the patients are alive, so it was unnecessary in those 40 percent, you could argue.  And in 35 percent of the patients, no matter what you did, the patient died of the disease so in that case, it was futile. 

So the question for somebody who is developing drugs and where we're going next in trying to improve the outcome is, who is this person, who is this person that is who can get away with one treatment alone, who needs combined therapy that we know in advance that we can plan for, who can we anticipate that can avoid any further intervention, and who needs something more added on?  The principle that Dr. Pettaway will tell you of ignoring the primary as we do, the prostate where it lies in among this disease is completely different than that used in any other cancer.  No breast cancer physician would consider leaving an active breast cancer behind just because the disease has spread.  Yet in prostate cancer we do that regularly.  There are some practical reasons to consider it.  So, if I were to anticipate, there will be more interventions in patients with higher-grade disease and less interventions with lower-grade disease if things are going the way I believe they're going. 

So, what are the principles of therapy for patients with intermediate risk of prostate cancer?  That is the one where the cancer is more aggressive and will result in a survival deficit, even taking into account the patient's comorbidities, the patient's other illnesses.  Therapy here is necessary.  For localized disease, either surgery and radiation.  Often combined treatment is necessary, and our ability to predict that is imperfect but getting much better.  Strategies needed to be considered in this subset of patients to reduce the risk.  We're looking at drugs, giving them immediately after, or immediately before, to try to reduce the prospects of the disease will come back.  Lifestyle changes in this subset of disease are probably important.  Admittedly, we don't have data yet to support it.  All the data seems to be aligned with staying healthy.  It makes it at least easier for us to treat you with aggressive therapies if needed to be and probably affect the disease in general.  And here, even in patients whose disease has spread, survival for 10 years and beyond is not unexpected, and we can do it, so patient preferences, effect on survival, sequence of therapies, side effects of therapies do drive decision-making process.  There is still an active negotiation.  It's not a monologue.  This is a dialogue. 

So let me give you an example of research that we're doing.  So this is a morula, the few little cells that get together that ultimately make this body that we know this human body.  They get together.  They interact, and they have to interact in a very specific way so you get this totally coordinated function.  And let me try to describe.  So one cell becomes two, two becomes four, four become eight.  But in that--but in each of these cells need a specific cue to stop and start growing because imagine if one cell became two like it was supposed to but decided on its own whim because it was irregulated and it didn't get the cue to stop to make another one.  You would have seven fingers in one hand, your nose would grow discoordinated with your ears so you'd may be a person with two noses and five ears or one nose and eight ears.  All this needs to be orchestrated.  Everything needs to happen in its appropriate time, and there needs to be a cue to stop and start and accumulate these cells at the proper time and the proper development.  This developmental paradigm—how we go from being a small number of cells to a well-organized functioning machine—we believe is increasingly at the center of understanding prostate cancer and specifically how it's done in bone, which let me describe. 

Now, this is an infant that is a cartoon of what happened to children during the thalidomide epidemic which was a tragedy that was not predicted from the experimental models when this drug was developed before it went into human use.  Thalidomide was a drug that was developed to treat nausea in pregnancy.  It was studied in mice.  No toxicity was found.  But when these children did this, they developed what's called phocomelia.  Their arms didn't develop because at the point in development when nausea occurred, arms in utero being developed, when the mother took this pill, it stopped the development of these specific bones.  The child was otherwise normal.  So it disorganized the normal development of bone and vessels in that specific site, which is a tremendous interest for us because of the association between prostate cancer and bone.  However, it didn't occur in mice.  So it tells us something that even the most casual observer of mammals will see that mice are different than men and sometimes scientist have difficulty agreeing upon and that is it wasn't predicted in mice.  This experiment only became an experiment because we saw it in humans and we went back and started studying it.  There is not a mouse model of this event.

^M01:00:04

>> So it tells us that we have to be observant in the clinic, and we have to prescribe research in the clinic, because if we don't do that, we'll never solve the problems.  This problem will never be addressed.  So how did we use that?  Well, we took thalidomide, which is now a drug that is approved for some cancers and approved for treatment of leprosy.  It really works in leprosy for the same reason.  And we noticed that when you gave it before, this is blood flow through the prostate, you completely block the blood flow in the prostate when you do this.  So what this told us is that the thalidomide blocked the ability of the prostate cancer cell to communicate with the prostate itself, the prostate tissue unlinking the interaction between the cancer cell and the host tissue, and remember the very definition of cancer is that it's able to invade, engage tissue. and cause a problem.  So we have now--we believe that we have the following evidence, that some of our best therapies to treat prostate cancer do the following.  They initially attack what's called the microenvironment—the vessels, the structure, the normal bone development—and create a barrier between that and the cancer cell, and the cancer cell, unable to benefit from that survival support that it gets from that environment, goes on and dies or develops a quiet state and coexists with the host.  So this has become one of the primary therapies that we now use and we have many drugs, angiogenesis inhibitors, MET inhibitors, other drugs that actually affect this and deregulate this, and there are most exciting drugs that we're using now in prostate cancer. 

So prostate cancer is a disease that tries to duplicate the organizational sequence that exists in bone for its normal development for its progression, and the central hypothesis for developing therapy is that if we disrupt that organizational sequence, we will in turn disrupt the progression of the disease, stop it, and prolong the life of patients with prostate cancer and reset the clocks so they run together. 

So finally, these are a group of patients where the prostate clock is really wound fast.  The disease is getting aggressive, and we have to treat it more, and age-dependent factors are less.  Now here is the biggest revolution that has happened in prostate cancer of recent.  We talked about the organizational sequence but in another universe we're talking about, we're always talking about the mainstay of therapy for prostate cancer is modifying the hormonal concentrations in the patients, the male hormones, and how it affects cancer growths.  We now have a unifying concept that brings them together as one.  So for 50 years, almost 60 years now, Charles Huggins got the Nobel Prize in 1966 for work that he did during World War II.  It was basically he showed male hormones are produced here in the gonads, in the adrenal glands.  If you block them, they then stop prostate cancer growth because the male hormone testosterone goes to the androgen receptor which then gets activated and drives the cancer growth.  We now know that's wrong.  When you block the male hormone, you indeed get a response in the sense that the cancer cell drops.  However, the well-established cancer that's able to adapt to this does what any sensible person would do that's dependent on a nutrient.  It produces its own and the environment around it produces its own. 

So we now know that prostate cancers have a genetic machinery that allows them, after you stop the production of male hormone, to start producing their own male hormone.  And when that happens, they have their own little autocrine machine, we call them, that drives the progression of this disease.  So this is how we proceed.  Fortunately, we know the genes, we know the pathways that do that, and this is an example of a patient who what we previously called androgen-independent prostate cancer, had his PSA taking off.  We give them one of these drugs that block the gene that is very specific for production of the male hormone in the cancer and where we see these PSAs drop like this.  Approximately 70 percent of patients will respond to these kinds of therapies, and we're trying to figure out how to give it earlier.  So this is after the patient had become androgen independent.  So we're realizing that this is a very important pathway, understanding this early and treating patients earlier with this is what we're trying to do. 

So personalized care, chemotherapy ,and hormones remain the cornerstone, not the kind of cornerstone we really wanna spend our whole future on, but that's what the cornerstone remains today.  Vaccines, maximal androgen ablation, soon to be available, okay and working, and other drugs, a panel of promising new agents will be available soon, and lifestyle changes are important here.  But here there needs to be a little negotiation because calories become extremely important to somebody has to suffer the rigors of surgery, radiation therapy, chemotherapy, and everything else we do, so maintaining calories becomes a critical aspect.  So what do we do here?  In each one of these, we'll talk a little bit about research. 

This is a model of a cancer growing in bone taken from one of our patients, put directly in bone, and we screen those, and we treat them for candidate drugs to see if we can stop the growth in bone in mice.  Now, this is a human cancer not isolated from its components, put in its entirety in the mouse and then blocked.  So while it’s not one of those mouse models were it's isolated, and it's all a genetic mouse, it's something between a human study and a mouse study because it's an entire unhomogenized human tumor, put in a mouse that is susceptible to engraftment.  And we can now screen for drugs that are there, and we have a panel of a whole set of new drugs—you can see the tumor before and after—that are in the clinic to try to block this. 

So for 50 years, we had one drug or variations of a drug and we had refinements and radiation and surgery.  And within about 15 years of the national investment on cancer we’ll have, I hope, within the next couple of years, 7 drugs with proven efficacies that will be in the clinic to treat patients with prostate cancer.  So your investment in prostate cancer research is paying off.  Within a decade and a half, which is lightning speed, you have a lot of drugs that are working.  Things are changing.  We're really changing this disease in a way that is very exciting. 

And our trial designs are changing.  The primary trial I will tell you that we’ll be doing here now for patients whose disease has spread, is initially deplete the testosterone with this blocking this gene that makes testosterone in the cancer cell, then giving drugs in individual patients.  It's not a randomized trial, nobody gets anything, but they go through it serially and get exposed to everything, so we can quickly learn how to develop combinations and go beyond this labor-intensive slow process of 1 drug at a time, and we're looking at trying to do that. 

So where is the future?  So medicine today is the kind of medicine that you all know.  You get a headache, you have difficulty urinating, something is wrong, you go to the doctor.  It's prompted by the doctor.  And what Sunil suggested is this is the way it currently happens.  You have a symptom, you have a diagnosis, and a treatment.  We do all this exotic, inefficient way.  What we will do in the future is we're gonna understand your risk.  We're gonna profile, we're gonna understand your risk.  We're gonna anticipate what you need to have done by understanding that risk and knowing what you need to have done to intervene before or after, and finally we will apply therapy based on that understanding the risk to avoid major problems.  Medicine is evolving very, very quickly down that way.  Organizational structures are gonna need to change to sort of adapt to this.  It's a completely different view of life.  This is medicine of the very near future and it's evolving very quickly in that way.  So thank you, thank you very much and I think we're saving questions for later.

^M01:08:19

[ Applause ]

^M01:08:26

[ Inaudible Remark ]

>> Okay.

>> How many types of PSA tests are there?  Which is the most reliable type to track?

>> So the question was, how many flavors of PSA test are there, and how do I use them, and how do I interpret them?  Ninety-nine percent of the value of a PSA can be derived--I'm exaggerating a little bit here but not by much--can be derived by the standard old PSA.  Remember, we use PSA for a number of things.  One is to monitor established disease, and one is to screen disease, to screen for the risk of disease.  In established disease, the standard PSA, regular immunoassay, is what we need to do.  You need nothing else.  You need no fractionated.  You need no complex.  There's nothing else, okay, once the disease is established, because it's the relative concentrations that are important.  The important issue in patients with established disease is that it be done the same way and it get interpreted in light of understanding what your testosterone is.  Testosterone is a switch that drives PSA.  So if you have an absent testosterone versus a normal testosterone, you'll interpret it differently, and the PSA may fluctuate a little based on the male hormone.

^M01:10:03

>> So in established disease, standard PSA is there.  In screening, it becomes a little more complicated because there is data to suggest that complex and free add to the predictive value, allow you to justify a biopsy by knowing your risk a little more or a little less, okay.  I personally and Dr. Davis and Dr. Pettaway can speak to this.  That difference and that refinement is not sufficient enough for me to ever sway me if the PSA is changing in an unfavorable way, despite the free or total or complex, to avoid a biopsy or to specifically do a biopsy.  So in populations, it's very helpful.  No question about it, thinking about complex and free-to-total ratios.  In individual patients, it swayed me less when I've seen a worrisome total PSA.  So for screening patients, there is evidence that complex and total and free ratios are predictive and they predict better than total PSA.  There is no benefit in established patients.  The improvement is modest, and it helps only in the subset of patients.  There is an ambiguity,and some physicians believe in it and feel that difference is worthy of worrying about and others don’t, because the difference is small.  Is that fair?

>> Yes.

>> They agree it's fair.

[ Laughter ]

>> Mostly everything that I've seen here would suggest that it's mainly intervention.  What is being done towards developing the human immune system [inaudible]?

>> So the question was why are you doing interventions and not doing the immune system, and this is sort of—I’m actually framing things in a simplistic way, did this intentionally.  Immunotherapy is an intervention.  Immunotherapy is a big deal.  We give this drug called ipilimumab, which is a very powerful immunotherapy agent that works some in prostate cancer, and the side effects rival some of those that we could ever imagine we were achieving with chemotherapy.  So if you unleash the immune system in a way that's not specific to the cancer, it's not an innocuous event.  So one thing is, immunotherapy is real.  Second is inflammation, which is how immunotherapy works, causes inflammation to attack the cancer, has good and bad forms of it.  Some forms of inflammation are cancer promoting.  Some forms of inflammation are cancer suppressive.  Chronic inflammation causes cancer.  So it's no longer a fringe science.  These drugs really work.  Provenge will be available.  There is a capacity issue right now still that's going on because it works and ipilimumab works.  But it requires the same set of details and knowledge like we are in developing other drugs and, in fact, we have some active clinical trials with those vaccines and those drugs because we believe in them.  But we treat them the same way as aggressive interventions, ‘cause that's what they are.

[ Inaudible Remark ]

>> Oh, yeah.  Well, I can go over that.

>> Yeah.

>> Let's--if you don't mind, let me come back to that and let's just get back to [inaudible].

^M01:13:31

[ Applause ]

^M01:13:37

>> That'll come up in screening.  Let me say one thing 'cause now it gets to the point we have to watch the clock, we're at 45 minutes.  We'd like this type of conference to kind of be a yearly thing you look for.  I can't tell you what Saturday it will be but it's September, nationally it's prostate cancer awareness month and that's why we target September.  And I think--this is the 3rd year we've done it.  I think you'll quickly realize that we can't do all of this disease on any Saturday morning, but what we can do is every year try to introduce you to a new--a couple of new people, a whole team of people that do prostate cancer at MD Anderson.  So every year, we'll bring out a few new people, go over some new topics we hope, reinforce some old ones, and then you kinda get it piece by piece.  You know, two years ago we did nutrition only.  Last year, we did a lot of treatment choices.  This year, we're having a mixture of prevention and lifestyle choices.  So we'll try to come at this in increments, if you will. 

Now, the final segment of today is just what I call question and answer.  These are the most common questions about diagnosis and prevention.  Many of them were actually your questions last year and like, for example, the common question is, your question about benign prostate hypertrophy.  So we have a speaker do that last year about treatment choices for that.  I picked one this year to answer that goes over testosterone supplements and that actually relates to the questions on supplements we've already been through.  So, Curtis, we’ll try to do about 20 minutes each, and these were the questions that actually--Curtis and I just went through a bunch of questions and he actually grabbed the first 4, that's fine.  So I want Curtis to focus on these 4 as much as we can within the time allowed.  So number 1 is, Do randomized clinical trials conclude or not conclude that I should be screened for prostate cancer?  And then number 2, There's a recently released American Cancer Society Guideline; what's new and important about that guideline?  Number 3, I have a family history of prostate cancer, perhaps [inaudible] at risk, so which guideline should I follow for screening?  And then the most controversial of course is, Should I take finasteride or dutasteride for prostate cancer prevention?  And then, I have mine coming up as well.  So, Curtis, let's see.  And are you--have you loaded already or?

>> Yeah.

>> Oh, there you go.  Good.

[ Whispering ]

>> Well, good morning, everyone.

>> Good morning.

>> Well it's good to see everybody come out this morning.  So we're gonna talk a little bit about prostate cancer screening and ask the question what's the evidence, you know.  Should we all randomly go get PSAs, and what's the evidence for this, as what's the efficacy of PSA in screening? 

So, with respect to screening for a disease, the World Health Organization has recognized that some criteria must be met in terms of this being applied potentially as a health policy and there are 4 criteria.  One, it should be a burden on the community, in terms of death, suffering, economic, or social costs.  The natural history should be well known, and the disease detected by appropriate tests, and furthermore, those tests should be highly sensitive, specific, and acceptable.  And importantly, if you're gonna diagnose it, there must be effective treatment available for screened detected cancer.  And fourthly, treatment of screened detected cancer should provide better outcomes than waiting for somebody to become symptomatic. 

So with respect to prostate cancer, what's the score card here?  So is it a burden on the community? Yes.  The natural history is well known, but is PSA highly sensitive, specific?  No.  Unfortunately, it's not.  It's acceptable but not highly sensitive or specific.  Is there effective treatment for screened detected cancer?  Well, yes there is.  And is treatment of screened detected cancer, does it provide superior outcomes compared to intervention in a symptomatic population?  The big question that we've been kind of awaiting the answer for and I'm gonna give a hedge here and say possibly.  [Laughter]  Okay. 

So with respect to--you know, talks this morning, some of the things that you'll hear us talk about evidence, and one of the things that evidence-based medicine has brought to us is kind of a hierarchical system for evaluating the level of evidence.  And the levels of evidence basically give us a kind of confidence with which we can counsel our patients with respect to the confidence we have in a specific finding.  And so when you look at it, level 1 evidence is really the gold standard, kind of randomized prospective trials or reviews of those prospective randomized trials.  And lower levels of evidence, specifically a case report, single case series ,or expert opinions, actually relatively low-level evidence.  So with respect to screening, what kind of evidence do we have?  Well actually, we actually do have some level 1 evidence. 

Now, with respect to screening, this has been an issue that we have been waiting for, for many years.  We've been wanting to know, does treatment of screened detected cancer produce superior outcomes?  And last year, 2 trials were reported to the largest trials, prospective randomized trials.  We thought this was gonna answer the question.  It really raised a firestorm of controversy when they actually came to different conclusions.  The PCL--PLCO trial, which we talked about last year, basically was the US-led trial, randomized 76,000 men to yearly DRE and PSA.  And in that trial, what they found over time is that there was no difference in the incidence of high-grade or high-stage disease when you looked at early patients that were screened or not screened, and there was no reduction in mortality whatsoever.  But when you look into the trial, you can see that in the control group, the men who were "not supposed to be screened," eventually the incidence of having a PSA 1 or 2 was actually about 50 percent.

^M01:20:11

>> So, there was a very high contamination rate in that trial. 

The European trial, on the other hand, randomized about 162,000 men to screening with PSA every 4 years.  We used a cutoff that was a little lower, about 3.  And in that trial, with about 9 years’ follow-up, what they found was that there was a significant decrease in the incidence of high-grade and high-stage disease in the screened arm versus the control arm, which is something that you might have expected.  There was also a 20 percent reduction in mortality, and so with about 9 years of follow-up, this was a positive trial, and even with that, though, when you looked at the actual implications, the questions became how many men do you need to screen to save one life, and at that point in time, the number was about 1400, how many do you need to treat, the number was 48 to 1, so tremendous amount of potential overdiagnosis and overtreatment to get the effect.  Now, to be fair, to be fair, this is with early follow-up, and there were already studies and models showing that with more follow-up, this number needed to screen and to treat is going to come down with time.  But the implications were that, you know, even if screening is of benefit, there potentially is a tremendous price to pay, and is it really worth it? 

Now, this year in July, the Swedish group actually published their trial, and they actually were initially a part of the ERSPC effort.  A subgroup of their patients was actually published in the overall ERSPC trial.  But this trial was conceived independently and had its own screening protocol.  And basically, what it did is it randomized 20,000 men—let me see if I can get this to go over here, there we go—randomized 20,000 men to screening or control groups.  Amongst the screened group, they basically was screened every 2 years, and the cutoffs varied, anywhere from three and a half to about two and a half over time.  And when you looked at the final result—the number of deaths in the control group versus the number of deaths in the men who were screened—there were 78 deaths at that time, which is about a 14-year follow-up, deaths in the control group and only 27 deaths in the men who actually underwent screening.  Now, because this was an intent-to-treat trial, some of the men who actually were randomized to screening didn't get screened.  So if you added these deaths to those, it actually was about 44 men, but it was a still significant reduction in death over time in the men who were screened versus those who were not screened.  And this slide basically shows the curves of the Swedish trial.  And it's about a 40-percent reduction over 14 years.  So this trial is markedly positive.  When you look at the curves here at 14 years and then you look at where the ERSPC curves were when they report it, they were actually back here.  So it's possible that when you look at the overall ERSPC group, that it's very plausible that the screening benefit will actually be more pronounced with time, as shown here with the Swedish trial. 

So, from the standpoint of view of the screening trial, with respect to the Swedish trial, what we can say is that more cancers were diagnosed overall, but that's not what's important.  What they found was that there was an increase in advanced-stage cancer among controls.  One of the things that was raised is, you know, is it possible that treatment differences could have made difference in mortality and here, clearly, at least among men with curable disease, treatment was very similar between the screened population and the control population.  There was a 44 percent reduction in mortality in this trial, which is a significant reduction.  Now, the practical implications here were more profound in that the number needed to screen was not 1400, it was 293, and the number needed to be diagnosed or treated was 12, compared to 48, and these numbers are much more like the numbers you see that actually justify the use of mammography in breast cancer screening and the screening mechanisms that we use for screening for colon cancer.  So, overall, what we can say is that screening for sure detects more cancers.  The data that exists thus far somewhat controversial, but I think we can say the screening certainly may reduce prostate cancer mortality, but what's unclear is what's the overall benefit, because we know there are some downstream issues that cause problems.  One, we know PSA is not a perfect test.  We have a number of men who have false-positive values, and that leads to unnecessary biopsies, pain, some morbidity from that.  We also know that we overdiagnose a lot of cancers that would potentially never come to clinical attention, so we have worry induced in patients who potentially wouldn’t need to worry about these cancers, and then, importantly, we know that when we treat cancer, you know, it's not a benign process, and we certainly induce morbidity with respect to erectile function, urinary incontinence, bowel dysfunction, and even in some cases, treatment-associated death, but extremely rare.  So we've got to weigh the risks and the balances. 

So when we look at the evidence we have today, I think that with respect to screening, it's certainly a consensus among all organizations that this is an individual choice.  It's not a mass-screening issue.  Prostate cancer testing is an individual choice, and men should discuss the risks and benefits of PSA testing with their physicians.  What's controversial is when to start appropriate PSA cut points, interval testing, and when to stop.  What we really need is we need a better PSA.  We need to know how to diagnose clinically relevant disease.  We need to factor in all of the things that potentially may be associated with more significant disease, and this is only gonna come through multiparameter assessments, and there are some tools that we can use that we'll--I'll talk about in a little bit.  Prostate cancer risk calculators are potentially helpful, and when we fold in some of the molecular cues that are now available, with respect to genetic SNP analysis and multimodal ways to incorporate this data together.  I think it will become the future that we're trying to get to is a strategy where we almost can put all this data into a calculator and know what your future risk of prostate cancer is, know what your risk of death of prostate cancer is, and which kinda cancer is going to--in essence, what factors you have that are going to be associated with a lethal variant of prostate cancer that was mentioned before.  So, I'll stop there, and we'll answer the question about the ACS guidelines.  Let's see, how do I get there.

^M01:28:14

[ Pause ]

^M01:28:21

>> Yeah.  Now, I gotta get back to the desktop.

^M01:28:27

[ Pause ]

^M01:28:32

>> Okay.  Here we go.

^M01:28:33

[ Pause ]

^M01:28:45

>> So, the second question was, has the American Cancer Society position guideline changed, and the answer is yes, it has changed.  This was their recommendation based on their 2001 update.  And basically at that time, basically what they said was that screening should occur for “informed men” with at least a 10-year life expectancy.  It didn't really say what--it didn't really spell out what information should be given, and at that time, they recommended a yearly PSA and digital rectal exam for average-risk men who are over age 50, and this should start at age 45 for higher-risk men.  Given the controversies in the literature and our new knowledge, the American Cancer Society updated their guideline this past year, and so the purpose was to develop a document that accentuated the importance of involving men in the decision of whether to initiate or continue testing for prostate cancer, given the uncertainties regarding the magnitude of the potential benefit of prostate cancer screening in light of the certain morbidity associated with treating screen-detected cancer and potentially overdiagnosis.

^M01:30:08

>> And so their aims were to basically make recommendations to providers and patients with average potential risk, make recommendations for screening men potentially at higher risk, make recommendations regarding the most appropriate tests and how often those tests should be given, and also make recommendations regarding the advisability and content of this shared decision-making, so kind of to lead you down the pathway. 

So basically, they reviewed the literature from 1950 to 2009, looking at screening efficacy, a variety of things related to test performance, physical and psychological adverse effects.  This was reviewed by the Prostate Cancer Advisory Committee of the ACS, and they developed this evidence-based kind of consensus, a guideline.  This was circulated to peer reviewers and their board of directors.  So, it was vetted by a variety of different groups inside and outside of the ACS.  And so their recommendation now is this--is that men with a 10-year life expectancy should make an informed decision with their healthcare provider regarding screening after receiving information about uncertainties, risks, and benefits.  Screening should not occur without informed decision-making, and this informed decision-making should be provided with their healthcare provider or other reliable source.  So in other words, what the ACS would now frown upon would be, you know, having 1000 guys lined up for PSA testing just because there is an announcement out there.  They would frown upon that now based on potentially a lack of informed decision-making and the fact this--the individual didn't have a chance to understand potentially what they were doing and ask questions about the downstream events of PSA testing.  They recommend this discussion occur for average-risk men at age 50 and for higher-risk men at age 45.  For higher risk, we're basically talking about African-American men, men with a family history.  And for those at very high risk, with multiple family members affected at early age, they would also recommend starting at age 40 for the discussion. 

Now, what should that discussion include?  So, they've actually outlined the core elements of what that discussion should include.  The fact that prostate cancer is an important health concern, the fact that screening with digital rectal exam and digital--and PSA does detect cancer earlier than no screening but the fact that screening may be associated with decreased prostate cancer death.  There's uncertainty about whether the cancer you would be potentially diagnosed with is lethal.  Treatment of that cancer may be associated with side effects, PSA and digital rectal exam may be associated with false-positive and -negative results.  Abnormal tests may lead to unnecessary biopsies, and not all men with prostate cancer need immediate treatment.  So these are thought to be the core elements that should be incorporated into a discussion.  Now immediately, one of the things that's recognized is that in a physician's busy office, he may not have time to discuss these issues with the patient.  So, one of the things that they developed in conjunction with others are decision aids that patients can actually be referred to, that will help inform them about the various complexities of early-detection testing for PSA.  And I use one of these aids in our community-based program by the American Cancer Society, and it's called “Testing for Prostate Cancer.  Should I Be Tested?  Is It the Right Choice for Me?”  So as information on those core elements that we just mentioned, about screening versus no screening, downstream effects, things like that, and in the end, it basically takes men through kind of a decision-analysis pathway that allows them to define what they value in making a decision.  For instance, it says you may wish to be tested if you value finding cancer early.  You're willing to be treated without definite benefit.  You're willing to run the risk of urinary, bowel, or injury from treating early prostate cancer.  Or you may not wish to be tested if you place a higher value on avoiding the risk of screening and treatment, such as worry or problems with urinary, sexual, or bowel function.  Or you're willing to accept the chance that you may have prostate cancer and may not know it before it causes you harm.  And so, it kinda helps you kind of decide where you fall in line with respect to risks or benefits. 

Their actual recommendations are these, a serum PSA level for those who wish to be screened.  Serum PSA level with or without a digital rectal exam.  Yearly PSA interval if your PSA is above 2.5, so they recommend a yearly PSA in that setting, but if your PSA is less than 2.5, they would recommend decreasing that to about every 2 years.  For threshold for further evaluation, they use the 4 nanogram per ml cutoff for males of average risk.  And for men in that kind of gray zone between 2.5 and 4, they strongly recommend that you consider other factors such as digital rectal exam, race, family history.  These guidelines are based on consensus.  I don't necessary agree with every point of them, but it does form, I think, a useful evaluation tool for patients to use. 

So, thank you.

^M01:36:16

[ Applause ]

^M01:36:25

>> All right, thanks.  So those were the key updates we wanted to do.  The couple of other questions I happened to prepare we'll see if we have time for.  So let me go to some of my slides and we'll probably run a little over.  I don't think anyone’s gonna kick us out of the room.  There's not another group that's coming in behind us, so that's good.  I remember I gave a talk in National Institutes of Health and we ran long and they turned the heat off on us.

[ Laughter ]

>> We were in overcoats by the end, but anyway. 

So, back to where I went on.  From my standpoint, again, I am a surgeon coming at you with this.  I'm not an expert on every aspect of prostate cancer and I spend, you know, hours a week kicking out prostates with a robot and trying to be very careful and precise about that.  But chemo, for instance, is an important question.  Is it feasible?  Is it necessary?  Let me just consolidate some things 'cause this is kind of the core of what the other speakers were talking about is where should we be sending everybody.  Do we need to send you, you know, to the gym?  Kind of an interesting device.  I don't where--I just found that in the Internet.  Google images is kind of--[Laughter]--you get some weird stuff when you put Google images, that's where I get.  Or should we send you to the pharmacy to get a prescription drug, or do we send you to the local nutrition center?  And what is the evidence behind those? 

Before--but you do have to look at the big question, which is, you know, what are the answers we're looking for?  What levels of benefit do we expect?  How much are we willing to pay for a benefit like that, and what side effects are we willing to risk?  And you know, sometimes you need to consider what the answers are before you ask a question.  Obviously, you know, the sheep will do very well on this vision test, and most of us should do well on this vision test, too, unless you just don't see the patterns behind it. 

If you look at other--Sometimes, it's helpful to look at other dilemmas.  So for example, there's a tamoxifen, you know breast cancer study that looked at a 4.25 percent relative reduction.  You can see people looking at stroke prevention models, the prostate model, cardiovascular events and taking aspirin.  I mean the highest is--will be the cumulative risk of breast cancer if you have this specific BRCA1 mutation--65 percent.  This gets into the level of strength of evidence before women considered prophylactic mastectomy if they're known to be that high at risk. 

So, in the prostate cancer, we would say that it is a suitable candidate because it's so highly prevalent.  It's potentially lethal, as we've talked about, and there are very heavy costs associated with screening and diagnosis.  There are many candidates in other versions of this talk.  We've discussed 5-alpha-reductase inhibitors or finasteride reductase, Dr. Sahai had some slides on that, people have looked at vitamins and minerals as we've talked about, COX2 inhibitors, which is basically inflammatory pathways.  There's a study on the selective estrogen receptor modulators and then, of course, get old-fashioned diet and exercise.  In summary, what do we learn from the Prostate Cancer Prevention Trial?  One interesting lesson we learned is that men are interested in this topic.  I mean, there are a lot of very important clinical trials that have been designed and closed because of poor accrual.  This wasn't one of them.  You had a free drug, free screening, well supported by industry, you know include thousands of men.  The SELECT Trial is the same thing we did here.  Vitamin E, we had thousands of men on this.  We have learned that there is a mild prevention effect.  It's likely to improve lower urinary tract symptoms, but at the cost of some slightly decreased erectile function, compliance is moderate, and there's this ongoing debate about whether or not more high-grade tumors are diagnosed.

^M01:40:11

>> So, it's PCPT and finasteride is worth discussing as you get older and looking at your risk group.  There's more of--this study's not over, this question is not over.  Overall, I think my personal attitude on this is that the ideal prevention agent needs to solve a problem but not create another one in the process.  So there's a little bit of a flavor of finasteride that it solves one problem and creates others potentially. So--but if people are really high risk, that may be ideal.  

So here is again the curves of people as they go along in time, and this high-grade debate does continue.  These are some of the slides from our American Urologic Association meeting, just to show you the latest thoughts on this, and in fact there is--if you download these from the various society pages, there's a Clinical Practice Guideline developed by the American Urologic as well as clinical oncology groups, and they have--because of the debate, they've had to come up with some very carefully crafted statements.  One is that if you go right here, there're these several randomized trials for asymptomatic men with a PSA less than 3 taking these preventative agents, they may benefit from a decrease of 7 years of prostate cancer, and perhaps, this--the tricky thing about being in the office with finasteride is that the PSA levels do cut in half.  So, you expect about a 50-percent reduction.  There's not a specific cutpoint for a biopsy.  The main conclusion would be men should be fully apprised about the remaining uncertainties surrounding high-grade cancers with finasteride, and the effect on mortality is currently unknown.  So there's some split opinions on this, as we discussed. 

Now, the selenium trial we brought up earlier is more clear cut.  That was a negative trial, and I think the take-home message of this is that well, if you look in the box, the editorial from this presentation, “Well-done studies are needed before recommending agents to prevent or control disease.  And selenium and vitamin E have no benefit in prostate cancer prevention.”  So why is that significant?  Well, 'cause there are many situations where you can do what's called an epidemiologic study, where you look at cause and effect, and you may imply that a certain group of patients have less risk of a disease, and you may assign that based on what they eat or what they do.  But until you study it in a longitudinal fashion and in more controlled circumstances, you don't really know the benefit of that.  But, I can tell you that I don't know what the--what do you think the ratio is, Curtis, for every one randomized trial like this? There must be 20 nonrandomized studies of a lower level of evidence that show a different conclusion, so I'm making up that statistic--but that's what it feels like.  And we're really not there.  

Other supplements as well.  People have looked at the zinc supplements, and one of them actually implied that it increased the risk of prostate cancer, and this is not randomized data.  So really, there's perhaps an unfavorable risk of zinc supplementation on prostate cancer, and really there's no good evidence of just generic multivitamin use. 

So--now, this toremifene is a special selective estrogen modulator.  It's an interesting drug, and then it's being duly investigated for prevention of hot flashes for men who are on hormone therapy for prostate cancer, but it also they thought would have a slight reduction of PIN.  I put PIN in here because it came up last year.  PIN is like a--it's called prostatic intraepithelial neoplasia.  And it's thought to be a precursor to prostate cancer.  If for the women in the room or men married to women perhaps, you might have heard of ductal carcinoma in situ.  So, if a woman who has an abnormal mammogram, they get a biopsy.  Sometimes it doesn't show cancer but it shows this in situ cancer, which is not invasive but it's thought to be a marker, and some women will actually have a mastectomy because you find that.  PIN and prostate cancer has an association with real prostate cancer, but development of it is not traditionally thought to be inevitable, but it was an attractive target for prevention, so they tried this drug.  They tried to look at whether or not it could decrease the risk of prostate cancer 10 percent within 3 years.  In summary, this is not really fully released data.  It was a nonsignificant trial.  So that's sort of a medication version of prevention.  

And then in our annual meeting, there was a long clinical trial that looked at selenium supplementation, specifically at people who had a biopsy that showed PIN.  I can show you pictures of it.  It's just a biopsy finding, these abnormal clusters of cells.  They're not invasive so to speak, but they're commonly seen on a biopsy.  Now, one of the important clinical take-home messages of PIN is that you wanna be sure if someone's had an adequate biopsy because if they've just had, you know, a few cores and you find PIN, they really--they need to have 10- or 12-core biopsy to be sure they don't invasive prostate cancer.  And there are different architectural patterns and, you know, we can have our pathologists run through that.  So the background was they asked the question if you could find people with PIN on a biopsy, well maybe they have a future risk of prostate cancer and maybe we can give them the supplement and try to erase that risk.  And this was conceived a long time.  It was even conceived before the SELECT Trial that looked at the prevention question also.  And so they got a repeat biopsy.  They took either the drug versus placebo for 3 years and at the end of—and actually this was a sort of an older data, so they mainly had 6 biopsies instead of the modern 12—at the end of the trial, they had well-matched groups, even vitamin E use was similar, and basically identical diagnosis of prostate cancer.  And in fact, the key mode of incidence when you plot out those curves we've seen in other slides, they just--they superimpose each other.  So in summary, selenium for prevention, even among people who may be at high risk based on their first biopsy, it didn't seem to be protective. 

It was interesting, however, that within 3 years of diagnosis of PIN, 35 percent of patients did later develop prostate cancer.  And that was seen in another paper presented at our annual meeting that showed that if people had multifocal, meaning multiple biopsies, with high-grade PIN over several years, you did see a slight increase in prostate cancer.  So perhaps the story is not over.  Maybe there will be other prevention strategies.  They could look at this target as well as the others that are well--the other well-known targets of course are African-Americans have a slightly higher risk and obviously first-degree relatives, your father or brother, might put you at higher risk for these strategies. 

So let me just try to close the loop on a common question that comes up, which is prostate biopsies and what happens after them because this--just to give you the whole picture.  If a man has an elevated PSA and gets a biopsy, well some of them have cancer and then of course, they get treated or observed.  Now, but what's in the middle of that--and this came up last year, because I think some men that attended this conference because they may have had a biopsy and it was not normal but it wasn't cancer.  It was either PIN or it was atypical suspicious, and some of these men are still confused about what to do, and I don’t blame them, it makes sense.  The current data is that if you just have PIN, we probably just need to screen you very carefully over the years, but there's not a specific intervention we can do outside of all the lifestyle changes we've already talked about.  However, if someone has atypia—suspicious findings—an immediate repeat biopsy is probably the best strategy.  So that's the simplified version of that. 

But the other question is just to show you what happens to people who don't have prostate cancer on a biopsy.  It's interesting in that some of the men, their PSA will go back down to normal.  And believe it or not, some of the men on our active surveillance trial who get put in observational course, when they come back in 6 to 12 months, many of their PSAs have gone back down.  So there're some men that get some inflammatory-type situation.  Their PSA bumps, they get some biopsied, then whatever it is kind of settles down on its own.  It's either that or if men are told they have low-grade prostate cancer, perhaps they skip the McDonald's drive-thru habit and you know, they do change their lifestyle, maybe that's why their PSA comes down.  But even some men who have a bump and get a biopsy, maybe there're some hidden lifestyle changes.  Now, some men will have a remaining elevated PSA, and maybe it goes up a little bit with age, and the point is that some of these men get a second biopsy or some of these men get the other PSA test that the gentleman asked about.  Sometimes the free-to-total ratios help us figure out who to do a second biopsy on. 

And then there's a--the most frustrating category is folks who their PSA just keeps going higher and higher and higher and, believe it or not, some of these men do not have prostate cancer.  They just leak a ton of PSA, and some of these men have had 4 and 5 biopsies over the course of years, but the problem is—and it's around 20 percent, maybe, cumulative—some of these men really do have prostate cancer.  I have one in the hospital right now that basically has what I call an upside-down prostate cancer.  Meaning, it grows on the roof, and it was a high-grade tumor, and you can't biopsy it unless you really push the needle in pretty far, and by that point, the man had had 4 negative biopsies, and his PSA was 30.  And then by the time we figure this out, it's locally advanced already.  So there, I mean, anecdotally, those patients drive a lot of other men getting a whole lot of biopsies to satisfy chasing this blood test forever. 

So these are some of the clinical dilemmas we face.  So in summary, for chemoprevention, yes, we can use the 5-alpha-reductase that comes with dutasteride or finasteride, there are some side effects in the high-grade debate.

^M01:50:07

>> Supplements, I think, is still only something you would--I would say only do in a clinical trial. 

Now--and this is just my own take.  As a surgeon, let me just give you the take-home message that because of the--all these issues of prostate cancer, I've had to become a little bit of an amateur nutritionist and an amateur personal trainer.  So I know I am a professional at this, but that's why I brought the speakers out ahead of me, to show you that it's all relevant to some--even for someone who's in the OR most of the week.  So a colleague of ours at the University of Michigan has this great slide that talks about what if we did have a prevention agent that decreases Alzheimer’s by 25 percent, colon cancer, depression, erectile dysfunction, heart disease, osteoporosis, premature death, and prostate cancer, the cost varies and the side effects or addiction in orthopedic injury and that of course is exercise.  So I mean, that kind of blows away.  [Laughter]  All those numbers blow away even if you thought the finasteride trial was an absolute smashing hit because that only solves one problem, creates another, and ignores the rest of your health, and that's my way of looking at it. 

Other trivia, just a take-home message as we wind down, cardiac disease is still the number 1 cause of death in men with and without prostate cancer.  Again, that's why Dr. Sahai was invited and basically as he drove home, all cardiac measures that help with that also help with your prostate cancer.  So in simplified, all the stuff your doctor is telling you is correct.  It helps your prostate.  They don't crisscross or coincide.  So really, the--your whole team care needs to include nutrition health, primary care physician, smoking cessation if needed, as well as the urologist downstream, and here's my two-cent guide to what Dr. Sahai was talking about, learn to count calories: you know, you either gotta burn it or quit taking it in.  So for burning it, you burn 50 an hour on a couch, 80 an hour in bed, at least during the non-sleeping parts, 100 an hour fast walking and, if you want the benefits of going to a gym and doing those ellipticals, is it counts your calories as you go on.  And if you're really huffing it, you should be getting 600 an hour.  And the other thing I have noticed on my own math, if you lengthen your workouts beyond 15 minutes, that's when it really adds up.  You can spend your first 15 minutes getting up to your target heart rate.  If you stay there to 30 minutes and 45 minutes, that's when you really can make a difference on the weight loss that he was talking about. 

And in terms of cutting it out, most dietary tricks--he put 500 a day, other experts have told me even 200 calories a day helps--and every diet book in the Borders bookstore is basically a trick to get you to lose 200 calories a day, and you know one method makes you count them, other makes you--you know, load up on proteins and feel full earlier, but count your calories.  I mean it's interesting, some men read some studies that made--that seem like pomegranate juice was gonna be the amazing prevention agent, so you started drinking pomegranate juice.  All right, that has 200 calories per serving.  Beer has 70, you know, light beer.  [Laughter]  So I mean, again that comes in the category if you might solve one problem but you're gonna create 5 more, if you start drinking in 2000 calories a day of pomegranate juice.  Anyway, diet soda's free, coffee and tea are free.  So--and I love this website, if you ever noticed that Lady Gaga, if you look at her in this picture, kinda looks like the alien in Independence Day. and by the same token, a 5-layered burrito kinda looks like a clogged artery.  [Laughter]  So, if Dr. Sahai didn't motivate you, maybe that can.  And there's a whole website devoted to funny things that look alike.  It's mainly making fun of celebrities, but I thought I'd finish up by talking about a topic that may seem totally backwards for this conference, and that's testosterone, because it comes up all the time. 

We take away prostate cancer--you know testosterone from prostate cancer, but there's plenty of ads out there telling you to go on supplements to boost it up, and I don't know if you listen to sports radio, half the radio ads are probably related to that.  Let me just tell you a little bit about the complexity of the male hormone, and Dr. Logothetis of course outlined it brilliantly, but just to go over, there's 3 sites of where this goes on, or at least 3 starting points.  The hypothalamus is in your brain.  It sends a signal down to the pituitary gland, right underneath it, and that sends out a whole host of hormones that affect your reproductive organs, your bone, your adrenal glands, your thyroid--you know everything basically that's--I mean, endocrinology is its own subspecialty in medicine.  For the male system, in simplicity, the hypothalamus tells the pituitary to make its hormones.  Those hormones go through the bloodstream to the testicles that stimulate testosterone, and all of these have a feedback loop.  So the body has sort of a thermostat, if you will.  If it feels a lot of testosterone, it will tell the upstream signals to calm down and vice versa. 

What we've learned over time is that there such thing as sort of an “andropause,” people will call it, that as men get older, the testicles start to kind of produce less and less testosterone that can have some effects on aging.  And some men actually come to the doctor with various complaints, and if you measure their hormone levels, it will correlate.  And let me just give you an example of how complex this is.  My father is an endocrinologist, actually, and I remember him telling me of experiments about in the '60s, they would measure testosterone on boys going through puberty to try to figure out the timing and the importance of all this, and they noticed that if you just bring a boy who is right in the full throngs of puberty and measure their testosterone in the office, its actually normal.  It's the same--not normal.  It's the same as a 6-year-old boy.  And so they were trying to figure out, how was that possible when they're--you know, they're growing like a weed.  And it wasn’t until they developed some sleep study models, well they have actually measured testosterone once an hour for 24-hour period a day, that they realized that it's because they make it at night.  So if you've ever wondered why your teenage boy sleeps all day on a Saturday morning, it's because their testosterone is through the roof and the body is like, you know, stay asleep, and that's why they're growing.  During the day, their levels are the same.  Actually as adult males, we have somewhat of a similar pattern in that the body spikes testosterone and then it comes down and then it goes up and down and up and down.  So we know to measure it, in the morning is a more accurate measure than late in the day.  And in fact hormone therapy for prostate cancer is actually--we superstimulate the upstream pathways into a continuously high level, and that confuses the testicles, and they quit making testosterone, in simplified terms. 

So let me just give you a summary of things about what we do and don't know about testosterone and some guidelines, and then we'll have some question and answer.  We know, again, that removing testosterone in advanced prostate cancer causes regression of the disease but it does not cure it.  We know that long-term suppression has all kinds of side effects, more than we've ever even known up until the last few years.  Bone risk, cardiovascular risk, muscle loss, weight gain, sexual dysfunction, hot flashes; you can measure cognitive dysfunction, depression.  We know that, again as mentioned, testosterone is necessary for prostate growth and cancer growth.  In fact, even when babies are developing from the embryonic stage, you know, the testosterone is required to convert the organs into the male.  The--if actually--if you have--there's some interesting enzyme deficiencies where they block the male hormone, and so the default setting is you have a female fetus, even if they have a Y chromosome; it’s kind of an interesting variant.  And we know that it’s interesting--and this may seem contradictory--there are subsets of men who chronically have low testosterone, and if they get prostate cancer, they're more likely to have a higher risk of it--not the risk of getting it but a higher grade, if you will.  So perhaps these are the more resistant clones growing. And on the other hand, we know that if men have symptoms of low testosterone and you give them more testosterone, you actually get measured benefits in energy, perhaps sexual function and others. 

But there's a lot we don't know.  We actually don't know that if we supplement men who have low testosterone back to normal, we don't know if we're increasing their prostate cancer risk, even though it seems like a dangerous thing to do.  You know, in theory, we shouldn't be hyperstimulating it either.  And of men who have sort of that low, semicastrate level of testosterone, we don't know that supplementing it will reverse risk of cardiovascular disease or all the other host of problems that men who were castrated on purpose can have.  And then an ongoing question is whether or not you can actually give testosterone to a man with prostate cancer who’s had a successful cure.  I will come back to that.  So--and I think is one of my highlight slides.  There are--I mean, look at that, two full columns of things that low testosterone can lead in terms of signs and symptoms.  And you know, again it ranges from sexual function, energy, differences in body hair.  I mean some of these are more objective versus subjective and you can read through--and there's a reference there to the guidelines this is from.  So what this group, this Endocrine Society--well let me come back to that.  In summary, there are lot of signs and symptoms a man can have of low testosterone.  There's a very plausible way to treat it, but there's very little high-quality evidence about the overall long-term effects of that, especially vis-à-vis prostate cancer.  And actually there's a bit of a concerning precedent.  There's a whole body of literature about replacing estrogen in women, and again, that--again fell under the category I mentioned of it might've solved one problem, but it created others in terms of their risk of having vein clots and cardiovascular events.

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>> So, here are just some take-home messages about what the Endocrine Society is recommending for testosterone, even though it's based on sort of weaker forms of evidence.  They certainly do not recommend just screening the population for low testosterone levels, and certainly not treating just because someone does have a low level.  You really wanna have clear signs and symptoms, and you wanna have a low testosterone repeated on a morning measurement, and there's actually a free testosterone level you can use to referee sort of low-normal cases, and those are men that can be considered for treatment.  But note that there's actually a workup involved.  This should not be something you do at a health fair, where you just measure a testosterone and mail it to somebody, because some of these patients actually do have pituitary or hypothalamic gland dysfunction that actually needs treatment.  So I mean, this is--this is something needs a professional evaluation.  They do give you a nice table of--there's a number of ways you can supplement testosterone.  They're all seemed adequate.  I think the most common is to use either a gel or a patch 'cause it gives you kind of physiologic up-and-down levels.  The older injectable forms are still available, but they tend to make the levels go through the roof, and then you have a huge crash in the next few weeks. 

What about erectile dysfunction and fertility?  At least with erectile dysfunction, fixing the testosterone by itself is usually not enough.  You certainly need to work the man up for erectile dysfunction, and then you can separately diagnose and treat androgen deficiency as needed.  It is worth noting that fertility—especially if the patient has hypothalamic or pituitary failure—often correcting the testosterone can restore fertility in the younger man, but if they have more of a testis failure problem, then there'll be less success.  And it's interesting that the age-related declines in testosterone may be mixtures of hypothalamus--you know, sort of your brain hormone function versus the testicular function.  And what about as related to prostate cancer?  They clearly recommend not using it on men—there's such thing as men with breast cancer—or prostate cancer, and there's a number of useful guidelines for the--and this is where it comes up in the clinic, is if someone does have symptoms of low testosterone and they get evaluated, often that probably should possibly include prostate cancer screening, and you need to look at their levels, look at their hematocrit, work them up for sleep apnea or other things that testosterone supplementation can be at risk for.  And then what they've recommended are some PSA metrics, so if they have more than an increase than 1.4 over the first year, they should be considered for a biopsy, and there's some other velocity calculations needed.  If men are at risk for osteoporosis due to chronically low testosterone, that needs to be screened for and looked at.  But notice up here, the patients need to be reevaluated and screened every 3 to 6 months.  Hematocrit levels have to be monitored, PSA and testosterone.  So again, if someone starts on testosterone, you're not done.  It's kind of like getting on cholesterol medications, they have to monitor liver functions in that type case.  So it does require an ongoing set of visits. 

Now, at MD Anderson, our personal thought is that there again--there's no strict guidelines recommendations on what to do with cancer patients and testosterone.  Our practice patterns have been if someone has surgery, and they have contained cancer with clean margins and undetectable PSA, we consider testosterone supplements, if they otherwise would qualify in terms they have legitimate signs and symptoms, they have low levels and, you know, after a period of treatment, they actually get better.  We currently cannot recommend it after radiation or cryotherapy because it interferes with monitoring the success of the treatment, and we've had limited use of actually using it on an active surveillance.  Again, if normal patients can be on surveillance for a low-grade tumor and they have normal testosterone, then why can't we supplement people who are low, especially if there are other health-related concerns. 

So again, that's my bulleted summary of a little bit about screening and testosterone.  And that brings us to the end of our scheduled time, so maybe if we'll have Curtis come up, and why don’t we just sit here and go back and forth with all these questions.  Thank you.

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