Prostate Health Conference 2011: Treatment Updates

MD Anderson Cancer Center
Date: January 2012

Speaker: John W. Davis, MD

>> So this is the setup we've always dreamed of in having this meeting is having panelists who could face you and your questions but they also have a monitor down here so they don't have to have eyes in the back of their head.  We can follow each other well and then I've put down a few of my questions. 

So, the setup of this is very straightforward and these are our panelists.  We have Dr. Surena Matin he is a urologist; he does surgery, Quyhn Nguyen in Radiation Oncology who does—now you do proton and IMRT and?--okay, and then Jeri Kim is a medical oncologist; believe it or not, even though she would be an excellent provider for advanced care with chemotherapy and, you know, advanced prostate cancer she also has a tremendous interest in early disease, so she can kind of is interested in both ends of prostate cancer and we do a lot of nice projects together.  Let me get to my notes so I can go. 

So, we'll just go down a case and again I'm gonna actually pretend more like I'm with you.  I'm the interested spouse, I’m gonna try to summarize the questions I get asked a lot and then--and then we'll just see where that takes us. 

Fundamentally, there are kind of three different risk groupings of prostate cancer low-, intermediate-, and risk group--and high-risk and so I kind of just want to put a little bit of time into each one. 

So, this is a common scenario.  So, we have a patient with prostate cancer and let's just pretend like he could be any age and then we’ll come back and talk about the relevance of age. 

Clinical T1C just means that the doctor did a digital exam and felt nothing abnormal, but the PSA was 2.6 and last year it was 1.3.  I can see someone else already wrote in a question similar to that.  What does that mean when the PSA jumps up by a couple of points over a short period of time?  But a biopsy was recommended and that was another question.  That's appropriate that came up.  What is a biopsy designed to tell you? Well what it tells us is three different things.  It can give us whether or not there is cancer of course.  In this case, there was and you get a Gleason rating it's 3 plus 3.  Gleason himself was a pathologist that came up with a scoring system that looks at the architecture of prostate cancer and believe it or not, he described the Gleason 1 and 2 pattern, but for needle biopsies for screening, we almost quit using the 1 and 2 pattern.  So, even though the scale goes up to 5, okay, the first number is the most predominant grade and the second number is the minority pattern.  So, even though this is 3 plus 3, that's actually the low end of the scale, I mean, it's all low-grade.  But biopsies tell us two other things.  How many cores have cancer?  Usually we do 10 to 12 total number of cores, in this case only one had cancer and then within that core the pathologist will measure how much of that tissue has cancer.  The chamber of a needle can capture at most about 15 mm of prostate tissue and so in this case only one of that had cancer on it. 
Now, this gentleman stated he has a family history of prostate cancer.  Often these histories are incomplete.  They will say yeah he was treated, but he died of a stroke at 84 and may, or may not have been treated.  Patient was told that he should have surgery scheduled in the next two to three weeks.  So, I threw out some questions and I will start with Dr. Matin.  When you see the setup, what's your--how would you characterize your initial approach to counseling this patient?

Speaker: Surena Matin, MD

>> Yeah, generally, you know, in a situation like this I think the first thing is to sort of ease the anxiety of the patient particularly when they've essentially been falsely put in a position of feeling like this is an urgent situation.  It's not.  It does not require treatment within that immediate time period whatsoever and they, in some ways, have the luxury of time to make an informed decision so that would be my first goal is to ease that anxiety so that they can listen to the rest of everything else that I have to say about it.

>> So, you maybe disagree with, "he has got to have surgery in a 2 weeks," or next available.

>> Absolutely.

>> Okay.  Let's get that cleared up.  Dr. Kim, how--since I left the age open on purpose, but just tell us how does age influence, what you would say to this gentleman, I mean pretending he could be 40, 50, 60, 70, we've seen higher.

>> Right.  So, age is really an important factor in the decision-making process for this particular patient. As Dr. Volks mentioned, that a lot of men are over-diagnosed and over-treated and so if this patient has a very slow growing tumor which probably he has, based on the data we have, and also if he has a life expectancy less than 10 years, then he may not really need treatment right away.

>> Okay.  So, age affects longevity, I would add it may even affect the side effect profile in some cases.  But related to that, Dr. Nguyen, how does age affect radiation eligibility?  I think a lot of patients are told things that may state like you're too young to have radiation, or you're too old to have surgery, or may be it doesn't matter, but how would you--how does it affect radiation in particular?

>> Age affects it but also so when we counsel patients we talk, we look at their performance status, life expectancy.  Their urinary symptom score also.  So, if you have a 70-year-old who has very little comorbidities versus a 50-year-old who has significant urinary symptoms in which I wouldn't recommend a radiotherapy seed implant for, or necessary radiation upfront. It's really everything, it's performance status, urinary symptoms score if they're not a surgical candidate, or other things.

>> Okay.  And then Surena, I wrote this one for you.  What are the--if a patient was inclined towards surgery and just asked you what are the arguments that favor surgery?  How would you summarize that?

>> Yeah.  I think the, you know, there's probably three I think that differentiate surgery and both short term and long term.  I think in one way, you know, surgery is informative.  It gives you more information down the line by nature of the fact that everything we remove is sent to a pathologist who looks at everything under the microscope.  So, surgery treats and then at the backend in follow up we have a pathology report that much more accurately gives us a risk of what the cancer really was, what the chances are that the cancer could come back.  The natural next question from a patient is, "Well doctor if you took it all out how could it come back?"  Well, cancer is not predictable to some degree.  So, even though it may have been looked--may have looked contained it doesn't rule out the possibility for microscopic cells to have gotten out through the blood stream or more commonly the lymphatic stream. 

And we can give you a fairly educated guess as to what the likelihood of that having happen was based on the pathology.  Is that complicated? 
Okay.  So, that's one thing.  The second thing is the PSA becomes undetectable after surgery, or it should become undetectable and then it becomes a really good cancer marker, prostate cancer marker.  That's in fact the first reason it was approved for use because after surgery there should not be any detectable PSA.  There may be very minuscule amounts that are made by the salivary glands and other glands, but they are really tiny amounts.  So, the only reason it would really go up after surgery is if there's cancer since that since in that sense it's a very powerful marker. 
The third argument that one could use is that it's much easier to treat cancer recurrence after surgery than after radiation.  Having said that, I don't think that's always a fair argument, because in many cases such as this, the chances of cancer being curative are probably just as good as with radiation.  So, that's an argument that someone could use very strongly to try to win a patient over versus, you know, trying to be fair about it and say it could be an advantage but in truth, you know, I think they're both gonna work equally well.

>> Good.  And Quyhn, what are the strongest arguments for the patient seeking radiation?

>> Well, like Dr. Matin alluded to, this patient's outcome is going to be very favorable.  So, when I counsel this patient I tell him they've got every option available to them.  They can pursue active surveillance, surgery, all forms of radiation whether it be brachytherapy, implant, IMRT, proton therapy.  So, when we counsel patients, it's really--it comes down to patient preference.  Some patients are adverse to surgery or aren't the best surgical candidates.  Some patients like to continue their daily lifestyle where they go and get their treatment for half an hour a day and continue to work.  So, it depends on their--what they favor in terms of their quality of life.

>> Now, let me cycle back to Dr. Matin and state--the question is what are the common misinformation facts that you hear in the clinic?  What do you feel like you have to correct about surgery, or the whole overall picture from your standpoint?

>> Some of the more common things actually are from the biopsy standpoint as, you know, that the biopsy spreads the cancer which, you know, there has been hundreds of thousands of biopsies done in the past 20 years.  There is one report of that having happened and that was with a very crude old technique.  The other thing that's a common misconception is, you know, if you open somebody up and the cancer touches air that it spreads and that, you know, that's just old--it's from the days when we didn't really understand cancer.  Didn't have scans.  Didn't have markers.  We discovered them when they were very late and didn't know that there was disease everywhere and then you do the surgery and lo and behold, you know, a month later or two you see lumps and bumps everywhere and, you know, people would make the connection that surgery did that.  But that's just--just doesn't happen that way.  Those are the top two that I can think of.

>> Okay, and Quyhn on radiation?

>> I think I commonly--patients when they come to me.  They commonly, you know, say, you know, I had a friend who had radiation and they got burnt or their bowels were burned and I think--we want to dispel that myth because radiation depending on what site you're being treated for, what type of cancer the side effects are often very different. Especially for patients with prostate cancer when it's very focal and radiation has become very sophisticated with newer technology, with image guidance, with the localization.  It’s become very focal.  So, the side effects that we’ve published are toxicity long-term and it's very minimal in terms of grade 3 or 4 rectal and bowel toxicities, so done properly because I think that's the key because it's very different wherever you had your radiation treatment.  Your side effects profile could actually be very minimal.  We don't see the patient is being burned or their bowels being messed up.

>> And I have to say, I agree with Dr. Nguyen, you know.  Early in my training in the 90s, we used to see a lot of radiation side effects back in those days.  A lot of blood in the urine and, you know just really awful symptoms, rectal problems.  It's rare, I mean, it is really rare for us to see that now and it's a urologist telling you that, you know, so believe me if I could, you know, have the, you know, use that I would but I can't and--but there are--there's a lot of variation in terms of, you know, where you get it done, how much they do, if they can localize.  They have the technology that localizes the prostate everyday because every day it can shift around a little bit and so if they don't adjust for that they can miss it and hit other target so, yeah, I do agree with that.

>> Dr. Kim, back to you.  What's your advice for patients to get unbiased information on this?  Do they need to see a medical oncologist?  Do they need to see a surgeon and a radiation oncologist?  How many opinions do you need to get the whole story?  I'm sure it's different for everybody, but your thoughts.

>> I think we have a great setup at MD Anderson in that patients who come in with newly diagnosed localized prostate cancer they have opportunity to be seen in the Multidisciplinary Clinic where they are seen by a urologist and a radiation therapist on the same day and also in certain cases also a medical oncologist like myself can have an opportunity to see the patient and introduce the concept of watchful waiting, so I think we have a great setup at MD Anderson.

>> Okay.  Let's have a little more fun with you now.  This patient was unsure and in my clinic and many others if we're unsure about treatment versus surveillance we often do another biopsy.  Just a--the way I lately thought of describing it is pretend like the inside of the prostate is like a thousand-piece jigsaw puzzle, but you don't know what the picture is and a biopsy gives you 50 pieces and depending on which 50 pieces you still may not know what the picture is and another biopsy, you know, it's getting another 50 pieces is kind of the analogy and hopefully with two biopsies you got enough pieces to know whether or not you're looking at a city, or a horse, or it could be anything on those puzzles so--and that's, you know two biopsies is not necessarily perfect and we're trying to get some, you know, specific information on the value, but it's been a work in progress to do that. 

So in this case, well I'm gonna giver her two different scenarios.  The top one is actually the most common which is that we don't see tumor.  Now, it doesn't mean it went away or that the first biopsy, you know, got it all.  It's just, you know, if a tumor is really small someone bulls-eyed it the first time, the second time you may not hit if it's small, and that's kind of the idea.  The second scenario and I'll get her to comment on both is we repeated the biopsy and actually there is more tumor in there.  For Dr. Kim, your thoughts on these two scenarios for this patient?
>> Alright.  Some of you may know that there's a lot of sampling bias on repeat biopsies of the prostate and--but what we have learned from our watchful waiting trial is that on repeat biopsy if the patient has no tumor.  There's a high likelihood that he has a very tiny tumor to begin with and so I think that is a good prognostic factor going into watchful waiting study. 


Now, in the second scenario, if the patient has now Gleason 7 tumor being the highest which means that his risk stratification or risk group has been actually sort of reclassified as having intermediate-risk prostate cancer and again age is a very important factor to consider in this case in that if the patient has again life expectancy of less than 10 years, even with intermediate-risk prostate cancer, the patient has an option of choosing watchful waiting, or I guess better terminology would be active surveillance and that we'll be closely monitoring the patient.  And of course if there is any sign of cancer progression and the patient will have option to consider therapy.


>> Very good.  So, Dr. Matin, let's say that patient picks--has the negative biopsy and picks surveillance and over the next five years they get an annual biopsy that again shows either no tumor or may be the same thing as the first, but no change in concern.  But for whatever reason, let's say that they elect to undergo surgery, five years later are you still going to be able to do surgery as well as if you just gone straight to surgery today, or has all that biopsy material can actually be a problem?


>> I think you worry about it but in truth I'm not sure it's not much of an issue as long as there haven't been any other problems, you know, infections which are very rare after biopsy if it's done properly and you take precautions and so, you know, I think we still worry about it but in truth having treated several patients that have gotten annual biopsies over time, I'm not sure it's that much of an issue at all. What do you think?

>> It’s occasionally it’s a little harder but it's nothing we can't handle and, you know, it's--I guess I would agree with you it's not a strong enough argument to then flip gears and say everybody has got to have surgery as a policy just because of that concern, you know.  I think, you know, as long as we, you know, counsel.  Dr. Kim has done a trial on surveillance where the men are getting surveys done every year so we're getting close to where we'll have some good data to show that the, you know, where [inaudible] maintenance of erections and quality of life is okay with repeat biopsies and then, you know, the next study after that is gonna be what happens to the men who didn't get treated on delayed basis with their quality of life, so. 

Dr. Nguyen, I'll just phrase it this way, if, just thinking from a devil's advocate from a patient's standpoint.  If the disease is not trivial, why not just radiate it if you can, you know use the latest technology and have minimal side effects?  I mean like, if this--if we're just talking about taking an aspirin pill that would be different than surgery and radiation, but--what about that way of thinking about it?

>> Well, you know, this patient has low-volume disease so he--I would also counsel him, this patient, all the treatment options whether it be active surveillance if he does not have a life expectancy of more than 10 years, or surgery, or all forms of radiation so--and I would tell the patient that their outcome long-term is comparable between surgery and radiation.

>> I've heard, and I'm speaking as a patient, that if you have radiation you can get a secondary tumor.  What's the truth on that?

>> So, the risk of secondary malignancy is low and the latency period is long, so when I talk to counsel patients about that, in a 60-year-old, if you developed a secondary malignancy which is a few percentages 15 to 20 years later it becomes--it doesn't really has to become such a huge issue.  In the younger patients who, now with our PSA screening, we're detecting these prostate cancers earlier in their 40s and 50s.  I do counsel them about the risk of secondary malignancy because it becomes a little bit more real.  So if they're concerned about that.  I say you know you can consider surgery or even brachytherapy if they're candidate because the total dose of brachy is less.  We've--our group have also done studies are very elegant in terms of showing that proton therapy reduces patient's secondary malignancy rate compared to IMRT.  So, that's also an option for patients.


>> Okay, very good.  Now Dr. Matin, can we or can we not do surgery after radiation?  I have heard two different things.

>> Yeah, so the truth is that we can do it, but we don't really like to.  Is the way I can put it very simply.  You know, it's--the fact is that it is--it can be more difficult both for the surgeon and as well for the patient.  Radiation causes a scarring effect over time and that scar can be difficult to dissect.  It distorts basic--it distorts the normal tissue planes that we would look for to separate normal from abnormal structures.  The example I might give to patients is if you take two pieces of paper and wet them and put them together, you know, you can easily peel them apart.  That's what we can do in an area that has not been touched, in the ideal situation.  If you take two pieces of paper and you put Elmer's glue and come back a day later and then try to perfectly separate them what's gonna happen?  It's gonna tear.  You’re gonna tear one way, or tear another.  And so, you know, prior surgery does that, radiation can do that, so the complication risk is higher.  The risk for injury to the surrounding organs like the rectum can be a little bit higher.  So, basically it's not like we don't do it, but there has to be a particular scenario for a patient's situation where that amount of risk is justified.  So, we do do it and we have people like you and others at Anderson who really sort of have an expertise in doing that.  But again, they don't do it on everybody who has had radiation and thinks they need surgery.  It really has to be pretty selected.

>> Okay.  Let's go to another case.  These questions continue by the case type but when we make some modifications you'll see some new wrinkles in the discussion. 

So in this case a 55-year-old, the PSA of 6.  The staging is clinical T2a, so what does that mean?  That just means when you do the digital exam with your finger on one side and limited to one part of one side of prostate, you can feel either firmness or a nodule.  In fact if you all want a quick lesson on [indurary] here it is.  See me here. The palm of your hand is what the prostate is supposed to feel like, okay.  It should have a little spongy softness to it.  If you then move your finger off to the bottom of your knuckle that's what an indurated area feels like.  It means it's soft, but when you push hard enough you can feel there is something harder down there.  That's early cancer so to speak.  What we used to see, that I'm actually believe it or not I'm too young to have seen much of before PSA came out was the actual knuckle of your fist.  If you did the exam and you felt a knuckle that's a nodule and that was--that was a very definable cancer in many cases.  With PSA screening, we hardly ever see this.  Now you can all do exams [laughter] hopefully not on each other anyway. 

So he had clinical T2a exam and the Gleason score is 4 plus 3, okay, and remember that someone asked about biopsies, remember we get three information points on a biopsy.  Gleason grade is higher this time it's 4 plus 3 and in fact the four numbers in the front position which means the predominant patter is 4, so this is really two notches higher in the grade, not one notch even though, you know, 4 plus 3 is 7 and 3 plus 4 is 7.  So, this is the worst kind of 7 so to speak. 

Four of the six biopsies on the right side have cancer, okay, so remember the last time was 1 out 12 now it's 4 out of 12.  But also look at these measurements, 8 mm.  That's over half the core in that one.  4 mm, 3 mm, and 1 mm.  Two other things, what's a SHIM score?  That's just a quick survey of a man's erectile function.  25 is perfect, 25 to 30 means you're bragging and you're off the scale, 22 is pretty good actually.  20, that's an AUA score.  That's actually a bladder inventory, okay.  That means that--you asked about seven different questions about bladder function, you add them up.  A score of greater than 10 means that there is starting to be some mild symptoms.  Greater than 20 means that the bladder is a symptom and many of those men may have come to the urologist just for that alone to get some relief. 

And then the third thing that we learn is that the volume of the prostate during the biopsy was high.  A normal prostate is 20 grams, this one is 70.  So that's large, it's not off the planet.  The largest I've ever operated on is about 180, so that was big.  70 is getting so big.  So, let's go back to the panelists on this.  So Dr. Nguyen, just summarize why--how is this case different from case number 1 and how did it--how are the radiation options different?

>> For a number of reasons, the case is a little bit different.  Now, you're getting to a patient with an immediate risk of prostate cancer with a higher volume of cancer as well as with significant urinary symptoms.  His AUA score is 20 and with a volume of 70, so my concern is this patient has significant BPH or an enlarged prostate which is causing his obstructive symptoms.  So, in a 55-year-old, I would say you know if you consider surgery it would actually affectively treat your prostate cancer as well as take care of your urinary symptoms potentially.  If for some reason patient declined surgery or didn't--isn't a good surgical candidate because--due to morbidities, radiation becomes an option, but not brachytherapy, because of the AUA score and his significant urinary symptoms.  If you--and then I would counsel him with external beam radiation therapy, but then he would--I would recommend he receive six months of hormone therapy in combination because there have been studies that have shown benefits for patients with intermediate risk with combination of hormone therapy and external beam radiation therapy.

>> And, again, summarize the use of hormone therapy for this type case.  How long and then why--what's the data rationalizing this?

>> Right.  So there have been two randomized studies that have shown for patients with intermediate risk disease.  A short course of hormone therapy have benefitted patients.  There are various ways of delivering the hormone but here at Anderson what we do is we do two months of hormone before, two months during radiation, and two months after, so a total six months.  The reason why we deliver the hormone therapy before is because it--we know that from prior studies that it can actually shrink the prostate up to 30% after three months.  So that helps us with the radiation field that helps us with cytoreduction before we radiate these patients.

>> Is there a patient similar to this who can't get radiation for some reason?  What features would you find that would just make you say now, go see one of the other docs?

>> Yes.  So, I wouldn't recommend brachy as first line because of his AUA score and his urinary symptoms.  For external beam radiation, patients who have history of ulcerative colitis or Crohn's disease or lupus, one of those inflammatory bowel disease, we know that this patient is gonna have a potentially a higher rate of rectal toxicities because we deliver high dose to the rectum.  So, if they have a history of those inflammatory bowel disease then I would say--I would recommend they be evaluated by one of our surgeons.

>> And just to be clear from our standpoint, how does a patient know if they have inflammatory bowel disease versus irritable bowel disease?  Does that make a difference to you?

>> Yes.  So, if they have a questionable history, we would take a detailed history and then we recommend a colonoscopy.  So, if there are indications on colonoscopy, oftentimes the gastroenterologist will biopsy and if you have necrosis, inflammatory cells, they can make the diagnosis inflammatory bowel disease.

>> Okay.  So, that would be a factor.  Dr. Matin, how do you plan surgery for this patient?  Does he need--what's a lymph node dissection?  Why would you do that and how would you deal with nerve sparing and should this patient have hormones prior to surgery?
>> So, just to start with the last question.  There have been several studies that I have looked at the use of hormones before surgery.  The bottom line what that appears to be that it does make our surgical results look better, but then if you follow those patients out they don't do any different than patients who didn't get hormones.  So, you know, it's unclear, you know, the best scenario we use the hormones then is to reduce the size of a prostate or if there's a lot of cancer we want to get smaller before we do surgery but not because necessarily we think long term it might improve things.  That's that. 

In terms of the lymph node dissection, patients frequently ask, you know, what are they?  Basically, what we, you know, these are small glands that are part of our immune system.  They live outside of the prostate gland near the blood vessels of the pelvic cavity that go to the legs and that can be an early area where the cancer can spread.  For whatever reason, prostate cancer likes lymph nodes and it likes bone.  Those are the two places we look.  So the lymph nodes what happens to be, in some patients like this, with intermediate risk disease.  We like to remove them at the time of surgery so the pathologist can look at it under the microscope and see if there are cancer cells in there.  And we don't really see the lymph nodes.  All we were doing is removing the fatty tissue where the lymph nodes are embedded and the pathologist is the one who examines the tissue and tells us how many are there.  And theres are no real side effects from losing those.  You've got thousands of them everywhere.  In terms of nerve sparing, the concern here is there are several concerns.  Four out of the six biopsies on that side show cancer.  That by itself predicts the possibility that there could be early spread of cancer outside the capsule.  Maybe just microscopically, but that is a predictive feature.  Also the fact that he has several, at least one, very high volume core, that 8-mm core, that by itself can also predict that.  So, there is the possibility that this patient may have early, not spread necessarily, but extension of cancer outside the capsule, or the skin of the prostate and of course depending on where that is, it can be real close to where the nerves are that allow men to have erections on that side.  So, one would have to approach this a little bit carefully.  There is no perfect imaging.  There is no perfect way to tell that patient.  They have that, or they don't have that until after we remove it and look at it.  So, we have to have some way of predicting the possibility and using that possibility, or probability to decide whether we're gonna do a nerve sparing on that right side, or not and I don't want to get into MRI yet, maybe we will do later.  I don't want to take up too much time either.  But there's some ways.  We sometimes if you try to look at it but the bottom line is there is no perfect way.  We're working with some limited information and it's the best we have, but it is still limited.

>> Yeah.  As a co-surgeon on this, I would interject that when we were, Surena and I were training mostly in the 90s, we would take almost always take out the side with the cancer and the nerve bundle.  It would be a wide excision there, nerve sparing left, now with imaging and a lot more stage migration and maybe just practice doing the operation.  There's a lot more ability to do nerve sparing even when there is some risk, but that has to be done tailored, so we'll leave it at that for now.  Dr. Kim, does surveillance come up for this patient as an option?

>> Right.  So, unlike--well the--the patient is pretty young since his 55 years old and he has intermediate risk of prostate cancer with a fairly large amount of tumor.  So in this case, again, I believe you have to consider two other factors besides the tumor characteristics.  One being the age of the patient which is very much linked to life expectancy and in this particular case we have to consider what other comorbidities does he have, so if he has the average life expectancy of more than 20 years then I think that given his clinically significant disease he should have treatment.  On the other hand, if he has a lot of comorbidities and he has a life expectancy less than 5 years, or even less than 10 years then you might consider offering this patient an option of active surveillance.

>> Okay.  Now, does this patient need any chemotherapy or I heard there is a prostate cancer vaccine?  How about that?

>> So, chemotherapy and vaccine therapy, which we can discuss later, that those therapies are more for patients with more advance prostate cancer, so patients who have failed hormonal therapy.  So in this case we would not normally offer chemotherapy, or vaccine therapy prior to surgery or radiation therapy.

>> Okay.

>> Would it be fair to say those are for basically cases where it's incurable?

>> Right, correct.

>> And you're just treating.  You know, this patient still has a good chance of cure.

>> Well, let's do two more pathways, okay.  So, same patient that go two different directions.  So for Dr. Nguyen let's say he undergoes radiation and six months of hormones, the PSA nadir is 0.5 or we can even say it nadirs to 0.3 at two years but in three years it's 2.4 and you have a biopsy proven recurrence.  That would never happen here, but [laughter] the question that's just a scenario to get to the question of how do you use PSA to follow radiation?  How do you define failure?

>> Right.  So, we follow patients after they have undergone definitive radiation so we follow their PSAs pretty routinely.  What we do here is we follow their PSAs every three months for the first year, every six months up to three years and annually thereafter.

There are a couple of ways to define biochemical failure after radiation.  We used to use the three consecutive rises but there were flaws in that.  Now we use what's called the phoenix definition where we take the nadir the lowest PSA and we add 2 to that.  So this patient fits that failure definition.  Oftentimes, you know, because we're following these patients more closely we all--both of us get nervous before that and if that's the case what I normally order is I order an endorectal MRI scan.  If we see a local recurrence that would be followed by a dedicated biopsy to that area to evaluate whether there's indeed a recurrence.

>> So, what then, the PSA of 0.5 at one year, is that just--does that mean anything or is that just incomplete?

>> So, there--if you look at some of the older studies the patients who have a nadir of 0.5 and below tend to have a better outcome.  So, it is good in the sense that it nadired at 0.5 as opposed to 1 or 2.

>> Does it ever go to zero?

>> Yeah, it can after hormone.  So, if we give these patients hormone therapy their PSA will become undetectable less than 0.1.  Patients who get radiation alone, their PSA opposed, you know, contrary to surgery, it tends to decline more slowly, so we look at the trend after the radiation.

>> Okay.  And then on, Surena, on that second scenario PSA nadir of 0.3 at two years but then it goes to 2.4 with a biopsy proven recurrence, to summarize again, what are the two--what are the main options for that circumstance from a surgeons standpoint.

>> So, what we're looking at is two scenarios.  What that pathology translates to is that its organ confined, the cancer is still in the prostate, the margins are negative when you look--

>> I'm sorry.  I'm still on the top run.

>> Oh, I'm sorry.

>> This is the radiation failure.  Then that's next. [ laughter ]

>> Sorry.

>> Let's put it around, okay.  And what was the question?

>> You gonna salvage that patient with radiation or you gonna observe that?
>> Ah--
>> Or just give hormones alone?

>> Well, you know, presumably he is still pretty young and at this point 58-59 years old so, you know, one has to consider treating that I think and assuming he is a healthy man, you know, doesn't have diabetes, hasn't had heart attacks, things like that.

>> Okay fair enough.  That's kind of what I was trying to go for.  We will talk about hormones in another slide here in a second.  Now, let's get Drs. Matin and Nguyen to discuss the bottom of the screen.  So the common scenarios we have for intermediate and sometimes high risk disease is you either sort of get it all so to speak or you have some risk factors on the pathology.  So the first scenario is it's contained, it is Gleason 4 plus 3.  The margins are clear.  The lymph nodes are clear or what you have is pathologic T3b.  What's that mean is that the pathologist can see tumor invading the seminal vesicles.  That's an aggressive marker.  It is still Gleason 4 plus 3 and not only that there is cancer at the edge of the margins of resections.  The lymph nodes, however, were clear.  So, I'll just outline and let them comment and obviously you can observe these cases and apply radiation if the PSA goes up or some--there are studies that have looked at immediate radiation.  Surena, we'll just start with you.  How do you referee the follow up in salvage therapies of these scenarios?

>> Yeah.  Let me just add one more variable to this--

>> Sure, sure.
>> And let's just make all the assumption that the PSA is undetectable--
>> Correct.
>> In six weeks, okay.
>> Right.

>> So less than 0.1.  So the first case, if this patient still has a pretty good chance of the cancer not reoccurring.  Let's put it that way.  There is gonna be a risk of that still.  Nothing is ever at 100% with cancer unfortunately.  But the odds are I think is still to his favor that the cancer will not come back and I would recommend just PSA surveillance. 

In the second scenario, this patient does have risk factors and there’s two particular types of risks we talk about.  We talk about cancer returning in the area where the prostate was that's called the local recurrence and the second type of risk there is this distant reoccurrence meaning that it had spread and it recurs in lymph nodes away from where the prostate was or in the bone for example which is also a distant site.  So this patient actually has both types of risks.  The seminal vesicle invasion or the T3b does predict a bit more the distant recurrence.  The positive margins predict to some degree a local reoccurrence.  So, I'll let Dr. Nguyen discuss sort of the role of radiation there but my recommendation for that patient would be that we should do additional therapy with radiation.

>> So, this sometimes can be a little bit controversial, but we've--the radiation literature shows in three randomized trials that when you compare patients after surgery who receive immediate radiation who have these risk factors including positive margin, seminal vesicle invasion and extracapsular disease, those patients who received immediate radiation after surgery, as compared to delayed radiation, those patients actually had the benefit in three trials showed a biochemical progression to be survival benefit meaning decreased PSA recurrence.  With a longer follow up, one of the studies have shown that there is an overall survival benefit as well as distant metastatic survival benefit.  The question becomes whether—there’s pros and cons to those studies if you look at it more carefully.  But I do have this conversation with patients and I tell them that there’s three pretty good randomized trials which have shown there is a benefit at least with local regional control as long as there is a local recurrence for radiation.  So I do have this conversation with patients.  I counsel them.  There are potential increased toxicities such as rectal and bladder side effects, but they can be minimized with newer technology delivering the radiation.

>> So Dr. Kim, let's just say this patient, at the bottom of the screen, is in your clinic and we have to kind of step back and look at the big picture and many of these cases--these patients were given a choice between surgery and radiation and they pick surgery.  Now you're a few years later with that pathology and let's say the PSA has gone up and it's 0.3 or 0.4, it's detectable.  And now they are being recommended to consider radiation.  Many of these patients didn't want radiation the first time and they may not necessarily want it the second time either.  What if they come to you and say, "What's the better strategy?"  Should I just do the radiation now and deal with those side effects or should I just let the PSA kind of increase and if there are ever symptoms just do hormone therapy?  How would you kind of counsel him about, you know, the risk of hormone therapy versus doing radiation after surgery?

>> Right. So there are a fraction of patients who present like this, who may benefit from salvage radiation therapy, especially those patients who had Gleason 7 or less in the prostatectomy specimen and also if they had a PSA recurrence more than about a year after having had surgery.  For those patients who have good prognostic factors I would recommend at least considering salvage radiation therapy.  On the other hand, if the patient refuses to have radiation therapy or he is not able to have radiation then certainly the first thing I would do is to further follow PSA levels and if the PSA doubling time gets to the point where it's less than about six months then I would recommend starting hormonal therapy.

>> Very good.  Let's follow up on one question from the audience because the gentleman asked about proton therapy.  Dr. Nguyen, would that patient, if they were gonna do salvage would you use proton therapy?  And just maybe give us your other final outline for the audience on proton therapy.  I know you mentioned that perhaps the bowel toxicity is lower but what--how do you have want to update us on that?

>> Sure.  So, most of our patients treated with proton therapy for prostate cancers are definitive, in the definitive settings so they have an intact prostate.  For patients who have undergone surgery for salvage treatment of proton therapy, there are only going to be selected patient patients that we offer proton therapy due to the physical characteristics of the beam.  So because the proton beam actually stops anything that's in its path will be very sensitive into stopping that beam such as metal clips.  So, patients who have undergone surgery and had high-density metal clips we don't recommend the proton therapy for because it can potentially change the dose distribution.  So if they're young and they don't have any evidence of metal clips we do offer that and we screen them pretty carefully.  We can x-ray.  We do CT scans to evaluate if there are any clips in the fossa.

>> Okay.  Let's do case 3 and there is just one slide on this one.  This is a 65-year-old with a PSA of 9, now the Gleason score is 8 so it's called high-grade cancer.  There’s three quarters on the right, 8 mm, 4 mm, 4 mm.  Clinical stage T2a.  We do an MRI that shows that there's no image evidence of it having spread.  The bladder and the erectile function scores look favorable and the patient is healthy.  So Dr. Kim, tell us in your view, how is this case different from cases 1 and 2?

>> Okay.  So, this patient has a Gleason 8 tumor, so he would be considered to have high now--high-risk prostate cancer.  So, we have talked about in case 1 low-risk prostate cancer and in case 2 he had intermediate risk prostate cancer and so now because this patient has Gleason 8 tumor, he would have--he'll be considered to have a high-risk disease.  And so he has PSA of 10 and clinical stage or tumor stage T2a.  So, because he has a high risk prostate cancer and he is 65 years old so for a 65-year-old man in the United States the average life expectancy will be around 17.5 or 18 years so given his clinically significant disease I would recommend treatment.

>> Okay.  Very good.  So Dr. Nguyen, how is radiation thought of differently for Gleason 8 with respect to which beam you use, can you use proton therapy for this versus IMRT and how's the hormone treatment different?

>> Sure.  So, like--this patient falls in the high-risk category so it's different from a couple of reasons also.  The hormone duration is going to be different because we know from multiple randomized trials that patients with high-risk disease benefit from longer hormone therapy, so we would recommend two years of hormone therapy for this patient in combination with external beam radiation which is IMRT or proton therapy.  So at Anderson we've commissioned both the pencil scanning beam as well as the broad beam.  You need the most protons [centers] in the country so that we will use the pencil beam to sculpt the dose of the bowels because our target in this patient would be the prostate as well as the entire seminal vesicles.

>> Okay.  And then Surena, how is surgery difficult for this setting?
>> Yeah.
>> Can you use the robot or not?

>> No.  You can certainly use do robotic prostatectomy.  I think what's important for the patient to know is that the likelihood of being able to get away with just a single treatment here is gonna be low.  The example I give to a patient is if you look at a patient with breast cancer now.  There is no patient who just gets surgery.  They get surgery, they get radiation, they get chemotherapy and they get hormone therapy.  That's what we put our women through, okay, and yet we wring our hands when we tell patients that they have to get more than one therapy.  So we have to get away from that.  This is a high-risk case and there is a real chance of, you know, just a single modality not being effective enough.  It's just the nature of that disease.  If you think about it with radiation, they follow that example that's why they don't just do radiation.  They do radiation and hormones, double punch.  So you kind of have to think about the same way if you do surgery and not have false expectations for the patient that you're gonna do surgery and everything is fine and go team, okay.  You're gonna have to be a little bit more cautious.  So what it comes down to for me is tell them be prepared.  If you wanna just do surgery first that's fine but we're gonna look at that pathology and that pathology report is really gonna drive what kind of second therapy we might need to do and there's a very high chance I might refer you to radiation therapy. 

Now, there's one other option and that is that if we have a clinical trial and the clinical trial means that basically we are doing the same standard of care which is gonna be in most cases actually surgery with hormones because that sort of the pretreatment, you know, if we're gonna delay time to surgery we have to do something that we know works, so that's hormones.  But now, we want to add something that is untested in that scenario and that scenario before surgery.  And Dr. Kim--that's basically her specialty and we work with her group so if there's some new chemotherapy that is effective in those who are incurable, we might want to try it in this early stage and that's part of a clinical trial.  When we're treating the patient but at the same time we don't know exactly what the results are gonna be and so it has to be as part of a, you know, ethically driven process of informed consent and so that I think would be the option for this patient, so either surgery first with a very high likelihood that we need to do a secondary therapy afterward, or enrolling in a clinical trial if that patient is a candidate for it.

>> Okay well great that was my next question for Dr. Kim.  Tell me again, what is a clinical trial involve?  What is that--how does that add to the picture?

>> Right.  So, as Dr. Matin mentioned that giving patients neoadjuvant hormonal therapy or hormonal therapy prior to surgery, it decreases the risk of having margin positivity but it does not change the overall survival.  For patients who present like this with high-risk disease, we have been trying to improve on the success we had with hormonal therapy studies so we have been actually combining chemotherapy plus hormonal therapy in the neoadjuvant setting and also we have been combining hormonal therapy with one of a targeted or molecular targeted therapies in this kind of setting and so basically--based on our studies, there seems to be patients who benefit from having neoadjuvant hormonal therapy, plus chemotherapy or hormonal therapy plus targeted therapies, but obviously the studies have to be followed longer to see if patient's survival is changed.  So, there are a few studies that are ongoing at MD Anderson.

>> Okay.

>> Can I add one thing?  I will feel guilty about it if I don't say it.  So, you know, people are looking at me or us and saying well the MRI shows organ-confined disease.  What's wrong with you?  And I told you there is no perfect imaging for prostate.  So, the problem with MRI is it's the best we've got.  That's not the problem, that's the good thing.  It's the best we've got.  But it's only really good when it's positive.  It's only really reliable if it tells you there is extension outside the prostate.  If it doesn't tell you that there is or it suggests organ confined disease, there is still about a 50% chance they're wrong and that there really is.  So, we have--that was sort of an undercurrent and I just wanted to verbalize it so you didn't think we're pulling out the shotgun to kill a little sparrow but, you know, that's the concern there which is the real possibility that that MRI may not have--may not really show the real picture.

>> So, given the time, here's what I will propose.  I'm gonna ask one last panel--panel-driven question for them all three to answer and then we're gonna stop the formal part of the talk and then we'll just be up here for, you know, another 10 minutes or so and you can work your way to one of the four of us to go over questions. 

The broader picture of the conference and why people are here is probably because they want to live a long healthy life not die of prostate cancer and probably other important things so let's not forget why we are here.  What is to be your final advise to the audience because, you know, we--I went--this is almost like an automatic, you know, firing squad of questions just to give you the scope outline if you will of all the different issues with the screening dilemma, with the treatment dilemmas and I've seen each one of those questions in of itself can be its own 20 to 30-minute conversation.  But at least you have that outlined and there's a framework to move on.  But back to the big picture starting with Dr. Kim [inaudible] what's your final thoughts on men--how do you--how do they live a healthy life and not die of prostate cancer?

>> Right, right.  So, as a medical oncologist, I would really promote eating a healthy diet and exercise although there really hasn't been studies showing definitively that eating a healthy diet or increasing physical activity prevent or treat prostate cancer, but I think that there are some epidemiologic studies that suggest that it would be beneficial for patients with a prostate cancer at all stages and also I would like to really emphasize that for patients who just get diagnosed with prostate cancer to really explore all the options because as we discussed in the first case that getting surgery or radiation therapy may not be necessary for some patients.

>> So, in addition to what Dr. Kim alluded to a healthy lifestyle and when I--when we see patients in the Multidisciplinary Clinic I think it's unique because you get multiple opinions from experts so I encourage patients to do their research because you don't have to make a decision immediately.  You actually have a little luxury of researching and finding more about your diagnosis.  Oftentimes, I'll get patients who come in and will say, you know, I was told from the community that I can't have surgery after radiation and that's off the table.  What I tell patients is that our surgeons are excellent.  So they perform cases that are very involved and they are very experienced so to get a second opinion or to do further research is actually important upon making your treatment decision.  Because there are different treatment options available to you.

>> So, I have sort of two very separate comments to make, you know.  One is I hope what you sort of take--can take away from this and from the very nice way that John had the spectrum of different risks presented of these three cases, you know, prostate cancer is not all the same thing and the example I use is the cat family, you know.  It can be a little kitten that you can pat and you're cute and cuddly with or it can be a man-eating lion that you can maybe not do very much with and it's gonna kill you.  Thankfully, those are rare and many patients sort of fall somewhere in the middle, but that's the important thing for you to know and so that individualized approach is really key.  Not everybody needs surgery or treatment within two to three weeks.  So, it's a wide spectrum and that's something we haven't even learned yet, you know, even in that low-risk population which are those patients that have progressed so just so you understand that.  The behavior can be very different. 

Second thing to address your question more directly I think Dr. Kim's comments, I spend as much time talking to patients about their unhealthy lifestyle and dietary habits as much as the cancer.  I don't have enough time to talk about the cancer because half the time we're talking about how incredibly unhealthy we live.  We live in a society, and I'm sorry this sounds so militant, but [laughter] you can feel my frustration.  We live in a culture that breeds cancer.  We have an incredibly calorie-dense, high-animal-fat, lazy environment that we live in which is completely different than anything humanity has ever really know and then after that the anxiety, you know.  There is a woman who goes around and talks about, you know, how we can treat our children better but--and to use her words we live in the fattest and most anxiety ridden, more heart disease, most drug addicted, you know, culture than ever than humanity has ever known.  And we can't make the cancer go away and unfortunately for most of you those types of interventions are not gonna make things turn around, but they may set you up to be healthier and stronger to handle whatever stresses the cancer and us may throw at you. 

What's more important I think from a lifestyle perspective is your children and your younger people because we think the whole process of cancer actually starts early on and where lifestyle changes and dietary changes have really shown to have an impact is early on as we're building our bodies in our teens, in our 20s and that's where it can make a difference.  So and not to take the wind out of the sails, physical exercise is important.  There is actually a study that came out published in the--I think it was JAMA or New England journal that showed that men who survive prostate cancer who exercise a certain amount--do you remember that I can’t remember I think it's maybe 20 minutes of intense activity three times a week or something had better survival that those who did not.  So it can make a difference, but if you're looking for big changes it's got to start early.

>> Yes.  I'm not sure we can finish much better than that [laughter] very good.  Thanks Dr. Matin.
>> And one last thing.
>> Please, yeah.

>> Actually for those of you who are interested in participating clinical trial at MD Anderson, we are on Twitter.  You can use GU--
>> Ah, social media.
>> GU ah, it's GU Cancer News I think.  So, you can find us in Twitter.
>> Thank you for coming.
>> So, first a round of applause for our panelists.  Very good. [ Applause ]

>> So you have two opportunities before you in the next 15 minutes.  One is to put some real thought into the evaluations about, because we--I can spend the next 10 years running around MD Anderson finding interesting speakers for you all to listen.  So give me some ideas about what you want to hear about. 

And then number 2 is for the very detailed questions that we couldn't get to, you know, we'll be here for a little bit longer so that's what you can do in the next 10 to 15 minutes. 

I hope you get to read the introductory slides, you know, the Oilmens Fund helps fund this, Shari Bane and Colleen Hubona have done a great a job helping me organize this especially.  Let's give a round of applause for our organizers and then of course our featured speakers.  So thank you very much.