Prostate Health Conference 2012

MD Anderson Cancer Center
Date: October 2012

>> Okay, good morning.  Just a show of hands, who's been to this conference before?  Repeat?  Good.  So we’ve got a core group of folks.  You know, this sort of grew out of mass screening with the actual PSA test and been more of an educational event and we try to vary the topic each year.  Let me invite to the conference table with me, Dwane Broussard, he's from Village Family Practice.  And I'm just going to try a slightly different format where I'm going to update you on some of the research with PSA screening.  Dwane is with one of the large family groups in town. From a practitioner's standpoint, we always wonder, you know, what's the impact of PSA screening and some of the recent controversy in the family practice.  Usually, when I see patients they've been screened, diagnosed, counseled—often multiple times—and then we see them, so please join.  And, you know, so we'll go through some of these slides and we'll pause in a few places and have Dwane give us some of the perspective of what it's like to be, I guess you'd call on the battlefront of the screening controversy. 

In many academic teaching circles, we have to disclose and I think it's a good exercise anyway.  I do do research with Genprobe which has a PCA3 marker and Janssen that makes abiraterone and consulting for some of the new tissue diagnostic companies like Myriad.  But beyond that, it's just interesting I just put raw percentages on scope of practice, anytime people talk about prostate cancer, they bring their own personal viewpoint and professional practice to that and you'll have a diverse array here from academic urologists, radiation oncologists and family primary care.  So I do about half of my time is in the operating room doing robotic prostatectomy, a growing percent probably 20 percent is now active surveillance, 10 percent screening and diagnosis and 20 percent research and other activities. 

So these are the objectives for this portion of the agenda.  So we'll try to differentiate populations at higher risk for prostate cancer, outline some of the strategies for screening, when to start and when to stop, connect some of the relationships between how a treating and treating the correct groups have been prostate cancer can impact over a value of screening.  And then what we're going to start with is this last objective understanding the strengths and weaknesses of the current randomized trials. 

Most of the media sound bites have been a little bit negative, this is in USA Today, with some of the trials coming out, where some experts will just be—very bluntly state that the PSA test is not worth the risk.  There are some structured analyses of why they come to those conclusions.  My favorite bullet is where they state that up to 1 in 200 men die after prostate cancer surgery, and we're working on a paper that will show with revised techniques that's more like 1 in 4,000.  So possible we don't take it lightly at the same time.

So we know that prostate cancer is out there and some of it is high grade.  This is a sort of pivotal study of man who volunteered, many in settings like you may be in where--where they were offered, do you want to go on a prevention trial with a new agent, this is called the PCPT trial that used finasteride then the follow-up to that study was the selenium vitamin E trial.  So at the end of the PCPT trial, they biopsied everybody.  So you see that even if you were not on the active drug and had lower levels of PSA you saw anywhere from 6 to 25 percent had prostate cancer and 12 to 25 percent were high grade and this is sort of a take home message slide that there's really not--no such things as a normal PSA, rather a range of risk and there's always a potential for high grade.  So how much effort you want to put in to finding these is what needs to be refined. 

The resources available to you and us will be summarized here.  There's the 2 randomized trials that we'll go over.  Almost every organization that is a stakeholder in PSA screening has a consensus statement if you would—AUA is American Urological, there's European, National Cancer Comprehensive Cancer Network, American Cancer Society, and you get a range of recommendations. Most of the treating groups say to treat, ACP says to do counseling first, US Task Force recently issued the controversial opinion not to screen. Interestingly enough the NCI still does not have a consensus statement.  And the family practitioner, maybe you want to comment—Dwane, is this actively discussed?  AAFP, in my understanding, is against screening, or perhaps education at best.  What do they discuss in your array of meetings?

>> Yes, the American Academy of Family Physicians is still looking at all the information that was presented.  But at this point they're recommending not screening.  That initial paper did come out, but most of primary care doctors are continuing to screen and following one of the other position papers that are listed there.

>> Okay.  Well, how I'm going to flow from here, let's--I'm going to update you on the two trials and then at the end of it we'll go with the NCCN guidelines because what--how they're constructed is they have about a six page document of talking points of the pro and con of screening.  At the end of the document, it's actually at the beginning, is a flow chart of a basic “how to screen” if you want to do it aggressively.  So let me just--I'll--we'll go over the highlights from that.  Those are publicly available if you just go to nccn.org, you can sign up for an account, and you can download them yourselves.  

So both--a couple of years ago, at this conference, Curtis Pettaway gave the nice initial introduction to the two randomized trials.  Since that meeting, both of those trials have been republished with more follow-up.  This is the European study and I think it's interesting and somebody, who can read the fine print on the left?  I can never tell on the slide.  I'll read you the numbers.  This--the left is called a CONSORT diagram.  I think it's an interesting exercise to just run through the numbers and maybe Dwane can comment as well of the effort it takes to do a screening trial.  So if you go up the top box, they screened a hundred--or they invited 180,000 men to do screening.  So when you think of the effort of hiring staff and personnel in multiple European countries just to go through 180,000 men who would be potential candidates to randomize between a screening strategy versus a non-screen strategy.  You flow down to here at this level and you end up with the two groups, roughly a little over 70,000 men told to screen, 70,000 not to screen, it's actually a little higher.  And then you flow down here to what happened to them.  So in the screening group you got about 6,900 prostate cancers, of interest 60 percent of them were low grade, 21 percent intermediate, 7 percent high grade and only 2.6 had metastatic disease at the beginning, you know, when they were screened basically.  And then this flows down to here, where you end up with 13,000 men died of any cause during follow-up and 299 died of prostate cancer.  So repeat the drill, you went from 180,000, divided men up at the end of the day, you had 299 men died in the screening arm.  On the other arm is the non-screened arm, they had about 5,300 cancers, it's a little skewed towards higher risk.  For example 12 percent were high risk and 8 percent had metastatic disease, so slightly more than the screened arm.  And at the end, 17,000 men died of any cause and 462 or .5 percent of the total died of prostate cancer.  So you end up doing all these calculations from an enormous population down to a few hundred men that died of prostate cancer and drawing conclusions about whether screening everybody, you know, drove that number.  And it is statistically significant, you do get, you know, roughly a 20 percent relative reduction in prostate cancer deaths.  There's ways to express that as absolute or relative.  The commonly quoted number when they first published this trial was that you had to do about--the number needed to treat was 1 in 48.  So you treated 48 men, you spared 1 prostate cancer death with a few couple more years of follow up, that number is decreased as I'll show.  So, yes you can put this on what's called a Kaplan-Meier curve this is just a graph where you go for years of follow up, 2, 4, 6 all the way out to 14.  The blue is the screening group for cumulative risk of prostate cancer death, not all cause.  And a little bit higher in the control group.  So here it is, this is NNI is the number needed to invite to screening, number needed to diagnose and treat, these decreased from 110 to 136 for the number needed to invite and the number needed to treat or diagnose went from 48 to 33.  The assumption is that, as you get closer, perhaps to 15 and years beyond treatment especially in younger men, the benefit could increase.  But clearly there's overdetection and overdiagnosis.  Any comments on this trial, does this?—or maybe I'll go through the—let me go through the American trial then we'll just see what you and your partner's take—what your take-home message is. 

The second trial is called the PCLO Trial, it got published as a negative trial meeting, they diagnosed more cancers, but they didn't diagnosed--they didn't spare any more prostate cancer mortality.  So again, another big trial, they randomized 76,000 men, you allocate those into two groups and you end up with 158 deaths in the intervention or screening arm and 145 in the observation arm.  And so here, you'll see the Kaplan-Meier curve, yes but you got a separation of diagnosing prostate cancer.  But on the bottom you see basically overlap of mortality.  So this was considered a negative trial.  Now that trial has been critiqued up and down every meeting, it's sort of old news at this point, but I'll just summarize the critiques.

At 44 percent of the men had PSA testing before the trial and the assumption being that you've—you'd already pulled out the worst of the cancers potentially before you started the study.  Only 40 percent had a biopsy when the PSA went up. 52 percent of controls—people who were not supposed to have PSAs still had them.  One report stated 85 percent had at least one PSA at some point.  So, the spin from the authors to their credit was that adding organized annual screening to a widespread opportunistic screening had no effect.  The more severe thing that Dr. Walsh from Johns Hopkins put into an editorialize, I'll just read this quote out, he argued that this was not even a randomized trial of screening because of the above critiques.  But regardless of the—how you interpret that trial, all that effort has to be weighed against biopsy side effects.  There is a risk of sepsis, bleeding and discomfort, treatment side effects and then overtreatment of low-risk disease.  So, Dwane, what were your thoughts on—what was the message you all got in your professional circle is about, you have a positive study with overtreatment and then a negative study and now what to do?
>> The most important take home message is that when you're talking to your doctor, despite all the research that's done and everything else, there's still an individual treatment that needs to be applied to you.  This is a very personal thing.  So when numbers come in from your blood test results and you have your PSA number, there is a lot of information that sort of goes into how we analyze that PSA.  What risk factors do you have?  What were your previous PSA readings?  Was this just a one-time elevation because of inflammation, or you had intercourse the night before, or something else, you had an infection at that time?  So looking at that one number is not all that actually goes into what decisions are made to refer you out for treatment.  So how do we look at this?  We know that the PSA is not a perfect test.  So we take the patient into account, the entire situation that you're in and then decide how we're going to follow up.  And, you know, the treatment options are again individualized.

>> Is it common, you know, for a man that go through all this and then actually state no screening is the decision, or is it more common to say screen but, you know, with a little more caution perhaps than in the past?

>> Most men want to get screened.  I think that just by evidence of the number of people that are here today, that are, you know, here to get more information.  Most of men are interested in knowing what their PSA number is and what their likelihood of having prostate cancer is.  The question is how many patients that have an elevated PSA don't actually have, you know, prostate cancer which is the worst fear that patients have.

>> Okay.  Let me go to another study that came out.  It's been out in abstract for a year or so, but the final publication came out this summer.  It's called the PIVOT Trial, and it's connected to this.  So if you're going to screen, you're going to find cancers and then you're going to treat some of these, probably a lot of these, and you'd like to know that this is better than either choosing not to treat it or maybe not even finding it the first place.  So this was an older trial, as many of the randomized trials were, where they sought to compare surgery to observation.  Most of the bulk of this effort was done in the '90s and then this past decade the bulk of the effort has been, of course, follow-up to draw the conclusions.  So the primary objective was again effectiveness of surgery versus observation, but in the PSA era, and there will be some discussions in another study where they, it was an even older trial where many of the men were diagnosed before PSA came out in the same kind of design.  They concluded that surgery actually did not reduce all-cause or prostate cancer–specific mortality.  In a subgroup of men with higher-risk groups there was a potential benefit.  Now, is this the definitive study to go by?  And obviously the devil’s in the details.  So if you go again to this same CONSORT diagram, in this trial they started with 13,000 men mostly at Veterans hospitals, those 44 VA sites, 8 NCI sites.  So from 13,000 men they got down to 5,000 that were eligible, and 4,200 decided not to do the trial.  So they were left with 731 men to pair into the two groups.  So you had 364 supposed to do surgery, 367 supposed to do observation.  Without going into the numbers, about 20 percent of the men didn't do what they were randomized to do.  So then, you're down to 80 percent of that actually did what they were supposed to do.  So you're down to under 300 men in each group with all that follow-up. 

So looking at the bullets on the right, and again those are the sites. Of interest, it’s wide open eligibility, they took any clinically contained disease with any PSA as long as it was less than 50, age 75 or less, and they--you had to have a judgment call that you were going to at least live 10 years.  They wanted to accrue 2,000 men and they got less than a thousand.  So, they had to repower their study.  You know, in some studies if you're really under-accrue, you just have to close the study and it doesn't get released.  So they were kind of in that in-between zone where they could still finish it but without as much statistical power.  So without doing a statistics course, so I'll just say that they had 90 percent power to detect a 25 percent relative reduction.  The way the laws of statistics go, the bigger your delta, or the difference you want to prove, if you want to prove a 50 percent or a 100 percent difference, then the fewer patients you need. If you want to prove a very tiny benefit, 5 or 10 percent, then you need more and more people.  Obviously if you want to prove perfect, you know, then it's almost infinity.  So they did get a mixture of risk groupings from low to intermediate and there is a lot of details about whether or not the pathologist at the site made the call versus a central pathologist.  I think what was more important is that the median age is 67 of the average age at start.  The median age for surgery here is usually about 60.  You know, with people older they tend to do more surveillance, more radiation.  So for a surgical-treated potential group, this is a little, this is several years older than the average.  And so, no surprise, this was a negative study.  Over here you see death from any cause, or death from prostate cancer.  You see it's more common to die of any cause.  Now remember, they were supposed to live 10 years, and I guess one of the interpretations from my angle on the trial is that only half the patients that were supposed to live 10 or more years did.  And so that just means that we're not as good at predicting longevity as we'd like to think we are.  You know, probably 95 percent of those men thought they were good for longer, but you never know.  So there is also what's called a "forest plot" where you can look at all the subsets of everything.  You're looking for trends, and basically the one at the bottom there is a slight trend towards the benefit in intermediate- to high-risk cancer.  Obviously this is—now you’re down to comparing like 40 or 50 patients in each arm once you do subset analogies when the total set is less than 300.  But let's just go to the critiques since we are in a summary mode, but the study does support the notion that the benefit of PSA screening is not just across-the-board automatic, but rather it’s subsets, it’s younger patients, it’s patients with more intermediate- to high-risk disease.  But it's also important, I would say to young people, the study has neither the youthful cohort, nor the statistical power to say that they don't have a benefit of having surgery over observation, so you almost have to keep both the conclusions possible.  And actually what I look as a surgeon is the sort of the “what if's” of the study.  What if they actually did have 2,000 patients? 

What if—actually more importantly—what if they capped enrollment at 65 instead of 75?  So they would have had fewer people dying of other things along the way.  And what if they actually had a detailed plan for observation, you know, at this conference we've had Jeri Kim and others talk about active surveillance.  And active surveillance is really a three-part plan: who goes on it, what are the monitoring plans, and when to come off of it.  In these types of studies that were done over 10 years ago, it was sort of like you went on observation and no one really knew what that meant.  What was the plan?  I think in modern times you would—you could actually tell patients that, you know, we're going to watch you carefully and treat you if it changes, and we do that all the time.  You see me up, I'm up to 20 percent effort on surveillance.  What's—Dwane, I'll just pause there and ask what's been your observation about the—any changes in active surveillance in the patients from your practice that end up getting diagnosed in counsel.  Have you seen more of that?  What are the questions they come back to you with about whether or not I should automatically treat versus, you know, take that surveillance route?

>> Right, no, there have definitely been more patients that are under watchful waiting, or active surveillance.  A lot of this has to do with the discussions that the patients are getting, are having with their urologist.  And how comfortable they are with the information that's presented to them.  You know, there was a period of time, you know, 10 years ago where we hardly saw anyone wanting to just, oh I’ll just, you know, I've been diagnosed, I'll just kind of watch and wait and see how this is going or my PSA is continuing to rise and I'll just watch and wait and not have any—you know, any radical procedures done.

So, this speaks a lot to the improvements that the American Urology Association has made and in sort of figuring out which patients are appropriate for watchful waiting and which patients are actually comfortable, you know, with actually having this done.

>> Very good.  All right, let me for time go ahead to—let's just go to the guidelines.  So, that's—those are some of the controversies, the pro and the con.  I do want to spare time to go through sort of the take-home messages of how to screen, since I'm keeping myself to 30 minutes and let the other speakers go.  So, assuming that someone wants to do screening, you know, with all the cautionary tales in there, the NCCN has a nice guideline: the take-home message actually is to start an initial screen at age 40, preferably with an educational component with it.  And the idea is that if the baseline screen is low, and actually the number you'll see is less than 1, then you can actually skip to the age 45.  And if it's less than 1 at 45, you can then screen again at age 50.  So you get a few baselines between age 40 to 50.  The exception would be at 40, African-American race, family history of prostate cancer, and like those type things.  If you're at elevated risk, then maybe at 40 actually go every year, or if you're 40 and your baseline is already greater than 1, you probably should go every year.  If you're greater than 1 at age 40, you're already in the upper 70 to 80th percentile PSA for your age.  It doesn't mean you need a biopsy, but it may mean—you're in the youngest category that potentially benefits from screening, so maybe start the clock now.  On the other hand, if you're over age 75, you really got to be careful in that age group.  The benefit you saw, and you'll see in other trials and discussions, the benefit of screening and treatment over age 75 really goes down substantially.  And you almost can't measure that at the population level.  Obviously an individual man with phenomenal longevity who are to be diagnosed with a Gleason 8, you know, high-grade cancer, could potentially benefit, but it's going to be washed out by many men where it's going to be more side effect.  So, no one is, you know, everyone hates to say you can't be screened when your birthday turns 75, but that's the age to start thinking about the benefits. 

There's a great—I don't have it on the slide—there's a very useful study out there from a guy named Vickers in New York.  He looked at a large data set and found that if your PSA is less than 1 when you're 60, your lifetime risk after that is quite low.  It does—he didn't necessarily say stop screening—but it's—I mean so that's one thing that's not out there in the literature as much as there are some good parts of screening.  If your PSA is low, you probably feel pretty good about that.  If you go back to that first Europeans trial, yeah, they screened over 180,000 men to get those deaths.  Well, a lot of those men were told, "Hey, your PSA is normal, go about your day,” you know, so there’s some reassurance, and most men who know that probably know their cholesterol panel point by point.  So, then your health maintenance can benefit from that.  So, other little tricks in there if someone's velocity, especially in the low PSA, is greater than .35 per nanogram, per mL, per year, that may be an early sign of prostate cancer.  You can use a slightly higher velocity for PSAs 4 to 10.  Dwane, is velocity a practical thing you all keep track off formally or informally?

>> No, absolutely, and if we start to see the numbers rise, we'll find out if there's a reason for—try to find if there's a reason for that rise that can be explained, like I mentioned before, you know, sexual intercourse the night before the PSA is done, or if there's an infection or anything like that.  And then we'll bring patients back in to see if the numbers have come back down, but we definitely do look at the rate of rise of the PSA.

>> And always tell your doctor what medicines you're on—if you're on finasteride or Avodart—then really you have to double your PSA and keep track of it that way.  All right, so, bullet number 2.  Now, obviously if the rectal exam, the prostate exam itself is abnormal, then you would biopsy probably regardless of the PSA number.  Again, if the PSA is low at a young age that can be an indication to skip some years.  Now, if the PSA is over between 2 1/2 and 4, that's when we start considering the biopsy or if that velocity triggers, and we will see referrals from family practice where PSA was 1 last year and this year it's 2.2.  So, yeah it's below the threshold of 2.5, but it took a big jump.  And so, if that's a young guy that may be a case—obviously we always repeat these, you don’t go right to the biopsy suite, but you're clearly going to evaluate for that possibility.  There are risk calculators that slightly improve the screening but, many of those risk calculators require knowing the precise three-dimensional volume of the prostate.  So, the flowchart of it would be kind of odd in that you'd almost have to—ah, your PSA is high.  You'd almost have to go to the ultrasound suite, put the probe in, measure the prostate and then take the probe out and then have a discussion about whether or not we're going to do biopsies or not.  So, everyone talks about calculators.  I'm not sure anyone actually uses them, but the—you can slightly improve the odds of a biopsy being positive by incorporating them.  Generally we don't use free PSA as a primary screening tool, meaning if you’ve never been biopsied, but if you’ve already had a negative biopsy, then these are the ranges.  Greater than 25 percent would say to consider deferring biopsy; under 10 percent, if it's very low, would be an indication to consider a second biopsy.  So, I'm sure you see free PSAs.  Do you all measure those yourself or is that mainly something you see the urologists get later or...?

>> No, we'll do it if the PSA is between 4 and 10.

>> Okay.

>> We don't do it if it's outside of those ranges.

>> Okay.  As the PSA goes up, if someone hasn't been biopsied or sometimes the first PSA is already 8 if they haven't screened, you know, earlier in life or so to speak.  You certainly consider biopsy.  The only difference for example, if someone’s first PSA were 15, yes, you do a biopsy, but then if that one is negative you probably do a second biopsy with a slightly different scheme.  So, whereas if they got biopsied at 2.6 and it was negative, you’d probably just watch that for awhile and see if it goes up before triggering a second biopsy.  So, that's the only difference in what the total PSA is like.  Now, often—it was interesting when we—often sometimes have more or less time for questions, but a common question from this conference was, what if I have PIN, which is prostatic intraepithelial neoplasia, or atypical suspicious finding...something—bottom line is I had a biopsy, doesn't have cancer but it's not normal either.  It's one of those kind of “what if's” kind of biopsies.  So, if it's atypia, suspicious, we usually would repeat the biopsy within 6 months, because that patient is at risk.  And if they just have the PIN—prostate intra—it's a mouthful—prostatic intraepithelial neoplasia—if they had a sort of a limited biopsy, you do a more substantial 10- to 12-core. Or if they have multiple cores of PIN, you might consider repeat biopsy.  And what's different on the guidelines is a little bit more imaging integration, meaning you consider repeat biopsies with transition or and top of the prostate sampling and what's actually new down here that I have been doing myself is that if someone’s had two negative biopsies and the PSA keeps climbing, we used to go to the OR and do a saturation biopsy, literally 50, 60 cores with a three-dimensional grid plate. 

Now, we're doing MRI exams.  And often the MRI will show us areas of abnormality.  And there's two ways, and we're not there yet, but there's two ways to use the MRI moving forward: one is the MRI will have a software package that will show you the abnormality on the ultrasound and then you use that in the office to target the biopsies.  Or another software package being looked at is the MRI itself.  You get kind of metal-free equipment and go to the magnet and the MRI guides the biopsy into the target.  So, we may have some better ideas than sort of being Texans and drilling for oil in multiple spaces.  So, it's good for you all too.  I'm 44, at some point I'll have to say it's good for me too. I have been too young for this for awhile, but I'm getting into that early.  I’ve had my PSA checked since the last conference, in case you're wondering about that.  So, now, interesting about NCCN guidelines.  Again, no one could agree on the significance of the randomized trials, so you get tons of talking points and commentary and that's worth reading as well. 

Well, the time is upon us to move to the next speaker.  There's a number of cases that we'll do at the final hour.  Probably what we'll do for questions is when we get to the 11 o'clock and then all the speakers will just kind of hang out and do the individual questions 'cause those move on.  So, Dwane any last parting, take-home messages for the audience from your perspective?

>> No, I just want to say that I do understand how frustrating it is to hear different medical societies have different sets of rules and guidelines.  And, you know, we feel the frustration as physicians and you feel it as patients.  So on behalf of the medical community, I want to apologize for that.

>> Very good.  We appreciate having your perspective, I think that it's more balanced that way.  So, we're going to go next to on the agenda, we have a new faculty member, Will Graber, is here.  And he is a general urologist who joined MD Anderson.  You might wonder why do we need a general urologist at MD Anderson.  Well, trust me, we're big enough, we desperately need help because there's a ton of other urologic issues that go on at a big hospital even if you're focused on cancer.  One of them is benign prostate hyperplasia and related urinary symptoms.  So I asked Will to address, obviously, BPH, as we call it, in abbreviation.  But also from the perspective of what if a man has both.  And we do have to manage men who have urinary tract obstructive problems and they have prostate cancer.

Now, obviously it's easy if its high grade and you're just going to take everything out.  But sometimes it's low-grade prostate cancer that doesn't need radical treatment, maybe you just address the BPH either with medicines or minimally invasive surgeries and monitor—so I sort of gave Will a wide template to sort of look at the possibilities that he sees in the clinic when a man has literarily two problems to manage.  So, Will please join us, and applause for Dr. Broussard, thank you.

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>> Okay.  Thank you guys for showing up on a Saturday morning.  I appreciate that.  So, I joined the faculty in December and I take care of, like John has said, a lot of patients who have so-called benign or general urologic problems.  Many of these are men with voiding complaints.  Many of them have been diagnosed with prostate cancer and are deciding what to do for treatment and their voiding complaints, their prostate size together can have an impact on that or perhaps they need—those problems need to be addressed before they have treatment for their prostate cancer or they may have had prostate cancer treatment already and have developed voiding problems and that needs to be addressed as well. 

So, the term that we're going to use today a lot is LUTS, lower urinary tract symptoms; it's a relatively newer term in the medical world, old terms such as prostatism, or bladder outlet obstruction are—have been supplanted by a more general and noncommittal catch-all phrase of lower urinary tract symptoms and that is because—just because a man has a prostate, and which we all do, and he has voiding difficulties does not mean that those difficulties are due to problems with the prostate. 

So, what sorts of things may cause lower urinary tract symptoms?  The most common thing is prostate enlargement or BPH.  You can also have bladder neck obstruction; the bladder neck is where the bladder and the prostate are joined, and what it is supposed to do is to remain closed when you're up walking around.  It remains closed when you ejaculate, but it's supposed to open up nicely when you urinate, and sometimes it doesn't do that, and that can cause obstructive symptoms just like benign enlargement can.  Urethral strictures can cause voiding difficulties; the urethra is the tube that passes through the prostate and then on out the body.  If you have a scar anywhere along the length of that, you can have symptoms which might mimic BPH obstructive symptoms.  Cancers can involve the prostate or can involve the bladder and create lower urinary tract symptoms.  You can have an extrinsic mass, such as a rectal or colon cancer, or even constipation which can cause obstructive symptoms.  There are any number of neurologic problems that can cause voiding complaints.  How the bladder works is really a very complex interaction of neurologic signals from the brain that involve the spinal cord and receptors from the bladder.  It's so complex that it doesn't take much from a neurological standpoint to make that go awry.  Infection, inflammation, any number of medications, and then food and drink can also have an impact on voiding symptoms. 

So, BPH stands for benign prostatic hyperplasia.  Hyperplasia is a proliferation of normal cells, and with BPH it's a proliferation of not just the glandular component of the prostate, but also what we call the stromal component, which are the cells which surround the glands and then kind of intercalate and go throughout the prostate and around the glands, including smooth muscle cells.  This is just a diagram of what comparing a normal prostate with what happens with an enlarged prostate, and on the image on the right, you can see the prostate just in general is enlarged.  BPH typically involves the part of the prostate that surrounds the central part, where the urethra passes through the prostate, and when it impinges on the prostate, that's what can cause obstruction.  Embryologically, the prostate is actually derived from the urethra—it develops from the urethra and that's why they're so—they're intimately associated.  It's a very common problem, BPH, or condition at least. Half of us are going to have some degree of BPH by the time we're 50, three quarters of us by the time we're 80.  Of those of us who have it, up to half of us are going to have some degree of symptoms from that.  And because it's such a common problem, you've got doctor’s visits, medications, surgeries, complications of BPH, it's an expensive problem, costing 1.1 billion dollars annually in the U.S. 

So, when a man comes in and he has lower urinary tract symptoms, we start of course with taking a careful history, and we do a good exam.  That exam will be augmented by checking urinalysis.  We do want to know a man's PSA, even if a man were say disinterested in prostate cancer screening, it's important enough to check a PSA in that sort of a setting that I would encourage a man to get a PSA.  We would also want to check some chemistry such as check of kidney function.  We use a variety of imaging techniques, we would ultrasound the prostate and we ultrasound the bladder, we ultrasound the kidneys to see if there's any signs of obstruction of the kidneys.  If there is blood in the urine, what we call hematuria, we would likely want to do a “CAT” scan to look for problems that may be causing blood in the urine, such as a bladder stone or a kidney stone or cancers.  I was going to say, we can also use cystoscopy, which is passing a scope up into the bladder to look around; that gives us a very nice assessment of the anatomy of the urethra.  It basically will rule out a urethral stricture or identify a stricture.  And it let's us get a sense of how big the prostate is and whether or not there's any overtly obstructive tissue.  Looking in the bladder also is important because we can find things like cancers, stones, diverticuli, which are outpouchings of the prostate, and kind of get a snapshot of the way that the bladder has been impacted by prostate enlargement. 

Urodynamics is a tool the we don't use in every man, but we use it to help get a more objective sense of the way the bladder is working.  That involves passing a small tube into the bladder, we fill the bladder up with a solution, measure the pressures inside the bladder as it fills, and then some of the important information we get from that is measuring the pressure in the bladder and the flow out of the bladder as a man urinates.  And that sort of dynamic can let us assess whether or not a man is obstructed or if he's not obstructed.  And sometimes we'll use a medication trial.  We'll put a man on something like Flomax just to see if it makes a difference, for two reasons.  One is, it might make such a big difference for him that he wants to continue taking Flomax indefinitely, or it lets us know if he responds and gives us some insight as to what the problem is in the first place, or if he doesn't respond, that's information as well. 

So, the treatment of LUTS—medications—many of you probably are taking some of these medications now.  There are alpha blockers; these are medicines that relax the tone of smooth muscles within the bladder neck and within the stroma of the prostate.  Flomax and Uroxatral are two of the more common ones.  There are medications that will shrink the prostate; these are 5-ARI agents, that's 5 alpha reductase inhibitors.  And what they do is to inhibit the conversion of the hormone testosterone into DHT or dihydrotestosterone, which is a more biologically important hormone that helps stimulate and maintain prostate enlargement.  There are overactive bladder medications, which we call anticholinergics.  You'll see them marketed often towards women, but we use them very commonly in men as well.  And we use combinations of these medicines as well.  And then there's the category of phytotherapy, which are medications or at least compounds that are derived from plants.  There is some discrepancy in the medical world about whether these things work or not, but the more scientifically rigid assessment of them is that they just don't—there's no general consensus that they do any good.  That's not to say that I would tell a man not to take them if that man feels like it's doing those—him some good, but I would—I don't think I've ever, ever initiated phytotherapy in any patient.  You know, these agents can be marketed however they want. They’re—not intended to diagnose, cure, or treat any disease, as you know, and these agents have not been evaluated by the FDA, but they have been evaluated by Hulk Hogan [laughter], so there you go. 

Okay.  So, there are a lot of procedures that are available, that have been developed to treat men who have LUTS.  They can generally be categorized into those which are extirpative, meaning we're actually removing prostate tissue, and those which use any variety of energies to—forms of energy to shrink, scarify, necrose, or otherwise make a prostate kind of withdraw from the impingement that it has on the urethra.

And so you may have heard of a number of these; we'll go through them a little bit later in some other detail.  But among the minimally invasive treatments there is TUNA, where you stick needles into the prostate, and radiofrequency energy is used to heat the prostate.  Microwave thermotherapy is where an actual microwave antenna is placed so it's straddling across the prostate, and then it heats the prostate, just like you heat a cup of coffee, to a point where the prostate cells can't survive.  And as they die and atrophy, the idea is they shrink away from the urethra to take away the obstruction.  Some of the surgical things that we have available—the kind of the old standard—is the transurethral resection of the prostate, or the “Roto-Rooter,” a great operation has been around literally for decades and for a long time was the second most common procedure done in men in the United States.  There have been, though, a large industrial and medical effort for us to try to present procedures that can provide the same sort of efficacy as a TURP, but with less impact.  Less what we call morbidity—less time in the hospital, less catheterization time, fewer problems with bleeding—and many of these are very good.  Common ones that we use are transurethral incision of the prostate, and that's good for small prostates where we just make incisions in the prostate rather than actually scooping out the prostate.

There are any number of vaporization procedures where the prostate tissue is not removed, it’s just—it's vaporized in situ, so that the prostate tissue turns into gas bubbles and tissue fragments.  A common thing that you've seen probably advertised is what's called the “green light photoselective vaporization of the prostate” which is a very nice operation. Lasers are also used, the holmium laser enucleation—that's like a TURP done with a laser.  You can use laser to also vaporize, a holmium laser to vaporize the tissue, that's a different sort of a laser from what the PVP is.  And then an open prostatectomy is where we make an actual incision in the lower abdomen and we will use often our fingers to scoop out prostate tissue, and that's a very nice operation when a man has a very large prostate and we think we'd be better served by an open procedure.  So as Dr. Davis alluded to earlier, a lot of men have LUTS, a lot of men have prostate cancer, and often the two will impact one another, either as a man is looking forward to making decisions for treating prostate cancer, or after cancer has been diagnosed. 

So there's a quality-of-life study in 2008 that looked—that followed men who had been treated either with radical prostatectomy, radiation therapy, and either the form of brachytherapy implant, where radioactive seeds are passed into the prostate, or with external beam therapy.  And men with—who had large prostates, it found that there was a worse impact on quality of life in men who had had the two forms of radiation therapy, versus men who had had a radical prostatectomy, who actually had an improvement in their quality of life.  That might seem easy to believe if we have good operations to reduce the bulk of the prostate to treat LUTS, then removing the prostate to treat cancer will also address the LUTS.  So for men who are choosing either not to have a prostatectomy, or they're not a good candidate for prostatectomy but are seeking treatment with radiation therapy, prostate size, the degree of “symptom bother,” or the degree of LUTS is very important in the decision that's—or in the process of getting the radiation.  We want to try to control that as best as possible prior to men receiving radiation therapy so that they have fewer problems after treatment.  If you look at those two forms of radiation therapy between brachytherapy and external beam therapy, there's a relative contraindication to doing the seed implant in men who have larger prostates or more significant voiding complaints—a greater degree of LUTS—because of the propensity for that to worsen more with brachytherapy implants than with external beam therapy.  We will often make sure that men's prostates or—and their LUTS are addressed before radiation therapy, either with medications, or possibly with surgery before they enter into treatment with radiation. 

So, many men have been diagnosed with prostate cancer at TURP or they have had a TURP prior to the diagnosis of prostate cancer and so what happens when you radiate those men after a transurethral resection?  It’s feasible, it's safe—you can see a higher incidence of what we call GU toxicity, or problems related to the bladder and voiding with men who had had a TURP than relative to men who had not had a TURP.  But with time, those problems tend to settle out, such that those—that spread between TURP and non-TURP patients becomes less of a time, and those symptoms tend to improve with time. 

Many men, as we mentioned, will need to have treatment before they undergo radiation therapy.  This is a relatively small study, but it looked at using PVP or the green light laser to treat men before they had radiation therapy.  And it was found to—that the good results that you had from the PVP were maintained after the radiation therapy.  If you have a T-U-R-P after radiation therapy is done, so a man has had his external beam therapy, he continues to have obstructive problems, they're severe enough to where he—he either can't urinate or he needs to have something done, and if we've diagnosed obstruction, we can bring those men to T-U-R-P.  We do see a higher rate of complications in those men than we would in men who had not had radiation therapy.  And that kind of stands to reason just in general; throughout the body, the more things you do to an organ, the less well it will respond to the next thing that you do to it.  So if you radiate a prostate and then operate on it, or if you radiate a prostate and then perform cryotherapy on the prostate afterwards—anything that you do that's additive to the tissue, that hurts that tissue, you're going to see a higher likelihood of problems.  And so among—if you look at just all TURPs, you ought to have a—you ought to see a—an incontinence rate of 1 percent or less if you're doing a standard TURP, and men who have had radiation therapy and then have had TURPS, that incidence is higher.  And this particular study at the top of the page don’t say, higher incidence of incontinence if there is a shorter time between the radiation treatment that was delivered and the need for the T-U-R-P.  Also it correlates to the amount of tissue that's required to be resected; fortunately, this is not a very common problem, the number of men, these are 16 patients out of 1,230 patients, so a little over 1 percent. 

Another small study, this is from a urologist in Kaiser, showed no patients who had incontinence after T-U-R-P following radiation therapy.  So the idea is yes, we can do that, but we want to make sure that that's the right operation to do, and we wouldn’t be as aggressive with the resection as we would in men who had not been radiated.  T-U-R-P after the brachytherapy implant is also sometimes needed.  There is a higher incidence of complications with that, particularly with incontinence, than there is with external beam therapy.  So again, you would want to go into that sort of a decision carefully, make sure that it’s the right thing to do; those are men that we definitely would want to perform cystoscopy on.  In fact, my practice is perform cystoscopy on anyone that I would consider doing a surgery on.  And we would want to take just the least amount of tissue out that we felt was necessary to provide relief of obstruction in those men. 

Many men with prostate cancer that is advanced—many locally advanced, where there's a large amount of bulky, firm tissue in the prostate—have difficulties urinating.  And so these are problems really related to prostate cancer, not BPH.  But we can address them as well with the same kind of surgical techniques.  The anatomy is distorted usually in these situations, and so the TURP that we do or other extirpative procedure that we do is different from our approach in someone who has normal anatomy.  Our goal in this setting is to create a channel through which the man can urinate.  We try to do as much as possible without creating any harm to the patient.  In those patients, as you might expect, you are going to have a higher incidence of less-optimal results.  More men are going to have the inability to urinate after that than they would had they not had prostate cancer, more men are going to have incontinence, and more men are going to need repeat operations. 

There is—at the bottom of the page, there is another small study in men who—this is at with the community neurologist who used PVP to treat prostate cancer in this advanced stage—he was able to debulk the prostate by about 51 percent, which is actually a fairly significant degree of debulking.  This is not an uncommon problem that I—for which I would see patients at MD Anderson, because we unfortunately have so many men who have locally advanced disease. 

So among the different sorts of procedures, we have the TURP, transurethral resection, that’s considered to be the gold standard—usually that results in a 1- to 3-night hospitalization, always with a catheter, there’re varying degrees of bleeding that occur with that.

With time, as we've had improvement in the electronic circuitry and the function of the equipment that we use, it has become in general a safer and better operation, frankly.  The TUIP, transurethral incision of the prostate, is something that we use, as I mentioned earlier, for small prostates.  So a prostate that’s in the 30-gram-or-less size—most of us, say, by the time we're in our 25s—around in our—around age 25 are going to have small prostates that are in the 20-, 25-gram range—some of us will have obstructive problems as we get older without BPH, and if we do have those problems, it's often because of the bladder neck, and we will use a TUIP in that sort of a setting, generally with very nice results. 

The button TURP is a—is one of those vaporization procedures where we use a—what's called a bipolar electrode that at the surface—I'll show some video of this later—surface of the electrode there is kind of a plasma that develops around the—around the electrode, and it vaporizes the prostate tissues—it’s really pretty cool—and it does it in a—in a nearly bloodless manner.  And that's something that we do in men who are on blood thinners and they can't come off of their blood thinners—maybe they've got a prosthetic heart valve, and the balance between coming off and staying on the blood thinners would favor the latter. 

A PVP and the green light procedure is also—can also be used in that same setting.  HoLEP, which is enucleation of the prostate using a laser, is something that is effective for big glands, and it is just that not many people—not many people do those procedures, it's just not widely available.  So I have some YouTube video here that I can share with you if you like to see this, we are approaching the end of my half hour, but I think it's nice to see this sort of thing just to know what we're talking about as we discuss the options for—surgical options for men.  And if you'll just bear with me for a moment.

[ Pause ]

So this is a TURP.  This is the loop electrode that we use, this is passing through a scope up the urethra, and you'll see the loop is electrified, so it's using electrical current to slice through the prostate tissue, and every time it does that, it takes a strip of prostate tissue out, and that's done repeatedly to remove that enlarged prostate throughout the length of the gland.  And that tissue in the middle of the screen is the typical appearance of benign enlargement of the prostate.  So what you're ultimately left with is an excavated and what we call a fossa within the prostatic urethra.  So next we'll see a—well, I probably would.  That's a button TURP.  Relatively recent—I personally started using this about 2 years ago.  It's a nice procedure, and for me, this is my procedure of choice for doing a so-called lesser invasive TURP than a TURP.  And so with this, the—you'll see the “saucer” at the end, so rather than a loop electrode, you'll see a saucer.  Here we go, come on; I'm not sure why it's not playing, but I’ll have to just drag it along.  But as you see, this is almost live action, I’m having to drag this myself, but as this passes across the prostate, it removes prostate tissue but at the tip of that saucer is the plasma, and we actually do this with saline, because it's—that's just the property of it; nice thing about using saline rather than water, which is traditionally used, or something called glycine for a TURP is you don't have some complications of fluid getting into the prostate and into the bloodstream what we call a T-U-R syndrome.  But this is a very nice procedure and as this goes through—you can see it just generally results in less bleeding as the prostate tissue is removed.  Those patients are almost always sent home on the same day, generally with the catheter overnight, and they can remove those catheters the next day.  Okay, it looks like it's going live now.  So that's a—that's a button TURP, and it's a very nice procedure. 

And then we have the PVP, this is photoselective vaporization of the prostate, the green light, similar to the button TURP.  And this had been my favorite procedure for a while until I had begun to use the button TURP.  So this is, this uses laser energy to vaporize the tissue and tissue just—it just disappears, it turns into fragments and air bubbles.  But what you see there with the green light is that the tissue is a little bit ragged, it's less of a clean dissection than the button TURP, but it is very hemostatic, meaning bloodless.  It takes a little longer I think to do a PVP than to do a button TURP, and I think you can do a more complete job with the button than with the PVP, but it's still a very nice operation. 
Okay, and so that's the end of my discussion.  John, do you want to do some questions now or do you want to continue on with the schedule?

[Inaudible Remark]

Okay, thanks everybody.

[ Applause ]

>> That was great; great analysis.  So our next speaker is Chris Logothetis.  Now it's interesting, since a lot of you all have seen me do this before, I'm actually—believe it or not—the median in years of service in Urology; even though I started in '06 as the new guy, I'm already in the middle of the group.  That's how much we've hired, you know, in the last 6 years.  And most of the panelists that we invited are the people we've hired recently: Dr. Graber, and you'll meet Dr. Chapin and Dr. Papadopoulos.  But even if you put the four of us together, we wouldn't get anywhere near our next speaker, who has 36 years of service at MD Anderson—had a busy day yesterday, as the prostate program was selected as one of the “Moon Shots” for our—massive research effort to change mortality rates in some of the key cancers that we face.  I gave him kind of the catchy title of—what happens in the clinic is people bring in clippings from the Wall Street Journal, and they want to know about the latest drug, and now, let's be honest, guys, so I know some of you guys want to know about these drugs 'cause you might need to take them, but I think some of you guys just want to know what investments to make, and we know the difference.  So but nevertheless, there's a lot of activity in the Wall Street Journal that is ready for prime time, and some of it’s years away, and some of it, quite frankly, disappears after a year or two, and you wonder what happened to that.  So I asked Chris to sort of address, you know, the new drugs in prostate cancer—how they get reported—and without a doubt, he's going to put his own twist on the talk.  So Chris, still take your same 20 minutes, we'll adjust it on the [inaudible].

>> Okay, thank you.  So, thank you, John.  So, I actually tried to speak to the intent of what John wanted me to describe rather than use the exact same title.  So one of the big issues that I wanted to discuss is why are we so encouraged by the multiple drugs that come out, but when you look at the figures, the gains were actually very modest.  So what is—what is this sort of apparent disconnect between all this excitement of new drugs and the very minuscule advances in survival.  So let me tell you what the basis for—help me here—what the basis for that enthusiasm is.  So I'm going to take you through a set of theoretical calculations that are based on actual numbers and logical projections, so to tell you how to think of it. 

So in the last decade, there have been six new agents approved for prostate cancer, which is unprecedented, because in the 50 years before that, no new drugs had been approved other than those related to changing the hormonal profile of this disease.  But, the survival prolongation in patients with advanced disease for each of these drugs has only been 3.5 months.  So somebody, very recent people could argue, come on now, why are you wasting your time and your money for such modest gains?  So let me explain.  These are now the theoretical calculations—and that caution sign there is based on some projections, based on assumptions that may or may not be true, but let me try to describe.  If every patient was able tolerate it and benefited equally from every drug that was used, six new drugs—and I'm using round figures here for the calculations that are on the conservative side—rather than 3 months, it would be the 3.5 months, so 3 months.  Every patient would benefit from an 18-month prolongation of survival, right?  They would get six drugs for 3, so, actually, the development of these six drugs would result in an 18-month prolongation of survival.
Still, I would argue with the side effect profile with many of these drugs, rational people could argue, well, is that a big deal?  But if the response rate is 50 percent—50 percent benefit, 50 percent don't—then all the survival advantage gets allocated to that half of the patients who actually have benefit from the drug.  So it now turns out that half the patients get a 36-month prolongation of survival if they were to benefit from all six drugs that were available.  Now, you're starting to talk, if you only knew how to select that half that are going to benefit. 

Now, let's go to another theoretical calculation.  In the patients, for the purposes of safety and the like, we are asked to do these studies on patients with very, very far advanced disease.  The median survival, the average of survival treated on patients in these studies was 18 months.  So the prolongation—the survival would go from 18 to 54 months, which is 18 plus 36, which represents a 200 percent prolongation of survival.  So now the question arises, is it more important to know the absolute figure with which you will survive 36 months, or the percentage improvement?  If it's the percentage improvement, which is true with most of our drugs, and if the average survival of patients who are threatened from the disease is 5 years, were you to select them earlier?  If we now treat patients with a 5-year life expectancy and the percentage of life's prolongation remains the same, then life prolongation is 200 percent of 5 years: we're adding 10 years on for a 15-year survival for patients who, otherwise, would have a 5-year survival.  Now you're talking business, because when you take patients who are going to live 5 years and make them live 15 years, you take—because you take information that is provided and created in the very end stage and apply it earlier, a big portion of patients outlive the disease. 

But that's not where the excitement stops.  Imagine, if we knew how to effectively combine agents or anticipate the needs before it was clinically apparent, and let me describe what that means.  In every other disease type—bladder cancer, colon cancer, testicular cancer—the big success of adult solid tumor oncology that occurred—sort of the Lance Armstrong story—in the last 25 years, each of these drugs that are effective individually, when combined with reasonable thought together, complement each other in a way, synergize, and one and one becomes 10, and you cross a threshold for efficacy.  So it's not a quantitative and arithmatic improvement, but it's an exponential improvement if you only knew how to combine based on understanding the underlying biology. 

The other way you can shift from prolonging the survival of patients to crossing that threshold that you now start curing a portion of these—is to not wait for that biology, what that mechanism that drives the cancer progression to engage itself, but you give the drug that targets that mechanism in anticipation of its development, so it never occurs.  And that's when you start crossing the threshold of treatment to the threshold of cure.  So the excitement comes from properly selecting patients earlier, developing rational combination of agents that have a very meaningful prolongation of survival in the advanced-stage disease, and developing what we call markers that point to the need to anticipate and prevent this event from happening that could result in the lethal progression of the disease.  So the reality, which we are aggressively and focused on trying to address, is there are now more agents available than on the knowledge and how best to apply them.  So this is a big deal.  So we have played—placed—tremendous amount of value in developing drugs appropriately, so we need the drugs to go to the next step, and place less a premium on developing the “handbook” on how to apply these drugs.  Now, all of you know that there's a difference—that's why you go to some doctors and stay away from other doctors—because some people have an insight in how to use them, because if the effect was principally determined by the pharmacy—what drug falls out of the pharmacy and goes into your mouth—the doctor wouldn’t matter.  But we need to codify that and develop a strategy by which that knowledge is based on substance and can be verified objectively. 

So the focus of our effort to try to reduce the mortality of prostate cancer soon—now—or to try to change things quickly, is to develop strategies to effectively combine and anticipate the need for therapy, we must link the understanding of prostate cancer—what drives its progression—to the clinical decision-making process—daily—which means examining your tissues in a way that can actually inform and drive the decision making.  So this is called “precision medicine.”  You come in the door, and we don't say you have prostate cancer but you have one of eight prostate cancers, we study and examine the disease in a way that tells us which “flavor” of the disease you have, and we provide therapy based on that understanding.  We're getting there in a hurry, and as I'll show you, that's the basis for us being selected as a Moon Shot.  So the over thing—tried thing that we're trying to do is develop a marker-driven treatment, which is precision medicine, and we'll need to achieve this to accelerate the conquest of this disease, and we think we're prepared to do this. 

Now, I'm going to provide you some very, very pragmatic evidence on how—what's the evidence that we should place more a premium or an equal premium on knowledge as we need to do on developing drugs.  The focus is too much on “give me that fresh new lollipop,” rather than “which one do I need?”  All right?  So this is the typical approach to drug development, which is comparing drug A versus drug B.  And if drug A, the new drug, is superior, what is called a Kaplan-Meier survival plot actually shows the difference between one curve and the other, and that difference is what gets the drug approved.  The problem is, this is almost never a truth for any individual patient, because as you can see on the bottom, you can live for 12 months or you can live for 48 months, and the patient who lives less than 12 months didn't benefit form either drug, and the patient who lives 48 months may have benefited, and that's not shown up by definition on the average.  So the average outcome never is the truth for an individual patient by definition.  So selecting therapy based on average makes no sense—especially when the differences are so modest where that average is completely lost in the background when you see an individual patient.  So many years ago, we thought about this, and we said we've got to come up with a better way to how we study this disease.  So if you walk into a smart physician’s, you know, general practitioner, whatever practices the physician does—Dr. Broussard and his practice comes in there—what does he do?  He sees a patient—and this would apply to antibiotics, it would apply to chemotherapy, it would apply to any intervention.  He looks at the patient and he makes a judgment what the pool of therapies are that are reasonable for him, given that the patient's specific circumstance at that time.  And he picks one based on his experience in what he thinks the patient needs, and then he tests it, and either the patient derives a benefit, as is seen in box A, or the patient does not derive a benefit.  Then he adjusts—he may adjust dose, he may adjust schedule, or he may change to another drug.  So if we had a treatment approach that we actually blindly said we'll give you drug A because we don't know how to pick with an individual which one is best, you would want us to quickly make an assessment to do a single patient research and decide whether that's helping you or not.  And if it's not, we switch.  And then you go to drug B, and if drug B works, you repeat drug B again, and you repeat drug B.  If it doesn't you—and if you're benefiting, you persist with A.  If you simply count up the frequency with which we use a drug, the best drug will get used more frequently.

It's a very, very efficient “horse race” to help the patient: you arrive at the best patient for therapy and constantly enrich and pick the best therapy, because the one that's less effective will drop off the table each time; the one that's more effective will get used frequently.  So that's a strategy that was studied by Randy Millikan, and basically what we called it—many years ago, this is now 7 years ago now—called it the “GU scramble.”  We all sat down together and say, "Why do you pick that drug?  Why do you pick that drug?  Why do you pick that drug?"  And we're going to codify our behavior.  We asked patients who came in the door to sign up to get a random pick between four regimens.  And we set up rules by which they would persist with the therapy or rules by which it would be called a failure, and they would switch the treatment.  And we counted up the frequency with which drugs were used.  We were able to find the best regimen that was confirmed by other people who decided to do a randomized trial on the average and found a difference.  But more importantly, we found that the entire population—when you used a model that took four of these regimens that were used based on pragmatic rules on how you treat patients, rather than comparing A to B—lived longer than would have been projected based on a model that was developed by SWOG, a large research group that assembles information and says this.  So this took four individual drugs that come out of the same pharmacy that everybody else in the world uses—not produced any differently for us—but instead of comparing A to B, we said we'll put the patient at the center, and we will adjust our therapy according to benefit by the individual.  And the difference in survival was far greater when you apply knowledge to four drugs than if you compare A to B, indicating that knowledge on how to apply things—as every patient knows who comes in the door in search for the right physician—has an impact on how well you're going to do.  And our obligation is to codify knowledge, and it's not just the drug.  It's the drug—you have to have availability of that—and the knowledge on how to apply it.  And the difference in outcome is greater.  That's called “treatment science,” and that's different than drug development, where you're looking at the drug in the center to make sure the drug is safe and it works to some degree.  Treatment science is placing the patient in the center, which is what we're focused about, and trying to use the specific needs of the individual patient, so those drugs which are in our “quiver”—all those options—actually have a major impact.  So that's sort of the idea on how we think about things.  And this has evolved over almost the last half a decade. 

Now let me show you the evidence in the path forward on how we're trying to do it.  First, let me provide you the conceptual framework for taking what was [inaudible]—principally an empiric clinical approach, to now integrating the science of how prostate cancer progression occurs and what drives the development and what drives the lethality of prostate cancer, and linking it to the selection of drugs.  Since World War II, we have known that male hormones drive the progression of prostate cancer.  And suppression of male hormone production by the adrenal glands, or the gonads (the testicle), results in suppression of the cancer.  So this is the model where the production of the hormones at a distant site drives the prostate cancer progression.  In the last 3 years, even though there was evidence for this a lot longer, this new model has taken hold—that the prostate cancer actually never becomes or rarely becomes androgen independent but rather becomes a machine that starts producing its own male hormone when you deprive it of the male hormone that is provided to it by the testicles or the adrenal gland and produces its own machinery to absorb that and use it.  So what happens in response to the challenge that the cancer faces when you deprive it of male hormone, it produces its own.  And this is what's called “endocrine to paracrine transition,” and it's the milestone that distinguishes those “cancer wannabes”—those that are never able to do this—from the cancers that can cause problems; that is, those cancers that are enabled by their genetic machinery to adjust to the deprivation of male hormone by producing their own. 

Now, the other issue with prostate cancer is that prostate cancer is a very, very interesting disease, in the sense that even though it sits in your body for many, many years, through a huge portion of it natural history, it can only survive if it's in bone; it’s actually a chronic disease of the bone.  It is dependent on mimicking bone, is our hypothesis, to survive.  It actually has to act like bone to survive.  Now, we used to think that the male hormone production in the bone were different, but there's a reason that prostate cancer male hormone in bone is one, and that is male hormone is essential to the normal development of bone.  So this is a model system developed by Nora Navone but we have almost 170 of these now.  Where under the skin of a mouse—and you can see where that area is—we take a cancer directly from the patient—it's called a xenograft— we take the whole tumor, not just the cancer cells, we put it under the skin of the mouse and guess what happens?  That produces entire bone in the skin of the mouse.  When you examine that little tissue that the arrow shows at, it's actually bone.  So in order for the cancer cell to survive, it has to recruit from the mouse bone elements to come under the skin to support its survival so it does it, which is prima facie evidence, experimental evidence for our part, that prostate cancer has to mimic bone or some prostate cancers have to mimic bone to survive. 

So this is the model systems that we've proposed and published, which is the cancers which are those ones on your left that are unable to produce their own male hormone or interact with bone are cancer wannabes.  They’re the ones that we want to distinguish from the remaining ones because they are not able to threaten your life, and the biggest risk for those cancers, we believe, is the risk of overtreatment.  And we're rapidly trying to define these as non-cancers, so we can spare you the consequences of being diagnosed with a disease which may look like cancer but does not have the ability to cause cancer.  Then there's a group of cancers in between—in that box that's shaded—where most of them live throughout the long natural history of this disease where they depend on very specific pathways for their survival.  It's either AR signaling, or those things that drive androgen signaling, or those things that drive the development of bone.  And finally, the aggressive variant of prostate cancer which we have people examining is the one where the cancer cell itself has enough properties to overcome all those constraints on it and becomes very aggressive and those are the chemotherapy-sensitive ones. 

So what can we do about this now looming challenge, which is this endocrine to paracrine transition, meaning the cancer now can produce its own male hormone.  Here's what we can do.  So let me again try to put another model on this.  So imagine if a cancer has now has this ability, it engages in this what we call this “progression spiral,” which means in response to deprivation of male hormones, it for starts producing its own male hormones.  In responses, I'll show you, to deprivation of its own production of male hormones, it produces another hormone.  So there's a series of events that occur that the cancer progresses through this spiral.  If that spiral is wound loosely, the pitch is wide, for any of you that know anything about—it doesn't matter, if it takes 10 years to evolve, it’s a nonthreatening disease.  So the pitch—the rapidity with which it adapts to each of these—is what determines a prognosis or what determines the probability of you needing an additional therapy so we can anticipate and prevent the disease.  So the rapidity with which, when we give one therapy, the cancer adapts with a new way of overcoming it, that speed with which that happens is a determinant of how much therapy we need to do to make you live longer.  The turns, every turn, are what we call predictive; every time this turns, it means a new mechanism has taken over: a new molecular pathway, a new gene, a new protein, or combinations of these.
We have, as I will show you, evidence that we know many of them.  If we had a marker that told us this was happening, and if we had a drug—as we do—that told us when to do this, we would interrupt the turn of the spiral.  And that's what we're actually doing.  So this is called a progression spiral, the rapidity with which it turns, determines, you know, how quick we need to adjust your therapy.  Each turn tells us what new mechanism is driving this and points to what therapy we need to give.  So anticipating the turn of the spiral will lead to predictive markers that will be used to treat you.  And that's what—how we're going to develop this marker-driven approach that is the precision medicine that you need over time.  You need to be monitored not to just be told you're at risk, you need to be monitored so you can be told this is what you need to do to prevent your risk or anticipate the progression.  It's a difference between creating dilemmas and providing solutions.  So the pitch is prognostic, and if it gets shorter, then the cancers adapt quick, we need to worry about them, and that's how we progress. 

So the transition from DHT dependent, which is this endocrine-dependent tumor, to this microenvironment dependence—the term “microenvironment” is used to describe those events in the microcosm with which the cancer lives in that nesting bone—is what we're trying to understand, monitor, anticipate, and intervene on.  So as many of you who've been in our clinic knows, bone marrow biopsies in the GU clinic occur regularly, and the reason is we consider this as a chronic disease of the bone, and we’re refining our technologies to be able to understand minute changes in there. 

Abiraterone acetate is a drug—Zytiga, as it's now used—that blocks the cancer for producing its own male hormone, producing the male hormone.  So we wanted to ask the question, does it do what it said it was going to do, and when it doesn't work, why does it not work, because that would lead us to the next anticipation of the next turn of the spiral.  And what we were able to do is demonstrate that the androgen receptor here on your left, called AR, and CYP17, the gene that is responsible for producing male hormone in the prostate tissue, did indeed predict for benefit from abiraterone acetate, and equally important, its absence predicted for no benefit.  So we already have two groups of cancer.  One group that tells us this is how you predict that this turn of the spiral is going to be important in your selection of the drug.  And the other one predicted what we need to do next to anticipate the problem that's going to occur.  And both of them are by taking a peek at the bone marrow and looking at cancer cells in the bone marrow. 

Now, the other piece of that equation is the cancer cell not only needs to produce its own male hormone but it needs to get a very efficient way—called the androgen receptor—for sopping up and efficiently using that minute amount of testosterone or androgens in the tissue, very efficiently, it's much less, so it has to develop what we call a high-affinity receptor to do that.  MDV3100 is a drug that blocks that.  We demonstrated, it will soon be published, that the androgen receptor is in the nucleus, which normally functions.  But when you give this drug exactly as you would expect, that receptor, which can only function in the nucleus, immediately shifts out of the nucleus and goes to the cytoplasm, a place where it shouldn't work.  But guess what?  It attaches to other proteins in the cytoplasm, and that attachment to other proteins, which we have drugs for, predicts for the next turn of the spiral.  And we have drugs for that.  So the world is out there debating and scratching their heads, “Do you give MDV versus abiraterone, and is there a 2-nanosecond difference from one or the other?”  And I would argue that that's interesting for some people but not for us, because what we can show is that the androgen receptor goes down, shifts from the nucleus to the cytoplasm when you give MDV, and male hormone level goes up in the bone marrow, as exactly as you would expect; if you blind the body from being able to see testosterone, it assumes it doesn't have enough, so it desperately produces more.  If you give abiraterone, you have the opposite event: you completely deplete testosterone, but the androgen receptor says, "What am I going to do?  I need to search for tiny amounts of testosterone,” and starts getting more aggressive and increases.  So we need to give both.  And that's actually what's happening in our clinic today: we've resisted the temptation of going from A to B, and we've said, "We’ve got to put the patient at the center: person who needs A, we need to give A; the person who needs B, we need to give B, and if they need to give both, we have to develop ways of giving it safely, giving both.”  And that's the active trial that's ongoing for patients whose disease has spread. 

Now, as I suggested from that theoretical calculation that's out, giving the drugs earlier may have a difference.  So we gave abiraterone early—I'm told time is limited and we'll go—and what I can show you on your right is total disappearance of cancer in the prostate, even in Gleason score 8 and 9 occurs, if you give these drugs before surgery.  So it's near PCr.  So that's a news threshold; it indicates going earlier makes a difference. 
So now we have a trial that will open up soon here, for patients whose PSA recurred, which is a “curative intent” trial.  We want to deplete every cancer cell from the bone marrow of patients under the assumption that a subset of patients have cancers that mimic the prostate and when its disease has spread.  And this is the ongoing trial of MDV plus abiraterone.  And we're now moving that quickly to the preoperative setting to try to control the disease from surgery, and I'm trying to go through, and these are patients for high-risk disease not for those patients with low-risk disease.  And we are confirming on 180 consecutive patients the findings that we had that the androgen receptor and the gene that produces the testosterone were important.  So this is the model, cancer wannabes through the progression spiral and finally altered cell cycle, which we'll go quickly, which indicates if they become chemotherapy sensitive.  Just to convince you, and I'm going to go through this quickly, we have other targets like we did 3 years ago, had ways of interrupting that progression spiral with those drugs.  This is a drug that blocks another pathway—FGF and Src—and we can show now in patients whose disease has spread that the portion have undetectable PSA concentration for greater than 2 years, even though the disease is spreading, it was castrate resistant with the use of some of these drugs.  Admittedly, this is a minority of patients.  But imagine if we could predict who that minority was in each group. 

And this is the large trial to now anticipate the next turn in the spiral and try to interrupt it.  Now why we need your help: we need you to participate in trials because these patients who signed on this trial—and more than 120 have already signed—have agreed to do seven consecutive bone marrow biopsies throughout this time.  We've maximized, we do it efficiently—the nurses do it, the leukemia doctors do it, it's not an issue—we can now take this 1.2-centimeter in diameter core and get 120 slices out of it, which means we've maximized on our part the ability to extract the information.  But we want to be able to anticipate the turns of the spiral and do this. 

The final progression is that the cancer has altered sensitivity, and this is when we see new targets I'm going to go through; this is another turn in the spiral called FGF, found by Nora Navone in one of these model systems.  These are called co-clinical trials, where mice help us figure out what to do, and this is predicted by a mouse—that we did the experiment in a mouse and then applied it to the corresponding human.  And as you can see, in patients who had run out of therapeutic alternatives, bone scan improves, and then lymph nodes disappeared.  That's called the co-clinical trial, where we actually do the experiment on the mice and then quickly apply it to the corresponding human. 

I'm going to go through this last one, because this is complex, further, and I'm being told appropriately that I'd better get done quickly.  So let me get—so finally, there's an event that happens very late, and that's called chromosomal catastrophe.  This needs to be avoided.  These are the chromosomal changes when you transition out of the microenvironment defended for the—and these are not random events, but they drive the aggressive and lethal variant of the cancer that we need to avoid occurring.  That cancer is very chemotherapy sensitive and in fact, it's very sensitive to cisplatinum.  So we are developing strategies to identify that chromosomal catastrophe, which means it emerges from its dependence on bone, becomes aggressive, and needs chemotherapy early—probably 15 percent of the total, and we need to find those very early. 

Finally, we're unique here, and that's what the makes the “Moon Shot” possible.  We have a group of investigators here that have made all this thing possible and funding that made this science.  But particularly, I want to point out that in this meeting, it reflects our relationship with our surgical colleagues, who are not represented on this, who make a huge difference and have made many of these trials, and our radiotherapy colleagues and our pathology colleagues.  But most importantly, patients and families who've trusted us with their care and have bought into this vision that I think has a real chance of conquering this disease.  Thank you very much.

[ Applause ]

[ Pause ]

>> Okay, switch gears one more time.  Thank you very much, Chris.  So, you can see how the significance of prostate cancer goes through so many different environments.  You saw the—sort of the—what happens in the primary care office, what happens in the medical oncology location.  So let me invite my panelists to come on up.  And so, we're really going to go over now—the other sort of reality of prostate cancer, which is that when we think there's a localized cancer that needs treating, how do we go about that, what sort of state-of-the-art surgery or radiation?  And I need John and Seungtaek—yeah, come on.  So, the—so some of our panelists that you haven't met—John Papadopoulos is one that we trained.  And after a brief stint in private practice, we are lucky to get him back into our department.  He specializes in the regional care center at mostly Katy, and does surgery of course down at the main campus, and Brian Chapin we trained—both our new president’s from Boston, Brian is from Boston, so there must be something going on in Texas that's attractive.  So, we're glad to have them.  And Seungtaek Choi, down at the end, is our radiation therapy expert; he and I share a clinic on Tuesdays, so I'm used to interacting with him.  We've actually tried to give him this conference for years, and his busy schedule finally allowed that.  And hopefully, you're here next year 'cause last year we had a very nice—I’ve gone blank on her name—who came?  Quinn, yes, right.  Then she left.  So, hopefully that's not a prelude. 

All right, so let's do the quick case.  So, we'll try to—we will go a little bit past 11, then we will do questions just to put it in perspective.  We do want to challenge you with new thinking, new questions and then—but then at the end, we do want to, you know, answer the question the way you want them answered—asked and answered. 

So, Case 1: straightforward case, newly diagnosed, no pain or symptoms, patient 68, maybe has a little bit of cardiac history, you know, the cardiologist, you know, came to the scene and put some stents in, and good for another 50, 60 years.  Little bit of a weight issue—BMI 32.  Clinical T1c—that just means you can't feel the cancer—common staging denotation.  PSA was 2.6 but a year ago was 1.3, and that's kind of what Dwane and I talked about, where people sometimes jump into that threshold in 1 year.  Maybe they—you probably see where they skip a year and then all of a sudden it's up and you have to redo the calculation.  His father had prostate cancer, lived to age 84.  He was told he has to have surgery in the next 2 or 3 weeks ‘cause it's there.  Let's bring up Brian; why don't you give us some of your slides on how you would address this using the PIVOT trial and others?

>> Sure.  So, we've discussed some of this already.  But I'm going to just bring your attention to an older study that was also in the New England Journal of Medicine, from a group of patients from 1989 to 1999.  So this is, for the most part, prior to PSA screening, although in the last 5 years of this trial there was PSA screening.  Eighty percent of these patients had palpable tumors, the clinical T2 tumors.  And the group looked at overall survival, death from prostate cancer, and development of metastases.  Now, this is a—you've seen these Kaplan-Meier curves today—you can see a split between those three with a radical prostatectomy and those with watchful waiting.

>> [Inaudible] so they can see it.

>> Yeah, sorry about that.

[Inaudible Remark]

>> And equally with metastasis, there's a split between those who underwent treatment with radical prostatomy versus those who are undergoing watchful waiting.  Now, in comparison, the more recent trial that Dr. Davis discussed, and I won't go over in too much detail, but because we have limited time here, but essentially, it's the similar type of observation looking at prostatectomy versus those who are observed for localized prostate cancer.  And in this group, the overall majority had low-risk to intermediate-risk disease, and approximately 80 percent had the intended treatment as discussed, and the follow-up was about 10 years.  And in this, 48 percent died by the end of the study.  The reason I point that out, as Dr. Davis already mentioned, is that, you know, we're not very good at determining who's going to live for 10 years or more as the study deemed necessary.  And in this patient particularly that we—for our first case—the patient had a history of cardiac disease, has had cardiac stents, is 65, and although the average life expectancy for a man in this day and age in the US is about 82, I don't know that that's going to be the case for this gentleman. 
Now, if you look at the Kaplan-Meier curves we've already seen today, there's no difference in the observation versus radical prostatectomy in this group.  If you look at the forest plot, which basically, you look at this as a whole, then the lines cross the middle, so there's no difference.  However, if you do look at the patients who had higher PSAs or higher-risk or intermediate- to high-risk disease, there was a shift in the protective effect of prostatectomy versus observation.

>> All right, so let me go back ‘cause I have a few meeting notes to throw around to the panelists.  And so, John Papadopoulos, any other things you would want to work up or know about this patient—

>> Yeah.

>> —the way you would handle it?

>> I would like to know when his PSA rose to 2.6 if it was rechecked; I think that's important to never, you know, act and trigger a prostate biopsy just based on one value.  In this case, it's kind of neither here nor there because cancer was detected but, in general, PSA fluctuates, and if you recheck it, it can often go down.  I'd also want to know about the quality of his biopsy: did he get an adequate sampling of his prostate?  These days its standard to get 12 cores, and so did he get a 12-core biopsy?

>> Yeah, we'll say a 12, yeah, one out of 12 kind of thing.

>> So with one out of 12 cores being positive with a small amount of Gleason 6 cancer, we know this is a slow-growing, nonaggressive, nonlethal form of cancer.  So that's just something to keep in mind, so.... The other thing I want to know a little bit more about the family history; I mean, his father died of other causes and was treated for prostate cancer, but did he have high-risk cancer or low-risk cancer?—because sometimes this can factor into treatment decisions.  But this man doesn't need a bone scan or a CAT scan.  Those are very unlikely to be positive and it would be helpful.  And so what I typically do is just sort of frame the situation for the patient, you know, discuss his disease-specific risk factors, look at his life expectancy, and then you’d want to know a little bit more about what his goals and preferences are in terms of quality of life, and where he is with his baseline sexual and urinary function, and then you start to discuss treatment options.  And so for this guy, the options would be active surveillance, where we just monitor the cancer for progression; surgery, which could be done robotically or open; and then, here in our institution, they would also meet in a multidisciplinary prostate cancer clinic with a radiation oncologist like Dr. Choi and discuss the radiation options.
>> And Dwane, I'm sure that some of your patients may just go from your PSA to the urologist’s biopsy to treatment and then, you know, you see them when it's all been done, perhaps.  But I imagine there are some patients who come back to you before treatment and ask.  What kind of questions do they typically want your help with?—prior to any, you know, definitive treatment decisions?

>> Well, probably one of the most common questions is, should I go to MD Anderson for treatment? 

>> That was not a set-up. 

[Laughter]

>> No, that wasn't.

>> Okay.

>> But it's actually true.  What should I do?  As I mentioned before, there's quite of bit of confusion if you just start to look at what information is available to patients that they're trying to cipher through themselves.  And it really depends on the relationship that they have with their urologist.  So sometimes they'll come back in and they will ask, “Should I get a second opinion?”

>> Is there a particular body of literature or reading source that you find works best, you know, beyond with the urologists tell them—a book or website, or anything like that?

>> One website that we sort of use, especially for the screening, is American Cancer Society's website is the one that we usually recommend the most.  But most patients will come back in with a, you know, a handful of information that they've received from their urologist.

>> Then one question I just have for any of the panelists, maybe you want to start, John, is what's the most common misinformation that you hear that you often have to correct?

>> Well, one is the timing of things.  A lot of times patients, you know, they feel like there's a rush, a need to hurry and to make a treatment decision and that things are happening fastly—rapidly—but that's really not true.  Patients have time to gather their thoughts, take a step back, and learn about their disease.  There's really no rush; prostate cancer really evolves over a period of months if not years and even decades.  And the other that I get is you're talking to the patient about his specific cancer, his specific situation, and then he'll just say, "But I had a friend who had this” or “a neighbor who had that."  And what applied to someone in a different era of treatment who may have had a different cancer really doesn't apply to your situation in the majority of cases.  So those are the two things I think I get the most.

>> Brian, this is your summary slide on, you know, if the patient comes and says, “Should I have surgery?”  What are your comments?

>> So I don't think that there's any strong cancer-specific indication for this individual to have treatment, and that's supported by the trial, the PIVOT trial specifically, but I think things that we need to know in order to, again, individualize treatment would be the status of both the urinary function and erectile function.  If someone has significant, you know—this goes back to what Dr. Graber talked about earlier—if someone has significant urinary obstruction and needs treatment and has minimal or little erectile function, a radical prostatectomy could solve both problems without the unnecessary side effects of the erectile dysfunction which would be the case if they were going into this with full function.  I would direct this patient toward surveillance, and, for some people, the anxiety of a cancer diagnosis is a bit too much to take, and that's the thing that requires counseling from our side and also an understanding of what the disease actually means.  And again, we've all said this and I think it's been—it's come from every department today—is that this is a personal decision, although treatment is an option, it's not a—in this case, not a necessary thing that needs to be done but something that has to be individualized to the patient.

>> And then Seung, you had a few slides on patients who freak for a variety of reasons.  Maybe the case is slightly different—choose radiation—if you want to do your slide’s up here.

>> Yeah, sure.

>> I think—yeah.

>> So I think—the three techniques that we offer at MD Anderson for patients with prostate cancer really sort into two big categories, and one is external-beam radiation therapy, also known as XRT, and we have both x-ray therapy using a technique called intensity modulation, and proton therapy and brachytherapy.  And I would say that this patient really is a candidate for any of those treatment options given the information that we’re—we have.  I think that obviously, the type of radiation that we offer or the extent of the treatment that we give depends on the Gleason score, the staging of the cancer, and the PSA.  We also sort of differ on giving hormone therapy along with the radiation therapy depending on the Gleason score, the stage, and the PSA.  This patient should be able to get treated with radiation therapy alone without any hormone therapy.  That being said, I think this patient which—or who’d be considered to be a very low-risk candidate by the NCCN criteria—I think that could be offered really active surveillance and that's how we would recommend at this time.

>> So, yeah that's a—good summary point would be often, yeah, it's a long process but often, for new patients like this, little old, someone who's low risk for dying of prostate cancer in the long term, you know, between Seung and I, we’ll probably spend 1 to 2 hours going over, you know, individually going over the options.  And while we may not treat the patient now, we still talk about all the possibilities because there will be repeat evaluation as the case might change with time.  Let's do another—or I'll just do an example of how this could play out.  So in one circumstance, we may actually repeat the biopsy on this gentleman.  And the most common finding—over half the cases like this—the repeat biopsy will show no tumor.  So I'll say, John, what is—if the second biopsy shows no tumor, was the first biopsy a mistake, or did the biopsy cure it?

>> Maybe.

[Laughter]

>> Yeah, so that's sort of we alluded to the first time.  You want to make sure that the first biopsy was an adequate 12-core biopsy.  And that gives you a pretty good sampling of the prostate, but it could understage cancer and—meaning, it could miss an area of higher-grade or more cancer, and—but it can also pick up small amounts of cancer that when you repeat the biopsy, you don't detect the second time around.  So overall, this is favorable, when that initial repeat biopsy shows no cancer or at least the same amount or less.  That's actually a favorable and reassuring thing, and we don't see that uncommon, I think it's, maybe up to 30 percent of the time...

>> Yeah.

>> ...in these sorts of cases. 

>> Good.  This is Brian's couple summary slides.  So if you want to just summarize, you can probably see it [inaudible]—

>> Sure.  So for, this is just our active surveillance as well as one of the other leading center’s.  At MD Anderson, if you choose to undergo active surveillance, you under—will go—undergo a confirmatory biopsy, and this is typically within 6 months of your previous biopsy, as well as a PSA and a digital rectal exam every 6 months.  Rebiopsy is done yearly or every 1 to 2 years, depending on the findings, or for cause.  And Johns Hopkins is very similar, they do a prostate biopsy yearly until age 75.  Eighteen months’ separation if there’re two negative biopsies consecutively, and then a PSA every 6 months and a DRE yearly.  Now, the data to support the idea of rebiopsy or why you're doing a confirmatory biopsy is there's three examples I give here of papers that are published showing anywhere from 17 percent to 30 percent of patients were actually upgraded or upstaged by their biopsy—by their confirmatory biopsy—and that—or did not meet criteria for the active surveillance protocol.  Now, for predictors of risk for progression, alluding to what Dr. Papadopoulos said, a negative rebiopsy, about 11 percent of those would progress, where a positive rebiopsy, about 40 percent would progress, so it is something that can be used for the prognosis. 

>> And here's a variant of the case, where a gentleman had the first biopsy with tumor—tiny—so we went on surveillance.  I think Seung and I both did the consult, probably in '08.  And then the '09 biopsy was negative, with a repeat that '08 was negative; '09 was negative.  And we actually allowed him to skip '10; '11 was okay, but the '12 biopsy showed—I'm sorry, mixing cases.  The biopsies are still negative, problem is by the time we get to 2012, the PSA keeps going up.  And then where we started around 6, now it's 10.  But the biopsy doesn't show any difference.  So we got an MRI, which is starting to work its way into management, especially on cases where the data just doesn't fit well.  And now—I'm not here to poke fun at radiologists but often they'll give us results where, you know, they'd say this could be this or suspicious, what we just call, you know, equivocal language.  This is probably the most definitive MRI ever.  If you look to the bottom, there's an area of abnormal signal at the top of the prostate that they say is “compatible with malignant tissue until proven otherwise.”  Like wow, wow.  So we actually scheduled surgery on him.  This is not the initiative, this is actually a real patient who is in his 50s, so there's no—it's not a medical risk for doing a surgery. 

And that's what his radical prostatectomy looks like.  Dr. Troncoso, our pathologist, has basically drawn an ink line around what's a very dominant tumor at the top, a few microtumors.  And then, you know, a typical biopsy will start here at the capsule—the rectum would be down here.  You would start here and the biopsy would probably hit like that, and you'd miss this iceberg sitting on the top.  To the right you see his pathology.  He’s still in pretty good shape, the lymph nodes are okay.  A little bit of spread outside the prostate, but Gleason 3 plus 4; PSA is down to zero.  So there are cases where we start on active surveillance but, you know, the philosophical question—that you saw that those other trials address—if you just radically treat the entire low-risk—you know, prostate cancer population, you get mostly side effects, minimal gain.  We know there's a few bad actors hiding in there.  So the trend now is to just spend more effort with either repeat biopsies, imaging markers, and, hopefully, novel discoveries that try to hold those guys out of the population, and treat them and then leave, 'cause it’s roughly 85 percent of them are actually correctly diagnosed. 
I have this one slide that I'll throw out for John.  What—any comments on anxiety related to active—surrounds—it’s also for Dwane—do you have patients who can't do surveillance just because they just, you know, can't live with the thought of having an untreated primary?

>> Yeah, so anxiety...it's an issue, and usually the first time you meet a patient for a second opinion or right at the time of diagnosis, anxiety levels are definitely the highest.  Patients come to you with the mindset of, "Doctor, I have this cancer in me.  What do you going to do get it out before it spreads?"  And so I try to defuse that anxiety as quickly as possible.  And tell the patients that nothing is happening quickly here, take a step back.  We have time to gather the information, get educated, and make the best decisions.  So it's really important to kind of defuse that anxiety, but a man who is well counseled and is presented the data and who participates in a high-quality active surveillance program actually does pretty well from an anxiety standpoint, and this has been studied and published out in the Netherlands, where they looked at anxiety levels...
...9 months into active surveillance, and they found that it was favorably low.  And I would say that's what we see here at our institution, so.... 

>> Dwane, comments?

>> No, I agree with everything there.  The analogy I usually use is, “This is not like your appendix that's about to rupture and we have to do something right away.  So let's just take a step back, let's collect more information.  Let's wait and see how things are going to progress.”  You know, and patients’ll usually start to get a little more comfortable with that.  I will add that there's—then they sort of diverge.  Some patients are comfortable with watchful waiting and with the protocols that are offered to them.  Other patients will say, "No matter what, I want to have this removed.  I just can't bear, you know, living—knowing that this is there."  And again, it's not the appendix that's about to rupture, there's time to actually deal with those patients that have that level of anxiety.  But most of those patients will end up getting a prostatectomy at some point.

>> And these are just some more bullet points to review that, you know, some people have problems with biopsies—pain, anxiety, bleeding—and if you can't get tissue, it may not be safe to do surveillance—some people.  I will comment on age.  We still put young people on prostatect—I'm sorry, on active surveillance—if they have minimal disease.  The difference would be that you'll pull them off of it a lot quicker if their future data is even slightly more aggressive or as the older you get, the more—you want a more substantial change.  So I don't want anyone to think that surveillance is only for people over age—whatever you want to call it—65 or 70.  And there are occasionally people who are worried about insurability—maybe that will go away with the health reform act; we'll see. 

Let's switch gears a little bit.  Seung, I’ll read you the differences.  I think you can see, but this one is a younger patient, 55; PSA is 6.  You can feel a little bit of firmness on the exam; the Gleason is 4 plus 3.  It's in four out of six cores on the right, that range from 8 millimeters—would be like half the core—and down.  A SHIM score is an inventory survey of sexual function; 25 would be—you know, perfect, you know, showing off.

[Laughter]

AUA score is 20: that just means the patient does void frequently at night, daytime; it’s, it's a mixture of some of the symptoms that would lead to having Dr. Graber have a look.  And the volume of the prostate, 70—normal is about 20, you know, when you're—when you're teenage to 20's—and then his grew, 2 to 3 times enlarged.  So Seung, just comment on how this—what are the fundamentals of how this case is different from the first one.

>> What do you mean, from the first slides?

>> Yeah, yours are coming up anyway, yeah.

>> Yeah, so I think that this patient is different from case number 1 because he's a patient with higher-volume disease, as well as a Gleason 7 cancer which is 4 plus 3—as I guess you’ve probably all heard, that’s worse than a 3 plus 4.  I do think he's also young enough that he’s going to, you know, probably live another 20 to 25 years easily.  So because of that we would definitely recommend definitive treatment.  In terms of workup, I think it's somewhat optional.  But I think we at MD Anderson, at least the radiation oncology department, is going to write up doing additional staging with usually a CT scan or an MRI scan of the pelvis.  And that usually includes an endorectal coil to look at the prostate more carefully, as well as a bone scan.  And we usually use the information based on those staging studies to guide our treatment.

>> Do you want to—here’re some of the curves of—

>> Yeah, so— [Inaudible Remark] —this patient if he does—well, let me go back.  So he is not a good candidate for prostate seed brachytherapy or the implant for two reasons, and one is the fact that he's got an enlarged prostate of 70 cubic centimeters, which also means that he will not be able to get a good implant due to the—I will call it pubic arch interference or the bone in the way of the pathway of the needles to put the seeds in.  Also he's got some obstructive urinary symptoms already, which would be worsened by the actual implant itself—and may be at some risk for developing actual urinary retention requiring a Foley catheter after the implant.  So the recommendation for him for radiation therapy will be radiation therapy from the outside.  For these patients, we also recommend at least 6 months of hormone therapy to be given with the radiation, and the way that's given is usually 2 months before the radiation therapy, 2 months during the radiation, and 2 months afterwards—that recommendation is based on the study that you see on the graph.  That's actually a trial that looked at patients who got radiation therapy for intermediate-risk prostate cancer, getting either no hormone therapy with the radiation or with 6 months of hormone therapy given the way just described.  And when that study was looked at, and it’s an 8-year follow-up, there was an improvement in overall survival.  The patients who got hormone therapy did better, they’re more likely to survive after treatment, they also had a lower incidence of death caused by prostate cancer.  So once again, these patients, we tend to recommend hormone therapy given with the radiation treatment.  The only potential—caveat is that in patients who have multiple medical problems—heart disease, diabetes—those patients did not seem to benefit as much from the hormone therapy as the patients who did not have those medical problems.  So we do look at that, too, when see the patients.  But if the patient is healthy with no other medical problems, we definitely recommend hormone therapy with the radiation treatment.

>> And this was your summary of, you know, what we do in the clinic looking for contraindications to radiation.

>> Yeah, so when patients ask me, you know, "Am I candidate for radiation therapy?" I would say that most patients that we see will be a candidate for radiation treatment.  The only really absolute contraindications are—you know, when we advise against radiation—is when they have had radiation therapy to the pelvis.  If they have a couple of other medical problems, which are inflammatory bowel disease, which includes Crohn's disease, ulcerative colitis, we often do not recommend radiation therapy.  If there's any connective tissue disorder, like lupus or scleroderma, we often do not recommendation radiation therapy.  I also put some other contraindications that we still look for.  If you look, I think large prostate was mentioned before—if you have a very large prostate, usually 60 cubic centimeters or higher, we often can't do brachytherapy very well.  If you have significant obstructive urinary symptoms, then you may also have problems with both the brachytherapy and the radiation treatment.  And as Dr. Graber mentioned, we often say that if you have significant urinary symptoms, you might prepare to do any procedures first before the radiation therapy to optimize urinary symptoms or function before that treatment is given.  Because if you try to do the procedure after the radiation therapy, you might be at higher risk for developing side effects or symptoms.

>> You also—

>> Stop right there—

>> That was to bring you down the case pathway, so let’s—since we're short on time, what we'll do is we'll finish this case out two different ways.  One’s with the radiation plan, one with the surgical plan, then I’ll adapt from there.  Let's take this—take us down the radiation plan including this case.

>> Okay, so let’s assume that the patient got treated with radiation therapy and 6 months of hormone therapy.  I think that the hormone therapy does have significant side effects which do patients complain about; probably the two most common side effects I hear about is hot flashes as well as decreased libido and erectile function.  These are almost always reversible; usually what happens is that when you give 6 months of hormone therapy, in my experience, it takes an additional 5 to 6 months beyond that for the testosterone to recover.  So if you get 6 months of hormone therapy like this patient, it can probably take about 11 to 12 months to really recover, and that's when the hot flashes should go away, as well as erectile function and the libido should come back. 

There can also be some fatigue from both the hormone therapy and the radiation therapy, but pretty much all my patients are able to work full-time during the radiation treatment.  And usually what I recommend is they be as active as they can, because I’ve noticed that the more active patients are, they actually do better.  So I’ve had some patients who come actually worked out every day during their radiation therapy 'cause they couldn’t really do anything else while they're in Houston.  And they actually felt better after the radiation therapy or at the end of the radiation than they did that at the beginning of the treatment, so I think that being active really does help.

In terms of the PSA follow-up, the MD Anderson guideline is usually PSA every 3 months for the first year.  And usually every 6 months thereafter for a year or 2 years to number 4, and once you get to year number 4, we're going to once a year after that.  If you do get—if you do get a hormone therapy with the radiation, we often will get a testosterone level, too, along with the PSA to make sure that we know exactly when the testosterone has recovered.  'Cause usually what happens with these patients is the PSA becomes very low—often detectable with the hormone therapy—is this only tells us exactly what's going with the prostate cancer.  And usually when the testosterone recovers, the PSA comes up with it, which is not due to cancer, just a recovery of the PSA with the recovery of the testosterone.  So we follow both for those patients.

>> All right, and let me—let's see, we can play that out further but let's just—let's let Brian go over his, so let's take this down a surgical direction.  What are the basic options to go on through this surgically?

>> Sure, so I think the—this slide is specific to “node dissection,” clearly.  You know, one of the questions that you had discussed with the group here was, when do you do a node dissection, what does node dissection do for us, and what does it tell us?  And the options are clearly to do no node dissection, to do a selected or obturator node dissection, which was historically what was done.  And then the newer thought is extended node dissections, which takes the—a larger amount of nodal tissue out of the pelvis.  And really the question is, what are we trying to accomplish here?  You know, it provides prognosis if there's a node-positive finding, and clearly, that person is at higher risk of progression, and about 80 percent of patients will have some progression at some point if they are node positive.  Can we—by doing this, can we delay time to progression?  And in some consideration of cure, is removing a node truly going to provide cure?  And then obviously the drawbacks of—any time you're doing more intervention, there's more risk of complication.  Next slide.

>> Well, let’s go to your trial.

>> Yeah, we should.  So this a newer trial that came out this past summer, and basically it looked at prospectively followed patients who had extended versus standard node dissection so that obturator versus the extended node dissection. And what I found was that in low-risk patients, there was no difference in outcome.  Both patients had progression at the same rate.  In the intermediate- and high-risk patients, there was a statistically significant improvement in time to progression in those who had the extended versus the standard dissection.  So this, in addition to experience and other retrospective data, kind of it supports the idea of doing a no node dissection in low-risk patients, and if you're going to do a node dissection, an extended is probably better than a standard.

>> Want to go over about nerve sparing?

>> Sure, and a little bit on nerve sparing, just so you all understand what it all actually means.  On the left is a prostate cut in half, on the right is kind of a rendering of what the anatomy looks like.  On the right, the yellow is the nerve fibers—and then—if you can hit the advance button.  The red is the area of the prostate—and hit it again.  The blue line is where—if you are going to do a nerve-sparing prostatectomy, that's where the resection occurs, and if you hit it again, the yellow—hit it again—the yellow indicates the nerve packet.  So the nerves are a fine group of hairlike fibers that are in the 5 and 7 o'clock position on the prostate.  And if you're attempting to do a nerve-sparing procedure, you are basically carving that tissue off of the prostate capsule.  And clearly if that—if the cancer—hit it again—if cancer is within the prostate gland, that's not an issue.  If the cancer is abutting the nerve or if it's extending outside of the capsule—if you hit the button again—if you do cut along that blue line, you’re going to leave cancer behind and you're going to have a positive surgical margin.  So considerations for nerve sparing are—things that I consider—are the clinical stage of the disease, so if it—there's a palpable finding on exam; the volume of disease based on the prostate biopsy—the greater the disease and the potential aggressiveness of the disease based on the biopsy; and then more and more we’re using the endorectal MRI prior to performing any surgical procedures.

>> I think for next year, we'll have to do this carpus in 3D with glasses, and tumors will come at you, get you in the front row; you’ll have to be careful.  Just go over your path.

>> Just to give you an idea, this is again a prostate cut in half, and this is similar to the tumor that we were seeing on the cartoon, but the black dotted area is the cancer.  And if you were to do a nerve-sparing prostatectomy and the cancer is growing up to an end or through the capsule of the prostate, that would imply a positive margin, which is what you're seeing in this lower—C—portion, where the prostate cancer cells are actually abutting that or actually cut through on that black line. 

So in this case—here in the Case 2—you know, looking at risk assessment, there are nomograms you can use for risk assessments: MSKCC has one on their website which I use frequently actually just to give patients a number to look at.  But, essentially, this patient would have a 45 percent risk of capsular extension, meaning T3 disease.  So in performing a nerve sparing, you think about the physical exam.  On this case, you could feel a right-sided nodule.  I discuss with the patient, typically, the risks of a positive margin and what a positive margin would mean as far as their consecutive therapies.  I do tend to use an endorectal MRI scan in those patients that are interested in nerve sparing.  And then you can do sparing of one side versus both sides, and you can even do partial versus complete sparing if you feel that that's something that might accomplish what you're trying to do.  So it really depends on the individual patient again; it's not a standard answer to the question of whether or not you nerve spare.
>> So, since we're kind of short on time, I think I want to bring it to a summary—two slides.  What I kind of wanted to give you a sampling was, was sort of the process of analyzing a case, sorting out options, getting the right experts involved.  And depending on the particulars of the case, you may end up with a surveillance option, with a treatment option, or sometimes a combination-treatment option—if we had shown you a high-grade case, often there would be a combination with local therapy of the prostate plus a systemic agent. 

I think a take-home message might be a very simple three-step process.  Number 1 again is, do you need treatment or not?  And, you know that's often the focus of the first question.  If the answer is yes: now or in the future?  Then you very carefully weigh the pro and con of surgery versus radiation, and you can see how there's a lot of technical issues about how radiation can be delivered—does it need hormones or not?  There's a lot of technical aspects with surgery—whether or not you use on open or robotic approach, how to handle the lymph nodes, the nerve sparing.  And you get through all that and get a decision.  And believe it or not, the least-important decision often is the exact technique of the surgery, you know, is it the open or robotic?  That can be its own lecture, but ultimately, a high-volume surgeon who’s good at either one of those is what you need.  And the same thing with radiation: you can get into the particulars—I’m not going to a whole seminar on proton therapy versus IMRT.  You know, once you're that far along the decision pathway, let Dr. Choi sort that out for you. 

Overall, what can a patient do to limit side effects?—which was the one of the themes I wanted to get home.  Obviously, only treat when necessary.  If it has lethal potential, try to get the cure done right the first time.  Use high-volume centers—they don't have to be academic; to Dr. Broussard's question, it doesn't have to be MD Anderson, but in prostate cancer, high volume does help.  And believe it or not, one message on a lot of our literature is that prostate cancer patients still die of other things more than the prostate cancer, so if you still—if you're going to go through the effort of getting at that prostate cancer, you’ve got to do the whole package: that includes avoiding smoking, paying attention to your weight, the rest of your health.  Patients still die of other sources.  If you want some entertainment, go back to last year’s conference and pull the clip from Dr. Matin jumping on the soap box; that was kind of entertaining.

[Laughter]

Anyway—so anyway, let's draw the lecture part to a close, and the faculty will stay here to do some one-on-ones with questions you may have.  Thank you very much for attending.

[Applause]