#273 ‒ Prostate health: common problems, cancer prevention, screening, treatment, and more | Ted Schaeffer, M.D., Ph.D.

Hey everyone. Welcome to the Drive Podcast. I'm your host Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness and we've established a great team of analysts to make this happen. It is extremely important important to me to provide all of this content without relying on paid ads to do this. Our work is made entirely possible by our members and in return we offer exclusive member only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to peterattiamd.com subscribe My guest this week is Dr. Ted Schaefer. Ted is an internationally recognized urologist and prostate cancer oncologist, author and speaker. He is the Chair of the Department of Urology at the Feinberg School of Medicine, the Urologist in Chief at Northwestern Memorial Hospital, and the Program Director of the GU Oncology Program at Northwestern as well. Ted has published more than 400 peer reviewed publications emphasizing at risk populations, diagnoses, treatment outcomes and the molecular biology of lethal prostate cancer. He is also the co author of a new book, Dr. Patrick Walsh's Guide to Surviving Prostate Cancer, which is available on October 3rd of this year. In addition to his work at Northwestern University, Ted is also a consultant to a variety of individuals who are going through various aspects of prostate cancer and prostate care and you can learn more about these services on his website, which we'll link to. Ted was a guest way back on episode 39 in February 2019 and a lot has changed since then and I wanted to have him back on to pick that up. In this episode, we talk about all things related to the prostate. We discuss the problems that can arise with the prostate as you age, including urinary symptoms and an increase in frequency going to the bathroom at night. We talk about prostatitis, pelvic pain and prostate inflammation. We talk about the very popular drug finasteride, used both to shrink the prostate and prevent hair loss and something called post finasteride syndrome, along with concerns that people have around this controversial diagnosis. We then move on to talk about prostate cancer. We talk about how androgens work, how testosterone and DHT work, how they relate to prostate size, how genetics and non genetic factors factor into prostate cancer and its pathogenesis. We discuss the blood based screening tools that are at our disposal for prostate cancer, including PSA free, psa, PSA density, PSA velocity. And then talk about how MRI works and how we use it to facilitate biopsies. And then of course, what biopsies mean, how do we interpret a biopsy and how does that tell us about which patients should and shouldn't undergo prostate removal? And lastly, we talk about prostate cancer treatments that involve not just surgical intervention, but also things such as androgen deprivation therapy. Lastly, I just want to highlight that prostate cancer is the second leading cause of cancer death in men. And it's not only the second leading cause of, of cancer death. I believe it's also one that is highly preventable. And as such, I think it is very important for everyone to listen to this because unfortunately, it's very unlikely that you'll go through your life not being touched by this or knowing someone who is. So without further delay, please enjoy my conversation with Dr. Ted Schaefer. Ted, awesome to be sitting down with you to talk about all things prostate related. It's been probably four years since we did this.

Yeah, thanks for having me.

So I think probably it's worth assuming that there are a lot of people who didn't hear that first podcast, and those that did probably don't remember much anyway. Also, a lot has changed in four years, so I think never a bad idea to start from the beginning. So let's start with talking about what the prostate gland is, what it does before we get into any of the pathology associated with it.

Yeah, so the prostate's an exocrine gland and it's part of the reproductive system. It sits just below the bladder in men. So it's a dimorphic organ. It does not exist in women. It develops in utero in response to fetal androgens. And so it produces basically most of the components, or about 50 to 60% of the components of semen. So it's used in reproduction in all mammals and, or a mammal. So we use it too.

I guess when you sort of think about things that start to go wrong in the prostate, I'm guessing that most men listening to this, the first thing that they might think of is prostatitis. Certainly, age wise, before you get into prostate cancer, which of course we're going to talk at length about, just as a layperson thinking about the prostate gland, I sort of think about inflammation, infection, I think about benign enlargement that leads to obstruction. And then obviously we'll talk about neoplasm. And is that how you sort of think about the problems associated with it.

Yeah, it's an organ that sits in line with the urinary tract. And so the urinary tract in men has a dual purpose. The genital urinary tract has a dual purpose. One it's used for reproduction, the other is used to kind of eliminate all the urine. And so because of that shared functionality, you can develop problems in one or the other of those two disease systems, and they result in symptomatic issues. And a lot of the problems that men, even at a young age, but particularly as they age, will experience are related to the prostate. So in some ways, it's kind of the nexus of the lower urinary tract. So, yes, it's absolutely true that in younger men you can develop infections in the urinary tract. They can be very problematic and difficult to solve and address if it's involving the prostate. Additionally, if you develop an infection, classic bacterial or potentially viral or other kinds of causes, you can get inflammation in the prostate, which can result in long term pain. So that's one of the things I see when young men come in with prostatitis. Then as men evolve and age, as the prostate evolves and changes, as we get older, different issues arise and they can result in and impact your urinary function because it's a shared system of elimination of semen and of urine. And so as we get older, 50 to 60% of men at age 50 and older will have issues with lower urinary tract dysfunction. And those almost always directly relate to the prostate in some way or another. Some of the stats are pretty staggering. So at age 50, it's probably 50 to 60% of men have lower urinary tract dysfunction. But by age 60, it's 75 to 80% of men will have lower urinary tract symptoms.

So let's talk about what those are.

Lower urinary tract symptoms. Weak stream, hesitation or slowness in getting your urinary stream started. Urgency to go to the bathroom, Increased frequency to go to the bathroom. And they're related to two things. One, functional obstruction of the urethra. That's the tube we urinate through, the tube that comes out of the tip of the penis. And that tube, the first part of it, passes right through the middle of the prostate. So as the prostate enlarges, it can compress that channel, and that can result in weak stream. It can result in dribbling and straining. Additionally, the muscle behind above the prostate is the bladder. The bladder is a bag, a storage device that is muscular. And so that muscle, as the diameter of the tube narrows with increasing size, for example, that muscle will have to work harder. Compliance will go down. And when the compliance of the bladder goes down, the capacity can go down, and the increased urgency to go to the bathroom will go up because it's less stretchy. So again, as we get older, the prostate. Parts of the prostate will grow. Oftentimes that growth of the prostate results in narrowing of the channel that can commonly lead to thickening of the bladder wall. And then that results in a whole constellation of urinary symptoms which can be managed. But many, many men have them. And it's certainly something that we talk a lot about with almost all of our patients.

Maybe let's talk a little bit about what the medical management is for those things, because this is an area where the surgeon does both the medical management and the surgical management, right? Typically, yeah.

Urologist. It's one of the more unique specialties in that we do a lot of diagnosing and then managing medically and treating surgically and then survivorship for almost all the conditions that we take care of.

So what are the first steps in the medical management of lower urinary symptoms?

Behavioral modifications. If you're an executive at a water company and all you do is drink water all day long, you're going to urinate a lot. A lot of it is just education and behavioral modifications educating people that a lot of what you take in will come out. The idea that the kidneys are designed to maintain our body's fluid status in a kind of homeostasis. If you increase your fluid intake, you're going to have increased urinary output. And so just basic educational things about that is really, really helpful in addition to regulating what you drink, it's when you drink it and what's in what you're drinking. So a lot of people come in with symptoms of nighttime urinary frequency. And a lot of that is just you can modify with education saying, hey, don't drink two glasses of water right before you go to bed. And if you get up in the middle of the night because you have to urinate, don't drink another glass of water right when you get up to urinate. So that component of the education timing of when you take in those fluids and then what's in the fluids, specifically caffeine. And there are some fluids that have natural diuretic properties. And so if you are taking or drinking something that's a diuretic, you're going to produce more urine. And that will result in more urinary symptoms within two to four hours after taking that fluid in. So caffeine, for example, is a natural diuretic and it will cause you to produce more urine over a certain amount of time than you would if you took in iced tea with no caffeine in it, for example. So a lot of educational things, a lot of education about what to do, when to do it. We often will have people do voiding diaries. Really. It's a diary of what you're drinking and then when you're urinating. And actually just having the patients just walk through that with them will be quite helpful.

So they're measuring their input in timing and volume and output in timing and volume.

Yeah. And that simple task, which is easy, easy to do, will result in a, a realization that, hey, I'm drinking 130 ounces of water a day. Like it's all excessive, it's unnecessary because you can show them that, yeah, you're urinating out the same basic amount of volume. Because we also get in our foods, obviously water too, or fluids. So mapping out behavioral modifications is the first step I always do. If it persists and they're bothered by it, then we'll talk about doing avoiding diarrhea, particularly if their symptoms are a little bit unusual. For example, if you're sensing that they're maybe urinating much more at night than you would anticipate after they've done these different behavioral modifications. There are hormonal deficiencies that can result in increased urinary production at night, for example. So if we're suspicious of any of those things, or if patients are still bothered by their urinary symptoms and they want to not go on a medication, we'll do avoiding diary. We'll map out when they're drinking, when they're urinating, and then we'll kind of go from there.

What if a guy comes to you and is sort of upset about the frequency with which he's waking up to pee at night? The medical term for that, of course, is nocturia. Is there a norm? So you and I are 50 years old, I would say five nights a week, I don't get up to pee two nights a week, I get up to pee once. And obviously that's probably more tied to the timing of my fluid intake and what it was than necessarily prostate specific symptoms. But what's normal if there's such a thing as normal for a 50 year old, a 60 year old, et cetera?

Yeah, great question, because there's a lot of Variability in terms of what you can expect based on the age of the individual. So there's a naturally secreted hormone, antidiuretic hormone, and it in younger decades of life, it has a surge of release around 7 or 8 o' clock at night. Antidiuretic hormone prevents you from diuresing or producing more fluid.

Alcohol, by the way, inhibits this hormone, which is why alcohol before bed is a great recipe for having to get up and pee for two reasons. You get the fluid in the drink and then you get a molecule that inhibits the release of antidiuretic hormone.

Absolutely. And so the classic one for that is beer, because it's a high volume intake. So we have natural diurnal release of antidiuretic hormone and that diurnal variation is attenuated per decade as we get older. So that peak of antidiuretic hormone goes down per decade and that can then kind of normalize your 24 hour urine production. Whereas when you're in your 20s or 30s, you would produce, let's just say, 80 or 90% of your urine during waking hours. During the nighttime, when you have high levels of antidiuretic hormone, you're not going to produce as much urine and your kidneys and your body will save that extra fluid for the morning when you get up.

Is there a biologic explanation for the attenuation of that hormone as we age?

I don't know the answer as to why that could be, but certainly we see it in general in aging populations, men and women.

After we had got through this, I wanted to ask the exact same set of questions around female symptoms. So right now you're saying there's an equalizer. Both men and women experience this reduction in antidiuretic hormone as we age.

And then there are other factors that are also similarly consistent among aging individuals, male or female, like the resiliency of the tight junctions in your capillaries, your vascular system. So it's less resilient and less tight as we get older, even if it's subtle and not fully appreciable. You have some capillary leak, and as you lie down when you're sleeping at night, that fluid will leave the extracellular space, enter the intravascular space, and your kidneys will read that as increased fluid. I have a very focused urology practice, but when I have people with urinary symptoms, I try to do a full body assessment. Because one of the main drivers of nighttime urinary frequency, or one of them that's particularly tracks with age, is Just peripheral edema. So are you developing edema and so forth.

So meaning people who have a lot of peripheral edema in nighttime, you get basically reversal of some of the third spacing.

Yes.

It's almost like they have an IV drip that's taking fluid from their interstitial space into their vascular space. It's like they're drinking at night.

Yeah. So one of my behavioral modifications, it's not really behavioral, but non medical modifications is knee high TED stockings for people who are having symptoms, who if I see them at 8 or 9 or 10 o' clock in the morning, they had any edema, any kind of wringing around their socks or something like that, then I definitely strongly encourage them to do that. I tell people if you're getting up twice a night and you have a little bit of edema, you do some behavioral modifications. We can reduce your nocturnal urinary frequency by kind of one. So you can go from two times a night to one time at night just by changing one. You drink and wearing TED stockings. Maybe not true for everybody, but it certainly encourages people to do simple things without doing the polypharmacy. The other thing that is a main issue related to nocturnal urinary frequency is sleep apnea. And I'm sure you've talked a lot about sleep apnea on your shows. It is a driver of a lot of just bad pathology and one of them is nocturnal urinary frequency. And we'll talk about it later, but in the post prostatectomy space it can actually result in profound nighttime urinary incontinence. But it will produce symptomatic profound urine production and nocturnal urinary frequency in individuals.

And why is that?

I think it's also related to the regulation of your antidiuretic hormones. And really there's profound whole body side effects from it. So there's a subset of men who this is a good way to encourage them to get their sleep apnea a diagnosed and then treated. So that's behavioral.

So then let's talk about the pharmacologic tools. So you've already kind of alluded to one and it's one that we use in our practice, which is when we have a guy who otherwise we don't have a clear explanation for why he's getting up to pee and he doesn't appear to have a particularly enlarged prostate. And we're going to talk about of course, all those things, a very low dose of desmopressin, which is this synthetic version of the antidiuretic hormone, typically 0.2 milligrams before bed has profound effects. So talk a little bit about that and then maybe some of the other things. And also, are there any contraindications to the use of that? I know certainly theoretically a contraindication or a concern would be hyponatremia, as you would sort of increase plasma volume and therefore dilute sodium. But maybe just talk a little bit about how you would use that.

There are very straightforward frontline medical management, pharmacologic agents to manage lower urinary tract symptoms. And generally speaking, frontline ways that we manage it would be with an alpha blocker. That's a class of compounds that are nowadays very, very specific to prevent activation of set of smooth muscles that are really isolated mostly in the prostate and somewhat in the seminal vesicles. So if you just take a step back and look at the embryology of the prostate, it develops from the ureter sinus, and there's mesenchymal and epithelial components of that. So there's a lot of smooth muscle within the prostate. The smooth muscle exists within the prostate in part to help with ejaculation.

It's like a pump.

It's a pump. When you're having an orgasm, the pump squeezes, the prostate will squeeze, and that will result in emission of the fluid. So what you can do for individuals who have lower urinary tract symptoms is that while you have this channel, this tube going right through the middle of it, that's the urethra, you can relax the smooth muscle within the prostate, and that will relax a little bit. Theoretically, it enhances the diameter of the prostatic urethral channel. That's the thought for how it works. And that could then result in relaxation and improvement in urinary symptoms. And it works quite well for most people. Now, originally, this was noted because of the first class of alpha blockers were used for blood pressure control. And so one of the side effects of the first generation of these medications was just profound hypotension until you've titrated up the dose and so forth.

So they're selective in that they relax those muscles without dropping blood pressure. Yeah.

And the newest generation of ones are even selective to the smooth muscle within the prostate and not the seminal vesicle. So the seminal vesicles in the prostate grow up right next to each other. For example, when you do a radical prostatectomy, you take out both organs. They're attached to each other. The seminal vesicles dump into the prostatic urethra. So the second generation Third generation alpha blockers would paralyze or prevent contraction of the prostatic smooth muscle. So you would have improved urinary symptoms.

But doesn't impede ejaculation.

The first, more targeted ones would, yes, because they would in fact paralyze both. Paralyze both. The newest classes of these medications really focus only on prostate. And so the impact on volume of seminal emission or semen is actually much less impacted. And so I usually will just reach for those. They're great.

Typically today you would only use these third generation alpha blockers. What are they called? What are the names of these drugs?

So alfuzacin is the one I usually go to, but there's another 3.5 generation medication called sildenafen. Alfuzacin and sildenafen are the two newest medications that are third generation that result in less impact on sexual dysfunction, specifically less impact on semen production, but have really, really outstanding efficacy in terms of relaxing the prostate and improving urinary symptoms.

Got it. Now, when I was in med school and I remember doing urology rotations and even in residency doing urology rotations, a common drug that was used to treat this was a drug that blocked the conversion of testosterone to dht. So Proscar was the name of drug, the brand name of that drug, finasteride was the generic name. I want to come back and talk about finasteride specifically so we can punt on the discussion of that syndrome that we're going to discuss. But strategically, whether we're talking about finasteride or dutasteride, drugs that block the conversion of testosterone to dht, which again, we'll bracket for a moment, that we'll come back and explain why are those drugs still in use today to treat this particular condition?

Yeah. So there are specific indications where you would think about utilizing a 5 alpha reductase inhibitor for men with lower urinary tract symptoms. It's second line. So if you have urinary symptoms, you failed behavioral modifications, then we would do an alpha blocker. If an alpha blocker is working, but not to the extent that the patient's satisfied and the individual patient has a large prostate over 70 or so grams.

You can easily diagnose that on an ultrasound or mri.

Yes, you would typically be able to size that, no problem.

Can a good urologist size that on a rectal exam?

A good urologist can. I personally kind of think about things like small, medium, large in general, for people in a relatively high quality urology practice, you're going to know the patient's volume of their prostate based on a variety of things you're kind of monitoring for. But if you have a large prostate and you're having progression on alpha blocker, you can reach for a 5 alpha reductase inhibitor, finasteride or dutasteride. And they have been shown to reduce the likelihood of urinary retention and reduce the need for surgical procedures in prospective randomized trials. But in general they're recommended for really the big beefy prostates. But remember the symptoms that they would treat. That is they result in the decrease in the size of the prostate by between 20 and 30% over the long haul. It doesn't happen immediately. When you take an alpha blocker, you feel better within a week. When you take a 5 alpha reductase inhibitor, it will take 6 plus months to a feel better, B, see the size reduction in your prostate. And then of course, most importantly, you'll have an impact on the PSA levels in the serum. And so it's critical that patients are aware that your PSA numbers will is artificially depressed.

You could be masking pathology potentially. Is that the concern? Yes.

The PSA value will decline because PSA is a androgen regulated product. And so when you reduce the amount of that potent androgen, you'll reduce the value of psa, it goes down by about half. So it's that useful drug. But it is not something that I usually reach for because it requires a lot of very active monitoring, has limited effects, effect, limited efficacy in my opinion.

And there's a downside we'll talk about.

There's a lot of potential issues that one can experience while taking it. So I'm very cautious about doing that. So for me, I reach for an alpha blocker. If the alpha blocker is working in terms of improving the kind of outlet obstruction symptoms, that's strength of the stream. How fast can you empty? But patients still have a significant urinary bother, increased urinary frequency, urgency to go to the bathroom. Then you can either do an antimuscarinic or an M3 agonist, which is the newest class in that category, which really helps relax the muscles in the bladder and really significantly impact the symptomatology for people with those kind of predominantly what we would call storage symptoms. You can have obstructive symptoms, alpha blockers are great for those. You can have storage symptoms.

And storage symptoms are frequency, frequency, urgency.

Just think about it, if you have a thick bladder, the compliance is poor, it doesn't stretch well, it just always kind of feels full. Then those are Things that can be very nicely addressed with these agents. The antimuscarinics are dangerous, or you need to be careful when using those, because in aging individuals, they are associated with worsening of dementia and other kinds of neurologic cognitive acuity. So the M3 agonist has the same net effect, are much cleaner, much less side effects.

And the antimuscarinics were just older drugs.

They were.

So we kind of put those in the same category as maybe the five alpha reductase inhibitors.

That's right.

You always look for a better option first. Are women as susceptible to urgency and frequency from the same underlying pathology? Obviously, women, when they go through menopause, estrogen withdrawal alone can produce those symptoms. And there the treatment is clear, it's estrogen replacement. So given that women don't have a prostate and therefore don't have something abutting their bladder in the same way, is there a role to use these M3 agonists in their frequency and urgency symptoms?

Yeah, I mean, most of those medications and the prescription frequencies is much, much higher in women. So that would be the classic overactive bladder. Women will have bladder symptoms that are also similar in men. The men have,000 to one more often obstructive symptoms. Because the urethra in a woman is very short. It's 4 cm long. The urethra in a man is 25 cm long on average, or something like that. So the obstructive symptoms are much more prevalent in men. And so that's why frontline is always an alpha blocker. But if they're having a good response with an alpha blocker but still bothered, you can reach for an M3 Agonist. For me personally, though, it's always a balance, because at some point you have to start saying, well, okay, how old is the patient? How significant are their symptoms? Because there are highly effective ways to manage these issues surgically these days. They can, most of the time, be done just as a simple outpatient. I usually begin to introduce the idea of, okay, well, if you're still bothered, we have outpatient surgical procedures that can basically fix this for life with no medications. That's kind of my stepwise process that I lead patients through in terms of thinking about their urinary symptoms.

Let's talk about the surgical procedure. So again, just kind of going back to my. What I learned about 25 years ago, the TERP, the transurethral resection of the prostate. Kind of a Roto Rooter job.

Yeah. The prostate develops from the urogenital sinus. The prostate, as we Mature in response to androgens and estrogens too, for that matter. It develops into different zones or different regions. The peripheral zone, which is outlying the prostate, think about a orange. And the orange peel and the pulp of the orange is the transitional zone of the prostate that gets bigger. Actually it's not just a testosterone driven thing. It's actually when there's more estrogens around that actually with testosterone that can result in hypertrophy increasing in the size of the transition zone. That is what causes all the urinary symptoms in individuals, with rare exceptions with an aggressive cancer, that's what's causing it. In those situations you can do what they call there's a variety of missed procedures, so minimally invasive surgical procedures that can address these urinary symptoms. So you can do a variety of things. You can introduce steam into the urine, transitional zone tissue that can then kill that and effectively kill all the smooth muscle and reduce to some extent the kind of hypertrophy of the epithelial cells. You can surgically resect it transurethrally. Transurethrally. So no incisions. A natural orifice procedure. You could suspend it surgically. So there's kind of tethers that you can put in place that tent open the urethra. But the mainstay, the gold standard is to remove the tissue, which can result in profoundly improved urinary symptoms.

And is that done with laser electrocautery? I mean, what is the gold standard today for the means by which you remove the tissue?

So the gold standard has always been the turp procedure, which is what you described. Now that procedure itself has evolved in that it can now be done with irrigation, that is with normal saline. Traditionally, to maintain a monopolar current, you had to use water because you would not want the sodium to disrupt that current. So now a modern turp is a bipolar turp.

Explain to folks why you need an irrigant when you're doing this procedure.

As you described it, this is a kind of roto rotor procedure, but you're technically removing bulky tissue in the urethra that's circumferentially surrounding the prostatic urethra.

You've got this thing here, using the natural orifice of itself, you have to expand the diameter of this thing by actually getting rid of prostatic tissue in the transitional zone.

Yes. So you scrape out small portions, usually one or two gram sized little scoops of tissue. You do that with effectively a hot knife. It's shaped like a loop, so you core out Little loops of tissue. And when you do that, you, A, have bleeding and B, the tissue collapses on you. It's like a cave. So it keeps falling in on you. So you have to suspend it open with the irrigant, and you have to use the irrigant to better visualize what you're doing. That's a traditional turp that was always done with water. And when you did it with water, and you were tenting open the tissue, putting it under pressure, you could have water move into the intravascular system and you could get something called post TUR syndrome, which is basically where you made the patient profoundly hyponatremic.

You diluted their sodium too much. And that's very dangerous.

Yes. And you'd have significant neurologic issues and so forth. So that particular procedure, there's lots of advances in urology in this particular space. That procedure. Fifteen years ago, they started basically redesigning the devices so you could do it with saline. So therefore, if there was flow of fluid from the procedure into the intravascular.

Space, it's just like giving them intravenous fluid that's isotonic.

Exactly. So that really prevented issues that you could have with this TUR syndrome. And TURP is a very effective. And it remains the gold standard that all these new mist, these minimally invasive surgical techniques compare themselves to in terms of efficacy. Now, I have the pleasure of having a partner at Northwestern, Dr. Amy Krambek.

We've actually sent a couple patients to her.

Amy does a procedure called holep, which is a homeium laser enucleation of the prostate. So the turp basically is effectively scraping out little 1 gram chunks of tissue. So if you have 100 gram prostate.

Your goal is to get that down to 50.

Your goal is to get it down to 15.

15. So even less normal, we would say, might be 30, right?

Yeah. Normal prostates increase in size as we get older. A normal prostate for a man who's 40 or 50 is between 20 and 30. But people can have profound urinary symptoms with prostates that are as small as 35 grams. So people often assume because you have urinary symptoms that you actually have this gigantic enlarged prostate. That's not always true, but the smaller prostates typically can be well managed with medications, and only will we be moving to surgical treatment when the prostates get larger.

So you've got sort of a selection bias going on.

You do. So frontline gold standard historical is turp. It's now a bipolar turp. So it can be done safely.

And the reason you go from 100, if you're starting there, down to 15, as opposed to 30 or 40, is you want to be one and done. You never want to be back again.

Yes, A good surgical procedure is effective for life. Now, they're not all like that. And so the ones that the less tissue remove, if you don't remove any tissue, for example, you're more likely to have a secondary treatment. My partner, Amy Krambek, is really one of the pioneers in modern whole lap surgery. So this is different. So, again, if you think about the orange analogy at TURP or any of those other procedures is basically trying to scrape out the pulp one little chunk at a time. Amy will go in, and she'll get in the plane between the peel or the rind of the orange, and she'll take it all out in one piece. She pushes it into the bladder, and then there's a morcellator that then chomps it into little tiny pieces that you then remove through the urethra.

Let's make sure people understand that, because I love that. I think your orange analogy makes this so much easier to understand. If you're doing a terp, you've got a pencil hole going through the orange. You got to put a hollow pencil into that pencil hole, and literally one tiny, tiny thimble at a time, pull out little sacks of pulp one by one by one by one by one by one by one.

Yes. Additionally, remember that when you're doing that, you're disrupting the kind of architecture of the orange, and there's lots of blood vessels that exist within the transition zone itself.

Now it's bleeding like a sieve.

Bleeds a lot. When Dr. Krambach, when Amy does her procedures, she gets in that natural tissue plane.

She shaves into that natural plane, and it's not bleeding as much. And she somehow manages to take that whole pulp minus the peel, shove it into the bladder, and when it's in the bladder now isolated, you can break it apart.

She'll morselate it apart. So she is spectacular. HOLEP was a procedure developed originally described in New Zealand, I believe, by a New Zealand urologist. And it was limited for a long time based on the technology that existed within the lasers. But the laser technology and Amy really helped develop the latest versions of these lasers that are just higher energy, more precise. Take that, and then you can then couple that with an experienced surgeon, and the outcomes for it are spectacular.

What are the patients who would not be considered candidates for that procedure? Is there a contraindication to that?

No, if you're talented enough, you can do it in anybody, which she can. Now, the smaller the prostate, the less distinct the differentiation is between the peripheral zone, the skin of the orange, the peel of the orange and the pulp. And so it actually requires more skill to do a whole EP in a smaller gland than in a bigger gland. When the prostate's really, really big, the adenoma is very well formed and it's easier to get into that plane. So a large prostate would be something over 80 grams. That's where you'd really say in, let's say a general urologist practice, the threshold for doing a turp like procedure goes down. It's really long to do a turp. It takes a long, long time to do it. If you're a talented whole lab surgeon, Amy can do a 200 gram prostate in about 20 minutes. I mean, it's just spectacular.

Tell me about what that patient goes through post procedure. They go home that day. Obviously it's an outpatient procedure. They have a catheter in place. No, no catheter. Yeah, because that's the other thing I remember, Ted, from when we were little spring chickens is the catheter management on that patient with a blood bag full of bloody water and urine coming out for days and days and days. And again, it's a relatively small price to pay, I think, for the ultimate relief you're gonna get. But how is it that this patient just literally leaves the office without a catheter?

So it has to just do with what you do at the end of the procedure. So how? Well, you're controlling the bleeding. And I think the big difference in holob, as I mentioned, is when you're in that distinctive plane between adenoma and peripheral zone. It's just the vessels are much more discreet, whereas in a turp there's these sinuses and so forth.

So the analogy again to the orange is perfect. If you try to peel an orange from the inside, ripping apart, you're going to get orange juice all over your hands. Whereas if you're taking the skin off.

It'S actually, it's less elegant, you remove less tissue, it's bloodier, etc. So, so big picture. If people are on medication and they have progression, you can start talking about minimally invasive surgical procedures. There are in office minimally invasive procedures, they're quick. In general, a take home message though is the less you do, the less durable and the less effective it is over time. So there are procedures where you can tent up the prostatic urethral channel. They work with basically temporary relief. I would only even consider those in individuals who could not tolerate the medications.

If you're gonna go to the trouble of actually putting a probe in the urethra to go through the tenting up procedure, why wouldn't you just do the procedure? Amy does.

I do. I'm just saying for your general audience. That may be offered for somebody. I never recommend it because it never works. It can cause a lot of pain. You put these clips and you're tethering things up. It prevents effective, high quality mri. There's lots of limitations, but people may who listen to your show may be offered these things. It's called Urolift. Next step up would be to basically use steam to ablate the prostatic cells. When you do steam, you're desiccating the cells, and that can result in pretty good symptomatic relief.

Do patients require general anesthesia for this? I've forgotten.

No. For the Urolift, you can do it in the office. For this procedure called Rezum, you can do that in the office with local anesthesia. It's uncomfortable for patients, but it can be done there or it can be done under, like, twilight. That works. It is a step more in terms of intensity and what you feel. Those individuals go home with the catheter. There's lots of edema and lots of swelling when you do that procedure. So they require a catheter for several days to a week.

Right, because that steam creates inflammation even though it's cauterizing. And if you don't leave that catheter in, they're going to get urinary obstruction. They're going to close their urethra.

Rezum would be the next step up in terms of invasiveness. Then you could always go to this traditional turp or bipolar turp. Those are all effective therapies to think about or talk about with the patient. When your prostate's less than, let's say 70 or 80 grams, holep was originally developed to just handle the bigger prostates, which traditionally, you and I, when we were training at Hopkins, we would do an open, simple prostatectomy. That's where you open the patient up from above, just below their belly button, you open up the bladder, and then you manually, with your finger, carve out that inner pulp of the orange, leaving the peel of the orange behind.

And the reason you leave the peel behind in that procedure is because it's not a cancer, you don't need to risk injuring the neurovascular bundle on the Outside, you see what we're going to talk about when we get to prostate cancer.

Everything around the outer peel of the orange is all the important real estate. So the urinary sphincter muscle and all the nerve tissue that goes to the sphincter and also goes to the cavernosal bodies that trigger erections. So that was what we used to do. Now that procedure's evolved that can be done minimally, invasively with a robotic procedure. And that was really emerging as a standard of care. And then the super talented surgeons like Amy Krambach came along and can do a 200, 400, 600 gram prostate.

First of all, can you just show me what a 400 gram prostate looks like?

Like physically, 400 gram prostates, a large grapefruit, I mean massive. Whereas a normal prostate is a golf ball. So a normal prostate is a golf ball. An orange would be 100 grams, a big grapefruit is 400 grams. That used to be a procedure that was technically very difficult to handle with an open, simple prostate. Robotic simple prostatectomy. Amy Crambeck can do three of those in a day and be done by noon. Spectacular stuff.

A couple of other just questions on the size of that prostate. So when a guy has a 2 to 400 gram prostate, how much of that is genetic? Is that virtually all genetic?

Yes. You see that a lot where it runs in families. So what it is that is underlying that overgrowth? Not well studied, frankly. Should the NIH be putting their research dollars behind, like, why do men get big prostates? Probably not.

Is there any correlation with prostate size in cancer? Yes, talk about those extremes.

So the bigger the prostate, the less your chance of developing aggressive cancer is.

Why is that?

Not sure. It may have to do with variations in the balance of hormones. Large prostates grow in response to not an increase in testosterone actually, but more of an even ratio of tde. So testosterone, estrogens. So actually, as your testosterone declines, as you know, as you get older, the T can go down, estrogens remain pretty.

Stable or can go up, especially if you have metabolic syndrome. Estrogen will rise.

As men age, their prostates grow, and I believe that that's more hormonal.

You're saying that again. Classic thinking that has clearly been proved false is that testosterone is causing prostate cancer. You're saying it's way more nuanced than that. And if the endocrine component of prostate cancer may be more related to the relationship of testosterone and estrogen, and a declining testosterone in the presence of a rising estrogen would be A more favorable endocrine milieu for prostate cancer than the younger phenotype, which is higher testosterone to estrogen.

Yeah, well, let's just take that back a second. So as you're aging and if you have metabolic syndrome, your testosterone levels will go down, your estrogen levels will go up, and that can result in prostatic growth. But it's typically more adenoma growth in the transition zone, causing lower urinary tract symptoms.

Benign growth.

Benign growth that somehow is protective, either the size or just the ratio. That difference in ratio of T to E is somehow protective for developing kind of later onset prostate cancer. Remember, in my mind, you're locked in and your code is effectively set in stone in your 30s and 40s, in my opinion, for prostate cancer.

Wow.

Right. When your estrogen levels are very low, your T levels are higher. Now, we'll talk a lot about testosterone and what it's doing in prostate cancer later, but in my opinion, it's the T to E ratio that is responsible for prostatic enlargement much more than the development of any prostate cancer.

Just to close the loop on the surgical procedures for lower urinary tract symptoms, two final thoughts. One is, what is the floor for.

What'S it called, the whole holep home? Laser enucleation of the prostates.

In the hands of someone as talented as Amy. What is the smallest prostate she would do that procedure on?

Well, somewhere on, let's just call it 25 or 30 grams.

Oh, wow. So basically, there's no limit in the hands of a talented surgeon.

Anybody who needs a surgical procedure, that's her. Go to technique. Now, below that, there's not a lot of transitional zone tissue. So the other key take home message for the listeners are if you're developing profound urinary symptoms and you have a small prostate, you have to start looking for other sources.

And by definition, you're not responding to two classes of drugs.

Yes, you have to worry about cancers, not prostate cancer, but you have to worry about urothelial carcinoma. Urothelocarcinoma, which is a cancer in the lining of the bladder, but also can.

Even get into the urethra.

The urethra has urothelial lining. Oftentimes people, particularly young women, will. It's a classic board exam. Younger woman comes in with urgency, frequency, you neglect to look at their urine for cancer cells, and they can have a cancer in the lining of their urothelium that's causing all those urinary symptoms.

So small prostate unresponsive to medical management, persistent symptoms you better be doing urinary cytology.

In my opinion, you need to do a workup to rule that out for sure. And there can be other central nervous system diseases that can result in urinary symptomatology. But in general, as a urologist, you have someone coming in with those symptoms. You really want to start understanding, well, what else could be going on because as we mentioned, those individuals may have had a history of prostate infection like a bacterial infection, or may have had a viral infection. They can result in prostatitis and inflammation in the pelvic floor itself. And that can result in all those symptoms. And so yes, you can have as your canary in that coal mine that you have urgency frequency. But it's not at all attributed to a large prostate. It's not attributed to drinking too much fluid. If you take away the attribution of a urothelial carcinoma, then you have to start saying, well, what are the other causes? And there's a lot of potential issues that can be addressed that can cause that inflammation that has unknown etiology to what incited it causing that urgency frequency, urinary bother.

Now, given the success of this procedure, obviously Northwestern is probably top five urology institutions in the United States. Does every city have an Amy? What's the frequency of surgeons of that skill?

I would say that in the U.S. well, I'm biased. I think there's only one Amy out there, but there's very few people who are as talented as she is. I would say that there's probably 10 whole lab surgeons that are on her.

Par at her level that could basically go all the way down to a 20, 30 gram.

It's not the small prostate. Yes, it requires a lot of skill to do the small prostate. But handling these very, very large prostates in individuals who are incredibly frail and older who were told look, you're too.

Old for a surgery.

I was just on call a couple weeks ago and we had a 95 year old gentleman came in from another major hospital in our city who was having bleeding from their prostate that was more than one unit of blood a day transfusion. What? Yes. And was told we can't do anything for you, you're too old and you're too frail. So I go around on this guy on a Saturday. Amy had done a whole. It was a hospital to hospital transfer, quaternary care to quaternary care center hospital. Right. Just speaks to her skill level, transfer in. She does the whole EP. It was a 450 gram prostate. She takes out 400 grams of tissue. And the guy, we left a catheter in him because, you know, we just weren't sure. We took his catheter on Saturday morning. He went back home age 95. So amazing. Like really a talented surgeon like Amy. And there are other Amy's out there, but talented surgeons like Amy, which are hard to find, really can transform people's quality of life.

Yeah. Okay, before we get into some of the pathophysiology of how the hormones impact the prostate, which is a good lead in, I think, to cancer, let's go back and talk a little bit about prostatitis. Because I would guess that for many men, that is their first brush with pelvic floor discomfort and a symptom associated with this gland. So I remember you probably don't remember this, but I remember having a brush with this about six years ago. And of course you helped me out. This is part of the problem when you start to play doctor to yourself. So all of a sudden I start having some discomfort when I'm peeing and I do all the usual stuff. I check, was it an infection? Dah, dah, dah, dah, none of the above. So it's not like I have a urinary tract infection or, you know, an STD or anything like that. And boy, and it's not unbearable pain. I don't want to over dramatize this. It's not like razor blades are coming out, which I've heard people describe that might be certain infections. No, no, it's none of that. It's just not comfortable. It's really uncomfortable to void. And I gave you a call. I remember exactly where I was when I called you, by the way. And you were the one that said, no, no, no, look, you started asking me a bunch of questions. Hey, you've been traveling a lot. Are you a little constipated? And one thing led to another, and the diagnosis in your mind was playing doctor over the phone. At least I'm actually more likely thinking this is prostatic inflammation. So walk us through the pathology of that.

I wish I could tell you in the next five minutes what the pathology was, because the short answer is we do not know. We call this constellation of symptoms chronic pelvic pain syndrome. What that really ends up meaning is it's a bucket we put a lot of different things into so you can have pelvic pain and discomfort if you have a large prostate and it's obstructing your urinary tract. Okay, that one we talked about, you can manage that? That's pretty easy to do. But there are other things that can cause pelvic pain and discomfort. One would be acute bacterial infection. And that's a classic. Frankly, if we find that, I feel good because I know we have a solution, we can address it and so forth. You can address the infection. Now, the inflammation and the discomfort and pain that results after that may take much, much longer to resolve. You can have a non bacterial inflammation that could be viral, although no one's really ever isolated specific viruses that are individual man tracks with that pain, but viral. And then there's pelvic floor dysfunction that is outside of the urinary tract. That pelvic floor function could be in the anus and in the rectum having to do with dysfunctional voiding or elimination in the rectum. It could have to do with dysfunctional elimination between the bladder and the urinary or urethral sphincter. Those are common in kids.

The other thing anatomically that maybe we failed to mention was the proximity of the rectum to the prostate.

Yeah, the rectum and the prostate are adjacent to each other. The rectum and the prostate effectively develop from the cloaca. Cloaca is the embryonic sewer. That's where all the waste in a fetus would go into and out of. And then it's divided anteriorly and posteriorly into the urogenital sinus. And then what becomes the anus and the rectum? And so, yes, they're intimately associated with each other. And the innervation between the two of them is actually there's a lot of cross innervation. So if you have inflammation in the gut, in the rectum and the anus, you can result in irritation and inflammation in the prostate. There also can be translocation of bacteria between the rectum and the prostate. So when we are talking about your individual situation, I said, are you traveling? Are you constipated? We think that that can result in maybe some increased transmural translocation of bacteria.

And by the way, to this day.

We don't really know what it was.

Yeah, but that said, I go to great lengths to make sure my bowel habits are regular when I travel. It's still difficult. I'm out of routine. I don't know if it's dehydration, I don't know what it is. It also might be parasympathetic sympathetic balance. I think there are lots of reasons. Most people I talk to as patients, obviously I don't have this discussion at parties, but will say, yeah, I just get Constipated. When I travel a lot, that almost always seems to produce some change in voiding quality 100%.

So there's a huge correlation. Number one, it's just physically the pressure on the prostate and so forth can just make it much more difficult. So the classic presentations for a man with urinary retention, obviously post procedural. So if you have a hip or a knee, anesthesia can shut your gut down and you can get constipated and you can do that. Or some of the different cough and cold medications can do the same thing. But in general, I think of travel constipation from changing in your bowel function, that will be a big one. And even if doesn't make you frankly go into urinary retention, it affects how you urinate and so forth.

So let's say you rule out the common stuff. Your father wrote a very important paper in the New England Journal of Medicine. Has it been 20 years now?

15 years ago?

Yeah, I refer back to that paper quite a bit. And it was actually following the algorithm of that paper that when I got back to New York from back in, whenever this was going on circa 2016, that we went through that diagnostic procedure, walk through that procedure, which again, I think for most people it's a long run. But when you're dealing with something so complicated, it is important to get some diagnostic specificity because the treatments do differ. Once in my case the treatment was identified, the fix was on.

There's a workup that you can do. You implement if you're concerned about or worried that someone has an infection in their prostate or potentially their seminal vesicles, that you would have to go through to distinguish that type of infection from an infection in the bladder, which is right next to the prostate. And so that is basically was described by a Stanford urologist, Tom Stamy, and that effectively was that you would capture urine as it comes out the urethra in different phases. And therefore you could track where that urine came from. So it's actually a four step process. So the first step would be to capture urine immediately after you start voiding. That would then capture and wash out any bacteria within the urethra, the long channel between the bladder and the tip of your penis.

So that first few cc of urine.

It gives you a sense for, is there any bacteria growing in the urethra? Urethritis. Then the second phase would be you would wait a couple seconds and then capture urine midstream coming out from the bladder. And then you could then determine, is there an infection in the bladder. Then what you would do is you would tell the patient to pause. You would do then a rectal examination and you would press on the prostate, pressing on the prostate vigorously so that you could effectively in some ways replicate what happens in an orgasm. That is where the smooth muscle squeezes the fluid out of the prostate. When you do a vigorous rectal exam, you're trying to push the fluid into the urethra. You can sometimes just actually capture that prostatic secretion by itself. We call that EPS or expressed prostatic secretion. You can send that off for an evaluation for any bacteria in it. It's not always the case that you can get that fluid out. So then what you would do is to send the patient back to the washroom, have them capture urine coming out of the urethra, the beginning of the flow, right after a vigorous exam. That will capture the fluid that may be still in the prostatic and the other parts of the urethra, but it was in the prostate. And that would be the kind of essence of the step. And then you can just complete the void. So then therefore what you can do is look for where are the cultures showing any bacteria? And the cultures that would be, let's say, for example, clean in the initial void, that would be VB1, the initial void and clean in VB2, that would be the bladder. But having bacteria in the EPS, the prostatic fluid itself, or VB3, then that would tell you that there's an infection within the prostate. Now, the key thing is that standard labs will call an infection if they see bacteria that's growing more than 10 to the fifth, so more than 10,000 plus bacteria in that sample. But if you're worried about having an infection in the prostate, for example, you.

Need to lower that threshold.

Are you having hundreds or thousands of bacteria? So it's 10 to the 2 or 10 to the 3?

Because that should be a completely sterile.

It should be completely sterile. The prostate is a hostile environment for bacteria to persist. It's very acidic. It's actually thought when people say, well, like, well, what's the point of the prostate, right? It's used for reproduction, but it's also thought that it can be somehow a barrier to developing an infection in a man in the bladder. So the hostile acidic environment of the prostate is thought, people speculate, to somehow prevent a bladder infection. Because remember, pre modern medicine, if you as a man would develop an infection in your bladder, it's life threatening.

Yeah. Especially if it goes up to the.

Kidneys, if it goes into the kidneys, or it goes into the blood, you get urosepsis and you often will die. So people think, okay, what's the prostate for? Well, it's used for reproduction, but it's also maybe used for helping to prevent, as a natural barrier for bacteria to go all the way into the bladder.

Do women have any such thing? I mean, women are so much more susceptible to UTIs because of the short urethra.

Yes, they're susceptible to UTIs. But remember, if you have a infection in the bladder of a woman, yes, it can also track to the kidney. But in general, there's limited stasis of urine in a woman's bladder because the urethra is so short and you can evacuate or empty the bladder so effectively in a woman. Whereas in a man, as you get older and your prostate gets larger, you.

Get more stasis of urine in the.

Bladder if you retain urine that's infected with bacteria.

So all things equal, women are less likely to develop urosepsis kidney infections based on the fact that it's easier for them to evacuate the bladder. If there's an infection, it's by decade.

So young men, they're the least likely to get any urinary tract infection, period. But as men get older, their chances of developing a urinary tract infection equal that of a woman. But you could argue because of the urinary stasis, et cetera, that that infection in a man is much more life threatening early on in their disease course than a woman. The probability that you would develop an infection in the kidneys is probably the same between a man and a woman. But remember, if you have a man who's older who has a bladder infection, that can go into the blood, but it also can go into the prostate. And as we were alluding to in our discussion of working up somebody for a prostatic infection, clearing an infection in the prostate is very, very difficult and very challenging. So you have to do this specific Stami 4 glass test. That's the different phases of the urinary voiding. You have to rule out that there's any infection in the prostate. It's rare that we would pick that up, but it's possible. And the other place that you want to look for in the kind of very unusual cases is in somebody who has maybe an infection in their seminal vesicles. Maybe we can put a picture up for the audience. But the seminal vesicles, they produce about 50% of your semen. You can get a bacterial infection in your seminal vesicles. And unless you're looking for that infection, you'll never clear that person because it's kind of very isolated from any continuity of the urinary tract, but can result in pelvic pain, can result in persistent issues of infection in general. We do that very specific test to rule out infections in the urinary tract that are related to the prostate or the seminal vesicles. The other way you could do it, a poor man's version, is to actually send off a semen for a bacterial testing. We like to do this express secretion kind of setup, but you could do that, too. If you have an infection in the prostate or in the seminal vesicles or the genital tract, then yes, we know how to treat that. It's with directed antibiotics that in many ways will address the infection and most of the time address the pain and discomfort that's associated with those symptoms. Now, the issue is that there are many people who have discomfort that is not associated with bacterial infection. Could be viral, it could just be inflammation, and it's not necessarily within the urinary or genital tract. So I see a lot of patients, and when I do a rectal exam on somebody who's complaining of prostatic pain, I always want to feel the muscles in the pelvic floor.

And how do you do that on the rectal? Is it just a broader exam?

So when you do a rectal exam and you feel kind of straight posterior, you're feeling just the prostate. If you just move your finger laterally.

You'Re into the pelvic floor.

You're in the pelvic muscles for sure. And so oftentimes you won't feel much of anything. But in a man who has pelvic.

Pain syndrome, meaning it's just locked up.

It feels like a guitar string, you'll feel bands of muscle. So think about when you tweak your traps. You have those bands of muscle you can feel with your hands. But the good thing about that is you can go get a massage and you can work it out. And that same thing happens in the pelvic floor muscles. So when I'm dealing with the patient who has chronic pelvic pain syndrome, or pelvic pain, I should say maybe not chronic, but oftentimes we'll see them after a while. This discomfort and pain, I try to treat their symptoms based on where the pain is coming from. So is it prostatic? If it's prostatic, I try to do things like alpha blockers, potentially. Cialis is another one to treat symptoms that are associated with that discomfort. If I pick up that they have a lot of tightness in their pelvic floor, I send them for myofascial release. So it's transrectal myofascial release. It sounds barbaric.

I've seen this change a guy's life 100% and the same for women.

Yes, true. So I feel great. If I'm examining somebody and they have that, it makes me feel good because I have a solution. The ones that are difficult are the ones that we just don't know what's causing. It can be related to food too. So if somebody has pelvic discomfort or pelvic pain, you do a very thorough diary of what they're eating. And it's more classic in women with the kind of female equivalent of this would be interstitial cystitis where you'd say, well, what foods trigger it for you? Because it can be triggered and irritate the bladder and that's causing the pelvic discomfort. So again, you take a thorough history. The NIH has a very good online questionnaire to help you kind of tease out where the symptoms are coming from.

That's under NIH's website. Or is it under specifically if you.

Google NIH, chronic pelvic pain Syndrome Questionnaire, you'll get it, you can take it and you can delineate that. And so yes. Is it common in young men? No, but it's more common for if a young man's seeing a urologist to have that than let's say BPH or something. Obviously the most common thing for a young man to come see us for is ed. But yes, it's definitely something that we can address.

And I've seen a number of men who go through the diagnostic workup. There is no infectious agent whatsoever. But simple prostatic massage, just like you describe a massage to an ailing muscle, alleviates the problem. It's a very anti inflammatory process.

Yes, that's a great point. So a why that works for some people we don't know, but it works and hey, we'll take it. The other classic thing I hear about and you'll hear about in medicine is, well, I have chronic prostatitis. Again, that's a very specific diagnosis. It's a bacterial infection you can't clear. So it's almost impossible to have that. But I have chronic prostatitis and I take an antibiotic and I'll go on 30 days or 60 days of this stuff and it makes me feel better. That scares me a lot because as you know going on, anything like a potent antibiotic has a lot of downstream consequences that you just gotta be careful of changing your gut flora. All these different issues, why is it that they work? And if you ask the patient, they'll say as soon as I get this discomfort, I'll take a Cipro, I'll take Olivaquin, I'll take a Bactrium and I feel better. It's because these powerful antimicrobial agents, these antibiotics, they are profoundly anti inflammatory too. So if that's what they're telling me, I try to transition them out of popping these month long runs of antibiotics and get them on an anti inflammatory.

Is there a particular NSAID that you find works better? Does Celebrex even work? I don't find it to be necessarily as potent.

I try to stick with the more potent ones. And I think naproxen is what I like. It's bid dosing, it can be a little hard on your stomach. Ibuprofen is incredibly potent, but taking the right dose three times or four times a day can be hard.

What about Meloxicam?

I haven't gone to it, but it theoretically should work. And people, you know, they have different sensitivities or efficacies with these different ones. So I start generally with naproxen and I'll do that with a little bit of an anxiolytic because some of the anxiolytics they relax a lot of your muscles and they'll help relax the pelvic floor muscles because although you want to treat that particular symptom, it's causing inflammation in all the structures around it, rectum, bladder, prostate and pelvic floor muscles. So I usually will try to do that for a limited time. I don't like people taking long term antibiotics for it unless they have a difficult infection to clear.

I have a friend who I sent to you recently in that boat, right, where kind of has prostatitis, believed to be bacterial prostatitis once a year. And that triggered my thinking that maybe that's not what this is and maybe we need to go down a different path.

Now there are individuals who we can't put our finger on what's causing the symptoms. But my father still has an active research lab. He is the worlds of Florida on prostatitis and pelvic pain. And one of the things he. And he's still at Northwestern, he's still at Northwestern. He has an ongoing clinical trial for people. He believes that a lot of discomfort and pain has to do with mast cell dysfunction. He has a clinical trial where he'll actually see individuals. He'll do an eps, he'll look at their voided fluid, he'll assess them for different markers for mast cells. If they're high, he'll put them on mast cell inhibitors in a clinical trial, and it's quite effective.

So if folks are interested listening to this, presumably this is a trial only for men, of course. Where can they find more information about the trial?

Yeah, on the Northwestern Feinberg School of Medicine under the Department of Urology's webpage, My father, Anthony J. Schaeffer and Praveen Tumbakat, he's my father's scientific partner, they are working on this.

We'll link to that as well. For folks who are interested in that.

Trial, there is hope for these individuals because there is a subset of men. We do see that it really is sad because it has a huge impact on the quality of her life.

We've talked now at length about two of the big problems associated with the prostate. And while both of these can be an enormous threat to the quality of a man's life, they're not often a threat to the length of life, though. I guess one point I'd make before we leave these is one of the questions I get asked a lot is how does somebody actually die from Alzheimer's disease? What I usually explain to people is they usually don't die from Alzheimer's disease. They usually die from something else that is brought on by the Alzheimer's disease. And one of the classic, sad, tragic cases you see is urosepsis. So you see a man with Alzheimer's disease, so one, he might have a catheter in him because he's unable to void on his own, and that dramatically increases his risk. But even if he doesn't, he's simply less responsive to the signs of an infection. He's not attentive to the fact that it's burning when he pees. And because of his age and his immunologic reserve, what starts out as a urinary tract infection on day one is a lethal case of urosepsis on day four. And so I do think of this as kind of one of the grim reapers of older men.

Yeah, I mean, as men age, and particularly if you have concomitant other significant medical issues, your frailty goes way up. And so any little insult to your body can do it. And obviously, classic things are aspiration, aspiration.

Pneumonia, smallest cellulitis, if you're not moving around Exactly.

And so I think it's a lack of awareness. It requires a very astute caregiving family or cohort of individuals to notice subtle changes, because obviously, if you can pick up an infection early, then it doesn't necessarily have to spread and it won't be so symptomatic.

If you could speak to someone listening to this, who's caring for an elderly patient, male or female, who is in the throes of dementia, what can a caregiver do on this particular front? Is there anything they can do to minimize the risk of a kidney infection or a bladder infection turned into systemic sepsis?

Good hygiene is obviously key. In general, if you're monitoring the individual, they're voiding history. So we obviously would prefer for people to void on their own. And many people can. Many times people have catheters in place for convenience of the caregiver. And so if you can keep hardware out of somebody, that's obviously very effective, and if the individual can't void and they're having trouble with that, then intermittent catheterization is what we obviously endorse and recommend. Where you just place a catheter temporarily.

Intermittent catheterization poses less of an infectious risk than constant catheterization. Little counterintuitive, right? You would think, gosh, if three times a day you have to cath somebody, that's three times you're introducing it, but you're saying if it's done with perfectly sterile technique, dwell time, right?

So three times a day for 60 seconds each. So that's 180 seconds versus 24,7 for the bacteria to be there. And we know if you leave a catheter In Place, by 48 hours, the bacteria has crawled up the tubing and is in the bladder. So, yes, if you can minimize the dwell time of the foreign body, the better. So, yes, it is a little counterintuitive. But for men and for women, if you can do intermittent catheterization, that's a profound way to reduce the chances that you develop any urosepsis. Will you develop or will you have bacteria in the urine? If you do intermittent catheterizations possible, does that mean that you failed with that technique? No, because if you're continuously emptying the bladder, you never can get overgrowth, and you can never get enough urine with bacteria in it to cause or pose a problem. That leads to another point, which I often see, which is in individuals as they're aging, dehydration is a key underappreciated contributor to all these medical conditions.

Especially because older people lose their relationship between thirst and hydration status. That's another one of those things that deteriorates as they.

Yeah, and if you have Alzheimer's, you forget to drink, frankly. And so if you have bacteria in the urine, but you keep the concentration at 10 bacteria per milliliter, well, that's not gonna be a problem. But if you're dehydrated and you have more concentrated urine and there's the same amount of bacteria with less urine, you could really have significant issues. So as we age and you have these comorbidities, a good caregiver is critical. Oftentimes in medicine, they're paid the least. It's really an important role that you have. So I think if you can maintain any kind of hardware in an individual, get them out walking around and just remind them to drink. If they have a catheter, you want to get that catheter changed every month or three weeks. And generally, a good caregiver and a good urology practice, we have a whole team of nurses that do this for our cohort of patients. They'll get an idea of the cadence for that individual, but we try to stay away from it if at all possible.

Okay, now let's talk about the third big pathologic issue associated with the prostate, which is prostate cancer. Prostate cancer is the second leading cause of cancer death for men, behind only lung cancer. And so, in order it goes for men, it's lung, prostate, colon, pancreas. The thing that stands out to me is we have great tools of detection for prostate cancer. Based on that, I guess it's a little surprising to me that it is still the second leading cause of cancer death in men. So one of the things I hope to be able to do by the end of this final part of our discussion is get a better sense of what an individual can do to flip the odds in their favor. Because you've probably heard me say this before, I don't think anybody should ever die of colon cancer for the same reason. We have remarkable tools of detection, and we also have a very predictable pathogenesis where we must go from a polyp, we must go from an adenoma to a carcinoma, and we can detect the presence of the adenoma because it is outside the body effectively.

So just to bring it back old school to where we first met, obviously, that would be the Halsteadian theory for how cancer would spread. And that would be a stepwise from a localized non invasive to an invasive tumor to a regionally advanced and then metastatic Lesion and colon follows that algorithm pretty well. There are obviously, obviously the cases that are outliers.

Sure. There are sessile polyps that are very difficult to detect.

In general, I would say that, yes, I agree with everything you're saying. And I would agree that, on average, prostate cancers follow a similar Halsteadian theory of spread. As opposed to Bernard Fisher and the Fisherian spread, which is the breast cancer model. Exactly. So, yes, 100% agree with you that prostate cancer is on average 250 to 260,000 new diagnoses this last year. So a lot will follow. More of a Halsteadian spread. Now, remember, if you keep that in mind, and you're the math guy, not me, if you do, just model it, 250 to 260,000 new diagnoses, 34,000 deaths. So, yes, on average, we are picking up cancers. But on average, if you look at the ratio of cancers diagnosed to cancer deaths, that ratio is pretty favorable.

It's much better than the other cancers. Conversely, to put pancreatic cancer in terms like that of the people diagnosed with adenocarcinoma of the pancreas, about 95% of those people will experience lethality within five years.

We have that in our favor. And so, yes, what keeps me up and gets me up in the morning and excited is to understand and identify what it is about the individuals who develop prostate cancer that is localized and doesn't have a lethal potential. And how do we better attack those subset of individuals that will ultimately die from their prostate cancer? So lots of progress, even since when we last talked. But, yes, big picture, it is still a real issue.

Okay, we've already touched on testosterone. We touched on estrogen. Peripherally discussed dihydrotestosterone. Let's explain how androgens work. Where are androgen receptors? What are these hormones doing? And for the purpose of this discussion, how do they factor into the pathogenesis of this condition?

If you go back, and I actually think it's a really good exercise for an individual to go back and understand where the prostate actually comes from. It comes from the urogenital sinus. This is a sexually dimorphic organ. And in the response to androgens, around week 10 or 11 in a developing fetus, human fetus, there's a surge of testosterone from the gonad. And that surge of testosterone results in the development of this ductal network. It's an exocrine gland, and it develops out of this structure.

By the way, how big a surge in testosterone? I know that it's much more significant than the levels that a little boy is born. A little boy is born with very low testosterone, but he did experience a lot of it in utero, right?

Lots in utero, lots at birth. And then puberty. Those are the three peaks, and they're similar. I think obviously puberty is the highest, but it's enough to impact a change. And we'll talk a little bit about that. Because it's not just testosterone levels, of course, that matter, but it's what the intracellular dihydrotestosterone levels are. So in the urogenital sinus, the mesenchyme, those are the things that eventually turn into muscle and connective tissue. They contain androgen receptors that then send a paracrine signal to the epithelium.

Let's even back up for a moment and make sure people understand this. So testosterone, complicated molecule derived from cholesterol. So picture a cholesterol molecule with all of its rings. Testosterone is very comparable. What is an androgen receptor? Explain what it is and where it sits.

The androgen receptor is a very fluid molecule that basically sits in the cytosol of a cell.

So outside the nucleus.

Outside the nucleus. And the androgen receptor is a transcription factor. So it turns on a variety of different genes within a cell. So think about in your house, if you have a circuit breaker and you turn on the circuit breaker and every light in the house goes on, that's what a transcription factor does in my mind. That's how I think about and explain it to patients. Androgen receptor is a transcription factor and needs to be in the nucleus of the cell to flip those switches. And it sits in the cytoplasm. It needs to translocate to the nucleus and then bind to the DNA of our cells.

And it only does that once testosterone or dihydrotestosterone binds to it in the cytoplasm.

That's right. So its signal, it has a conformational change that permits it to enter the nucleus when it's bound to testosterone or dihydrotestosterone. Now, dihydrotestosterone has a much stronger, higher affinity for the androgen receptor and enables it to be. It's about 10 times more potent. So one molecule, DHT, is the equivalent of 10 molecules of testosterone. Now, that conversion of testosterone to dihydrotestosterone does not occur anywhere in your body. And just for the listeners, by the way, women have an equal distribution of androgen receptor, as do men, but they don't typically have androgens around, I guess.

Let's do the math. A woman will have probably 5% of the androgens.

Yes.

She'll have about 5% of the testosterone that a man will have.

But theoretically, at birth or in utero, they have the equal distribution of androgen receptor, but they don't have dihydrotestosterone. So men have five alpha reductase in their hair follicles and in their prostatic tissue, predominantly. Those are the two main areas where it exists. So if you have the same amount of testosterone floating around in your blood, it will have one effect, let's say, on your skin. It's never converted to dht. But if that same testosterone molecule hits a hair follicle or hits the prostate, it's converted into a very potent androgen, DHT, through 5 alpha reductase. And that can then have a much more potent effect in terms of the subsequent effect of the androgen receptor.

So just make sure I understand. If a male has a normal testosterone level, but he's taking a 5 alpha reductase inhibitor. I want to talk about that now. Which lowers the conversion of testosterone to dht. Young guys will take this all the time to prevent hair loss. These are the most common drugs that are used to prevent hair loss. Part of the story I guess we didn't finish here was DHT in the hair will damage the follicle. It's leading to baldness, early death.

Yeah.

So it seems to me like he's short, changing his androgen receptor potential. He's short changing the ability to experience testosterone. It's almost like he's taking a testosterone haircut without taking the testosterone haircut.

Yes. What you end up with is less intraprostatic dht, more intraprostatic t actually, because you can't convert it. So you're pulling it in there. You normally would convert it. That's true in the hair follicle. Also, as we'll talk about, because there's significant pathology associated with taking finaster. We used to think that it was predominantly in those main structures, follicles of your hair, prostate, et cetera. But now we know it actually has profound potential impact of that centrally in your nerve system. Right. And it can affect your sex drive, it can affect your sex performance.

So let's talk about this, because I had never heard of this until a few months ago, post finasteride syndrome. So we talked earlier about finasteride when it's taken in a drug called Proscar, 5 milligrams a day. It has a cousin called Dutasteride or Avodart, I think that's 0.5 milligrams per day.

Yep. That one theoretically is more potent because it blocks 5 alpha reductase 1 and 2. The efficacy is equivalent in the human body. And then lower dose finasteride. So not 5mg.

1Mg per day is called Propecia and that's the branded version that's used for hair loss.

Yes.

The first thing I remember you telling me about this was it's a little bit of a scam that these drugs are taken daily because their half life is quite long.

They all have a very long half life. So if you took a single finasteride 5 milligram dose, it's generic, so it costs nothing anyway. But if you took that, it would hang around in your system for a week or two. The reason it was reformulated at 1 milligram versus 5 milligrams was for a new patent, new indication. I haven't worked it out. You could probably just take a single 5 milligram of finasteride once a week and that would be the same as 1mg of the other stuff every day. It has a much longer half life than anyone appreciates. That's the least of the problems that I think is associated with this drug.

Let's get to the issues because this is also a very controversial topic. There are people that get up in arms on both sides of this discussion. Describe what post finasteride syndrome is.

It's a variety of symptoms that men will complain of after taking either the BPH dosing or the kind of hair loss dosing of these medications. Decreased sex drive, impotence and ejaculation, inability to ejaculate, Inability to ejaculate. Those are obvious and apparent things for any young man trying to do it. But there's a lot of other associated findings with it, like depression, change in your affects. So those are harder in my mind to attribute to medication. But patients do complain about it. But when you have a patient who's young, healthy, has a great interest in sex, et cetera, and they take this medication for hair loss and they can't get an erection, they have no interest in sex, they can't have any orgasm, those are real and those are directly, in my opinion, definitely related to the.

Drug, what do you think is the approximate frequency of this post finasteride syndrome?

That's probably where there's more debate. Some people would say 5%, some people would say 15%. Depends on where you look. I think about it. Like 1 in 10 guys will have appreciable issues with it. And it's not just the young men, it's in older men too. It's just that they're maybe on average less interested in sex or less sexually active.

It's less apparent in an older guy.

I definitely see it. So that's why I never really use it in my practice. I mean, it's just such a limited drug, in part because the efficacy is limited in my opinion, in terms of managing lower urinary tract symptoms. And then the side effects from it. This post finasteride syndrome are real. The duration of these symptoms can be highly variable. So some people will stop the medication and they'll have resolution within a couple weeks once the drug washes out. But there are people that I know who have it permanently.

Yeah, there are case reports, and that's the really scary stuff, which is the case report of the guy who goes to see the hair doctor. They put him on finasteride experiences all of these symptoms, they're horrible and they're very noticeable because he's 25 or 30, he stops taking the drug and it never comes back.

Those are rare like you say, but they're real and they are associated with the drug. And there's no doubt in my mind.

I guess the obvious question here is let's assume that the frequency of this is 1 in 10 and we want to avoid it at all costs because we never know if it's reversible. Is there any sense of what predicts susceptibility to this?

It's a good question. You know, it's a post hoc diagnosis. I haven't seen a great paper that really took 100 or 500 men and really tried to evaluate what it was that would predict it. So I'm not aware of any high quality study that can help predict that association.

Would you be comfortable then and feel free to say no, but would you be comfortable recommending to a patient who's considering using a 5 alpha reductase inhibitor for hair loss that they might be better off looking at other medical and non medical therapies for hair loss?

Yeah, I mean, I don't recommend it.

For use in any man, BPH or otherwise.

Yeah. Why? If you're taking it for hair loss, which I experience at a very young age, so I know what that feels like and it can have a real impact on a young individual's life. There's a lot of really effective therapies that you can do. I mean, hair transplant works very well. It's very precise and I know people who've done it and they're very satisfied with it. So I think there's alternatives. I think understanding what that spectrum of alternatives is, is really important. Because when young guys go to these pop up shop clinics, they're not given the full.

They don't have a consent. Yes.

And they don't understand what the long term effects are. Because in addition to the post finasteride syndrome, as a prostate cancer biologist and individual who treats people with prostate cancer, the other big thing has to do with what its effect is on your PSA value. So it halves your PSA value if you take the medication for one to two or two to three years and after five years of being on the medication, it reduces your PSA number by about 2.5x.

And that does not come back.

If you stop the medication, your PSA will rise. But the biggest issue is not whether or not it suppresses your PSA or not, it's lack of awareness that it does amongst the patients and the providers. Because if you're going to some men's health clinic for your finasteride or your finasteride for your hair loss, you may not mention it to your internist. And usually when you start that for hair loss, you maintain it for life. The classic case, I see it probably every other week of a guy whose PSA is rising on finasteride. If your PSA begins to rise on finasteride. We'll talk about PSA in general in a sec. If your PSA rises on finasteride, you have a problem that is a warning sign that there is a cancer, and likely an aggressive cancer, growing in your prostate. And guys aren't aware of it.

And not just guys. It might be that physicians aren't aware of this.

That's right. So if you're a man, you take finasteride starting at age 25. You start at age 25, your PSA is 0.5. Think about this. It may begin to rise, let's say now you're 50. So 20 years later it goes between 0.5 to 1 to 2 to 4. That's four years where your PSA is doubling, which tells you you got a really bad problem before it's even anywhere near being on the radar of the patient or their internist. So in my opinion, it's just you gotta be very, very careful with these medications, particularly taking them that long.

And this says nothing about the other issue, which is not having DHT probably isn't a good thing if you're in the business of taking advantage of your androgen receptors, you're taking away the most potent androgen in the body. And androgens do really good things.

Absolutely. I mean, the extreme examples are those individuals with no testosterone. We induce that in individuals with advanced prostate cancer. And they're rare cases for men who are born with no testosterone at all. But in general, yes. I mean, for a healthy man, it's absolutely imperative, in my opinion, that you maintain a eugonadal state. That's debatable what that means, but I think in my opinion you can titrate to a functional eugonadal state in almost all men if their testosterone levels are low. But having testosterone around is just critical.

For everything from metabolic health to structural health. Really for everything, probably mood and a whole bunch of other things.

Exactly.

Now let's talk about the relationship between testosterone and DHT and the development of prostate cancer over a man's lifetime. So one of the obvious statements is when a man has the most testosterone and presumably DHT in his body. So let's just take out the case of guys who are taking five valproductase inhibitors. So when a man is in his 20s, call it 18 to 20, 18 to 30, his testosterone and DHT are through the roof. We don't see guys getting prostate cancer. Similarly, by the way, we don't see women getting breast cancer when their estrogen is at their highest either. We know that the story is more complicated than the caricature is, which is not to say that these hormones don't matter, because to your point a moment ago, when you have men with metastatic prostate cancer or untreatable prostate cancer, hormone deprivation therapy is a core treatment. So how do we reconcile those two observations?

There's a time dependent covariable here. There's lots of things that testosterone does at a cellular level. Right. It impacts damage to the DNA, repair of that damage to the DNA. All these different things that people, I don't think really fully appreciate. But I think when you go through your surge of testosterone, whatever that may be, if your puberty peak is age 18 or age 25, wherever your peak is, I think you begin to reset the functional code. So you're born with your DNA, but it's not really, for the most part, what's in your DNA that matters. It's the epigenetic changes that result in the RNA translocation transition that really is the most important thing. So I think that you begin to mark and see differences in terms of the epigenetics of different genes within an androgen responsive organ. That then sets the stage for your potential risk for developing prostate cancer. So I think that there's a correlation between testosterone and subsequent future diagnosis of prostate cancer. But it's just one of the many factors that plays a role. So if you don't have any testosterone, you're not gonna get prostate cancer. Cause you won't have a prostate. That's the obvious one. But I do think that there's a correlation between T and A being a healthy male. And part of being a healthy male is a potential risk for developing prostate cancer. Does that make sense?

It does. And there's this other very interesting observation, and I don't know if this has been subsequently refuted, but I remember this probably when we were in residency, Ted, that there was that paper that came out that found that men with lower testosterone, this was in the New England Journal of Medicine, were at risk for higher grade prostate cancers. Yes. The sort of teleologic explanation was. At least this was my teleologic explanation. If you are developing prostate cancer in the presence of low androgens, you have a cancer that's very sensitive and therefore is probably much higher grade. Is that still kind of a thinking or has the thinking evolved significantly?

So we just published a paper on this. We looked at 100,000 prostate cancer transcriptomes.

Where did you get so much?

We did this in partnership with a company. Originally it was called Decipher. Now it's owned by a company called Vericite. And I did this with the founder, Eli Da Vincione. We looked at their database of. They now have 140,000 plus prostate cancer transcriptomes. We just asked a simple question. If you take prostate cancers and you do AI based hierarchical clustering, just looking for patterns, do you see different types of cancer? Not grade or stage, but different types from the perspective of the transcriptome of prostate cancer? And you do. So you see two general themes. One, you see luminal like prostate cancers and basal like prostate cancers. And then within that sub classification of luminal basal, there are kind of effectively aggressive luminals and then aggressive basals and then less aggressive ones. So where is this all coming from? So if you take a look back at embryonic development, people have done this. I did this in my postdoc study. What happens to the prostate in a mouse or a rat when you begin to take away testosterone and give it back? You can see that the prostate, as we mentioned before, grows in response in part to testosterone and to estrogens around. But if you Castrate a mouse, all.

Of the luminal cells post maturity.

Yes. You develop a normal prostate and you castrate a mouse or a rat with the prostate. It will regress and think about it like a plant in the middle of a drought. It looks dead, but there's roots that are still alive. Those roots that are still alive in the prostate are predominantly basal cells. If you give that prostate back its growth fuel, testosterone or dht, then it will regrow a new prostate and the basal cells can begin to repopulate and you'll get also a proliferation of these luminal cells that will then form the big bulky, meaty prostate that we think about, let's say just the BPH portion of the prostate. So you have luminal cells and the luminal cells in development, and we believe in prostate cancer, are exquisitely sensitive to testosterone's androgens. The basal cells, the cells that survive the drought, the cells that survive in the absence of effectively any testosterone at all, those are the ones that form more basal like tumors which are very, very aggressive. So when I look at somebody with prostate cancer, yes, I look at their grade, yes, I look at their stage, but I also look at the genomics of their tumor and what's the biology of their tumor. Because they may have a big bulky luminal proliferating. A luminal tumor. But I know A, it's exquisitely sensitive to testosterone suppression, which is something that I have in my back pocket, and B, it's less likely to start spreading to other parts of the body.

Why is that? Because it's on the basal side?

No, if it's a luminal type tumor, think about it, it's more dependent on that testosterone rich microenvironment with the DHT around, it doesn't do as well theoretically living in the bone marrow when it metastasizes to the bone or the lymph nodes.

This is very counterintuitive. On the one hand you're saying it's a more aggressive tumor, locally bulky, but on the other hand you're saying less likely to survive. Metastatic spread.

Yeah. If you look, which we've done, the distribution of a luminal differentiated tumor in a localized state is about 40%. If you look at how many metastatic lesions. So you take tumors that are metastatic, it's less than 10% are luminal differentiated, they just don't have the capacity to survive and spread to other parts of the body. Whereas a basal tumor, which is by nature able to survive in the absence of testosterone and or uses alternate growth pathways to testosterone because it's not dependent on it, those tumors are more capable of spreading to other parts of the body.

So this is kind of a great tragedy. It means that the prostate cancers that are most likely to kill you, which by definition are the ones that spread, are also the most capable of thriving in a low testosterone environment and therefore are least hurt by androgen deprivation.

Yes, I mean, this is just things that we've been working on this thesis, Eli and I, for now a decade, but we have this data now we just published this year, and lots of other interesting studies coming out that really kind of support this idea. So that's why, in my opinion, I am very comfortable with a patient who has a low testosterone being on testosterone supplementation. If they have a low t, either during the process of being diagnosed with their cancer or in their recovery phase, because I know that. But if they were to develop a recurrent disease, a recurrence of their cancer, it's most likely a luminal type. And we can exquisitely modulate that tumor with testosterone. So it's a big step. It's a big step in a different direction. It takes a lot to think about, in my opinion. It really helps us understand the biology, not so much of localized prostate cancers, but rather when you have a localized cancer that has the capacity to spread. So a localized cancer with lethal potential, and what's the nature of that tumor? How do you begin to attack it? And understanding the molecular underpinnings of it is key. That's precision medicine.

Yeah, absolutely. So you've got these hundred thousand transcriptomes. They've given you this insane amount of insight. How often can you now predict based on a man's genetics, or do you need a tissue biopsy to map to the transcriptome to say, aha?

Now let's talk about the transcriptome of the tumor. So once a patient has a diagnosis, you can get the transcriptome information. It's provided to the providers. It's not commercially available. It's not provided commercially because you have to be cautious about how you interpret that data and what you advise the patient until we have more information from clinical trials about, well, what does a particular molecular phenotype mean for the A, how you treat their new diagnosed, localized, or potentially, if they have a recurrent disease, how you should better treat it. But those trials are now in process or are just being built based on some of this work.

Sorry, just to be clear, Ted, does that mean that someone listening to this, who has a biopsy of their prostate. Their physician will get this information back, but won't necessarily know how to interpret it.

If a patient gets a biopsy of their tumor and they have genomic testing with decipher varicite, which I don't have any conflicts with, by the way, they will then get a simple readout of how aggressive is their tumor. It's a molecular Gleason score. But on the back end, in addition to measuring those 21 different genes that consist of the decipher score, they capture the whole transcriptome of that tumor, and you can get access to what they call the grid report, which gives you this whole deep dive into what's the biology and nature and phenotype of that particular tumor, which for me, I look at, and I will then look at that and then say, okay, this patient on paper perhaps has an X or Y or Z, but the molecular phenotype of the tumor is favorable or it's not favorable. I'm going to alter what I recommend to the patient based on that. So that's how I interpret it. It's kind of experimental use only, so.

To speak, but it is the direction of precision medicine.

It's the future of it. And so, based on these papers and many, many others, not just the one that I did, this one, but many, many other papers with really great scientists, they are the platform through which all clinical trials in prostate cancer are now reliant on. So the cipher score as a entry criteria, as a predictor for intensification or de. Intensification of therapy, is part of almost all clinical trials going through the National Institute of Health right now, which is exciting.

Yeah. So let's talk a little bit more about the pathogenesis. You talked earlier about the transition zone and the peripheral zone, the orange analogy. I'm assuming that most prostate cancers develop in the peripheral zone.

Correct.

And the reason for that is we didn't state this earlier, but you would think, or hope, I suppose, that any man who's undergoing prostate tissue removal for BPH would have a lower risk of prostate cancer because, hey, you just shed 80% of your prostate. That doesn't seem to be the case. Correct.

It doesn't necessarily change their risk for developing prostate cancers in the future. However, it changes your ability to monitor them for the development of prostate cancer. Because remember, the PSA blood test? It's been often criticized, but it's a very powerful tool, and it just depends on how you use that blood test to identify people at risk for potentially having prostate cancer.

I want to really talk about this In a minute. Because there are a few things that annoy me more than people who harp on how bad the PSA is, which to me means, no, it's how bad you are at using it. The PSA is a remarkable test.

Yes. So the issue arises from this overlap in the test because it's not prostate cancer specific, it's prostate specific. So the beauty of having my partner, Amy Krambach, do a hole up and take out 90% of your prostate is that reduces 90% of the PSA producing cells. The PSA should be below 1, but it makes the test way more sensitive for me to follow for a future potential risk of developing prostate cancer. So in general, I would say that, yes, the specificity of the tool changes based on how much prostate tissue you have. So the PSA test is actually exquisitely sensitive in young men to their future risk for developing prostate cancer because they have such limited amounts of transition zone tissue and the bulk of their prostate is just peripheral zone.

So why is it that the cells in the peripheral zone are susceptible to becoming neoplastic as opposed to the cells in the transitional zone?

Under the microscope, there are some subtle differences as to how they look, but people don't know why that particular zone or that zonal anatomy is such that you have a higher risk of developing it. There's. It's obviously very unfortunate because as the name implies, it's in the periphery. And what's just outside of the prostate is the high price real estate of the nerves for erection, the nerves for urinary continence, and the muscles for urinary continence. So that has a big impact on how we manage prostate cancer. And it's been a result. That's what results in a lot of the potential side effects that occur. But in general, yes, in young men, PSA is a very potent way for us to initially screen someone for their prostate cancer risk. And your psa, if you're young, good numbers to remember for the listeners. Median PSA for a 40 year old, 0.5. Median PSA for a 50 year old one. So if your number's over those medians, those age adjusted medians, then you need to just take action. Do you have to have a prostatectomy? No.

But then here's the problem we talked about earlier. A lot of those guys are going to be on 5 Alpha reductase inhibitors these days. And now those numbers become very difficult to interpret.

Yes, they do. They become difficult to interpret and difficult to follow. So if your numbers are over those, then any you should Just consider a kind of annual or twice every other year intensive follow up. It doesn't mean that you have prostate cancer, but it means if you're over that median, that you have a much higher risk in your future, next 20 or 30 years of developing it. Again, the issue is in young men who are on five alpha reductase inhibitors or PSAs, or going to be very, very low, and you may miss an early blip. As a somewhat sidebar, there's a great paper published out of the group at UCSD looking at finasteride and dutasteride use in veterans. So it's a closed access system and they asked the question, is use of dutasteride and finasteride associated with more prostate cancer lethalities? And it's hotly debated about whether or not the drugs actually induce more aggressive cancers and result in that. But if you just take that as a more public health issue, the answer was glaringly yes. There was a huge increased risk of death from prostate cancer in men on finasteride and eutestride. Why? For the reason we talked about neglect. You don't realize you're on it. You don't know your numbers are rising. Your internist has no idea that your PSA of 4 isn't really 4. It's 10 because you've been on the meds for 10 years.

We certainly don't know if 5 alpha reductase inhibition impacts prostate cancer biology, but to our point about detection, it impedes detection.

Yes, I think that there may be an impact subtly on the biology, but that's less of a real general issue. It's really being a lack of awareness of the biomarker that you use to screen for prostate cancer and the effect that dutasteride and finasteride have on that biomarker.

How many cases of prostate cancer are associated with germline genes that we know are drivers, for example, the equivalent of a BRCA mutation in breast cancer, or is it virtually all somatic mutation?

It is very limited. So there are a class of proteins, molecules that affix homologous recombination defects. And those HRD classes of molecules include BRCA1 and BRCA2. The actual protein complex that fixes double strand DNA breaks is really, really big. So there's lots of different genes that fit within that protein complex that fixes a double strand break. That's what BRCA1 and BRCA2 do classically. But the most potent of the different genes in that grouping of HRD molecules is BRCA2 for men. So individual men, it's about 1% or less of the general population, have a BRCA2 deficiency. BRCA1, BRCA2 deficiency. Those men are at increased risk for developing breast cancer and prostate cancer. And in the case of prostate cancer, if you develop prostate cancer, it's a more aggressive disease course. And you have to be very, very careful with individuals who have that deficiency and have prostate cancer. But on average, it's very rare. Probably less than 2% of prostate cancer cases. Localized prostate cancers diagnosed are attributable to a germline genetic alteration. There are mutations in those same pathways somatically seen within the tumor. Right. Not in the germline, but in the tumor that are attributed and related to cancer aggressiveness and progression of cancer. The classic one, in my opinion. So the way I think about prostate cancer in very general terms is you can have localized prostate cancers. These are these lower grade lesions, on average, localized prostate cancers with lethal potential. So lclp, you got a localized cancer with lethal potential. And in my mind, the general genetic trait associated with that transition from localized to localized with lethal potential is something to do with the PTEN AKT pathway. And that doesn't mean that you have a lethal tumor. If you have PTEN loss, in my mind, it begins to open up the book to say lots of other mischief and nonsense can go on within the tumor. We know from lots of studies that if you have loss of P53, for example, that that's associated with lethal prostate cancer. Amplification of myc.

Lethal cancer in general.

Yes, exactly. Amplification of MYC is another one.

Okay, so it's interesting. So basically between MYC and P53 and all of KRAs, I mean, I'm sure KRAS is associated as well, less so.

KRAs, but yes, those are classic markers of lethal cancers. And so prostate is not immune to that as well.

Got it. Okay, let's talk a little bit about non genetic risk factors, or at least we can include sort of polygenic stuff that's embedded. So one of the things I always remember from training African American men at.

A higher risk, why no one knows. There's a great paper published by this scientist at USC, Chris Heyman, and they looked at genomic risk through SNPs for individuals who did or did not develop prostate cancer. It was like 235,000 guys, a ton of individuals.

How did they know what SNPs to look at?

There's been lots of work in single nucleotide polymorphism and risk for prostate cancer. And then this paper was a Refresh. Look at saying how many SNPs are actually out there associated with risk of developing prostate cancer? And it's somewhere around 250 or 260. I don't know the exact number, but there's a certain amount. So what they did was they developed a genomic risk score based on how many SNPs you had and your likelihood or probability of developing prostate cancer. And what they showed was that although there's no difference between SNP profiles in men of African ancestry, because they could look genomically where their ancestry was, and Caucasians or non black men, there was an enrichment for that same group of SNPs in black men and an enrichment in men who were diagnosed with prostate cancer at a young age. So why is it that there's an enrichment of these different portfolio of SNPs in black men, and why is there an enrichment in the younger men? We don't know. But it doesn't appear as though the tumors are profoundly different from a genomic perspective. And we've looked ourselves. We had a series of grants to look at, again, somatic alterations in prostate tumors between black and white men with lethal tumors. We found a difference in the cell cycle gene pathway, but again, these are single percentile differences. So what exactly is driving the development of more prostate cancers in black men than white men is thought to be, at this point, kind of environmental. So what is their exposure to epigenetic changes? What's their exposure to smoking? It's in general, in urban populations of black individuals, there's more smoking correlates with the food deserts, all these different kinds of epigenetic factors.

I see. So it may not actually be hardwired.

It's not hardwired.

That's great news.

It is good news. And so, yes, I think people would bundle that under this kind of umbrella of social determinants of health. But you can actually begin to really begin to connect those two ends of what are the social determinants and then what is the impact on the SNPs and the epigenetic changes that occur? So I think a great future project would be to take that and look at exposures. Think about it. Your exposures in an environment with high smoke, high pollution, poor foods, and the epigenetic changes that occur when you're having a surge in your Testosterone in your 20s, that begins to hardwire that person's cells for future development of prostate cancer. And that's kind of how I think about it now. I spent a decade looking for the smoking gun the heritable germline change. There are some out there, but they're not very big guns. They're not big enough to be associated with that change. And so this paper that Chris did and his team of there's like 150 authors, is spectacular work, really begins to provide more insight.

This is the UCSD group that led this usc. Oh, usc.

Usc. Chris Heyman is the last author and great publication.

We'll link to that paper.

So it gives you a sense of why are there different subpopulations of individuals that have different risks. It's likely just enrichments for these single nucleotide polymorphism changes which by the way, if you look at that paper, if you had the highest, let's say decile or quartile of SNPs, you had about a five fold increased risk of developing prostate cancer compared to the average man, which is the same fold increase as if you're BRCA2 deficient. So having a poor genomic risk score is just as potent as having deficiency in BRCA2, which we know is not good.

And the penetrance of BRCA2 and BRCA1 for prostate cancer are how high? 80% ish.

No lifetime risk is less than that. Lifetime risk is somewhere on the order of 60 to 70%. We would definitely do intensive screening for them, but it's not a guarantee.

Obviously women that are highly penetrated and.

At a very young age, that's not true for men in Irish.

It's not unreasonable for a woman to undergo a prophylactic mastectomy if she has a deficient copy of the BRCA gene. Are any men considering prophylactic prostatectomy?

Not at this point. The difference is we have very powerful screening tools.

It gets back to Halstead versus Fisher.

And those screening tools work just as well in individuals who are BRCA deficient. So their tumors may be more aggressive when they're diagnosed. But we have very powerful tools to A identify them early and B monitor them once they're picked up. And so it doesn't necessarily change that paradigm, which is different for breasts because you have to wait till you have a visible lesion, which a visible lesion on mammogram is 40 or 50 million cells.

I would guess closer to a billion a centimeter.

Well, we'll try to find something for the show notes, but yes, it's a ton of cells, whereas we have much better tools to look at that with.

The blood test and hopefully with breast cancer. We're going to see liquid biopsies and cell free DNA Adding more to that.

Resolution as a biomarker, it's definitely shows promise. I mean, there's lots of those liquid things. It's not essential for our space because we have a very good one.

Another esoteric risk I kind of vaguely remember, and I don't know if I'm remembering it correctly. Is there an inverse relationship between the frequency of ejaculation and the development of prostate cancer?

Yeah, there's an epidemiologic study that shows that men who were ejaculating more than 20 times a month that there was a lower risk of developing prostate cancer. The paper you're remembering is really the paper on that topic. It still exists.

How big was the hazard ratio? Is it worth paying attention to?

And I don't remember because it's so old, to be honest. I've never thought about encouraging increased ejaculation.

For the as a preventative strategy.

I mean, it's not a bad idea, but it's never occurred to me to kind of encourage that.

The idea isn't that prostatic stasis in the absence of ejaculation allows something to occur in the prostate that leads the development of either through the microenvironment or other genetic issues. Point is, we have no further insight than that epidemiologic study, that is.

But it's not a bad one. I think the converse would be horrific for men. Don't ejaculate because it'll lower your risk of cancer. So it's kind of a win win. Right. That's how I think about it. So let's talk about a couple other risk factors besides ancestry, which is huge.

Bigger than many cancers.

Yes. So it's not just African Americans, but anybody with West African ancestry is really what is the most significant in that risk factor. And then there's other ones. So Ashkenazi Jewish individuals have a much higher chance of harboring foundry mutations in BRCA1 and BRCA2. So I always talk about ancestry and then I talk about all cancer risks. Right. When I'm taking a family history, I say, what's your personal history of prostate cancer? And if you have a personal history of prostate cancer, you're a father, uncle, or brother.

So first degree relative, father, uncle, brother. Okay.

The number of individuals and the age that they were diagnosed. And we'll put a link in the show note for the table, it increases your fold risk of being diagnosed with prostate cancer significantly. It doesn't mean you shouldn't have a prophylactic prostatectomy, but you should just have Intensive monitoring.

What about grandfather?

Grandfather is not.

If it skips the generation, it doesn't matter. So your grandfather has prostate cancer, but.

Your brother, it's not considered to be a family history of prostate.

Okay, what about grandfather and father? Is that worse than just father?

Father is the driver for that ancestry and then family history and then individual patients. So smoking, it is classically linked with lung cancer and classically linked with bladder cancer, urothelial carcinoma. But smoking is associated with the development of more aggressive prostate cancer.

So not necessarily more prostate cancer, but when you get it, it's worse.

Yes. And at a younger age, the correlation is younger age onset, more aggressive cancer.

What's the youngest patient you've ever seen with prostate cancer?

34.

That is staggering to me. I would have never guessed that.

I'll never forget that gentleman. I have his picture in my brain.

He didn't survive, we treated him.

He's still alive now. But still, when you have a 34 year old and his wife sitting there going like what? I've subsequently diagnosed young men with prostate cancer and then subsequently treated their fathers. So they had their cancer before their father, which is also mind boggling.

Tell me a little bit about this guy's case. Was there just some freak gene?

The youngest man, the 34 year old was early in my career at Hopkins where we had such a lack of understanding of the genetic risk and so forth. So I would love to go back and pull his tumor and just sequence the whole thing.

He presented how he wanted to get.

A $250 discount on his health insurance for the year. So he got a routine screening through his work and they picked up a PSA that was like 10 and he's 34 and he wasn't from an infection.

But anything below what is freakish? 50.

So the median age of diagnosis for prostate cancer is 68. We would consider early prostate cancer, which would be a criteria for doing genetic screening at around 50. So hereditary could be young age of.

Onset, so 50, if I'm not mistaken. I believe type 2 diabetes and metabolic disease also increase the risk of prostate cancer as it does breast cancer and endometrial cancer and a number of cancers.

And also the aggressiveness and likelihood and probability of recurrence. All the other things really have never been fully supported with any decent follow up studies. So these different products in the skin of grape, broccoli, tomato.

Oh, you mean as preventive things, they.

Really haven't been linked with any real increased or decreased risk for developing prostate cancer.

So let's talk about the PSA a little bit, because we've alluded to it a number of times. So let's explain what it is, where it comes from, and more importantly, of course, how we use it.

Yeah. So PSA is a protein. It exists to aid in the liquefaction of semen. So it's produced by the prostate. And if one were to measure PSA in semen, it would be very, very high. I always tell people if you looked at PSA in the semen, it would be, I don't know, 100,000 nanograms per milliliter of PSA and semen. It's designed to be there, and it exists there to liquefy the semen to help in the process of fertilization. It is not designed, and it should not exist in the blood. But a certain percentage of PSA made in prostatic epithelial cells leaks into the bloodstream. And when we do a PSA blood test, we're measuring the PSA that has leaked into the bloodstream from a prostatic epithelial cell. Now, most of the PSA that leaks into the bloodstream is bound to other proteins.

Is that albumin? Mostly, or sexome, or binding globin?

Alpha chymotryptin.

Oh, so it's its own separate binding protein.

Yeah, that's the most common protein that PSA binds to. But it can bind to a family of three or four, four or five different.

But these are prostatic proteins.

Yeah, it's bound now how much it's processed, because, as you know, proteins just don't come out finished. They grow into their final state. And they grow by shrinking. They get things snipped off of them as they're maturing and going through that process. As PSA is evolving in the normal kind of development of its exocrine function, it gets snipped into smaller and smaller states. Fully processed, PSA can float around in the bloodstream freely. That's free psa. So if you have a benign prostatic epithelial cell, a lot of its PSA will be fully processed and ready to go in the ejaculate, let's just say. And if it leaks into the bloodstream, it can float around freely. You can measure it in an assay, and it's what we call free PSA. A lot of the unprocessed or incompletely processed PSAs bound to protein alpha chymotryptan is the most common one. And that is what we would consider to be when we do a measurement of when we're Looking at total psa, you're measuring mostly bound PSA and some free psa. And that ratio we use, you and I use in our practices to help discriminate against PSA that's in the bloodstream that may have leaked from a cancer cell or may have leaked from a benign epithelial cell. Now, there are other siblings of PSA that are also produced in prostatic epithelial cells, of course, all in response to androgens. They're produced in those cells and they can also leak into the bloodstream. And we use those in some advanced PSA based blood testing as well. But in general, when we are measuring psa, we are measuring the amount of psa, this protein that's leaked from a prostatic epithelial cell into the bloodstream. We can refine that value by saying how much is there and how much is free. If we have high amounts of free PSA, 30% for example, then we can have have good reassurance that most of the PSA in the blood that you're detecting is from benign cells. When most of the PSA that you have in your blood is bound very limited amounts of free psa, that's a strong marker that there's something going on, that is that cancer cells are leaking the PSA into the bloodstream. Now, as I mentioned, you can also measure other byproducts, other types of free PSA or other sibling molecules to PSA. PSA is called HK3 or human kalkine 3. You can measure, for example, how much of human kalikrine 2 is in the blood. And these are part of more advanced PSA tests like the 4K score or for example, the prostate health index. These are both mathematical equations that predict probability of aggressive cancers, but they're built off of looking at not just the PSA itself, but the PSA and how much other people types of processed PSA exist as well.

Let's go back and talk a little bit about the free psa. Does the amount of free PSA that we would want to see to be more assured of a benign nature of the PSA vary by age and absolute PSA level?

Yes, it does. So we begin to use the free PSAs and the free PSA ratios and all those things when PSAs have crossed over certain thresholds.

If your PSA is one, we can't even get a lab to check a free psa.

That's right, because we know if you're screening someone and your PSA is 1, then the probability of a prostate cancer that's Lethal is incredibly low. They don't have the assay set up to check it. And oftentimes or some labs will not do that secondary default testing, unless it's over 4, for example, or over 2.5. Our lab's set up to do everything at levels as low as 2, so you can get them at lower levels. But in general, the idea is, well, if your PSA is below 2, the probability you have a lethal prostate cancer is less than one in a million. So we don't have to worry about that individual. And we really want to use the percent free PSA to discriminate individuals who have elevated PSAs and having it discriminate between elevated because of BPH and elevated because of a cancer. So yes, as you get older, your prostate enlarges. As we talked about, metabolic syndrome causes your prostate in large part to grow just because of the TDE ratios. As you get older, your prostate gets bigger. We begin to use that as you get older and your prostate gets bigger, you can have a proportional rise in total PSA in your bloodstream just because your prostate's bigger and it's leakier. But you can easily tease that out by looking at the percent free PSA. So if the percent free PSA is over 18 to 20, then you can be rest pretty well assured that that's likely not coming from some aggressive bulky tumor.

What about with prostatitis? When we see these huge spikes, everything.

Goes up in those cases. But.

But does the free still remain disproportionately high?

I don't use free PSA in people because I'm tracking it. I'm literally looking for trends for coming back down to a new baseline.

So, yeah, okay, let's talk about two other ways we use the psa. The density and the velocity. How do those work?

As I mentioned, as you get older, your prostate on average gets bigger. Not for all men, but for many men. And when that happens, your PSA can concordantly rise because it's just your prostate gets bigger and gets equally leaky. So the PSA can kind of go up. Now, what we look at is the ratio of the prostate, the PSA value to the prostate volume. And that, as you alluded to, is called PSA density. And in general, when I educate patients, I tell them, well, we want a PSA to be about 10% of the volume of the prostate or less to kind of be in a safe range. So if your PSA is 4 and your prostate's 40 grams, which is about average size for a 60, 65 year old guy, that's a PSA density of 0.1. We know that that is correlated with a low risk of having an aggressive prostate cancer. When I'm looking at someone's case, I want to know what their PSA density is. If the PSA density in a young man, frankly is more than 0.1, I get a little worried. If on an average age person, if the PSA density is more than 0.15, I start saying, let's do some additional testing. You put everything together, but yes, PSA density predicts likelihood that you'd ever be diagnosed with prostate cancer. It predicts aggressiveness of a cancer if you're diagnosed with it, and it actually predicts your outcome if you have a prostate cancer. So the higher your PSA density, the more significant your disease will be.

So the faster it increases and the.

Faster that your PSA rises. It is a canary in the coal mine to say, hey, you need to do some additional evaluation. Now, it doesn't mean you have prostate cancer because I often have, and we share patients where their PSA went from one to five, but we tracked it and it came back down because they had a flare up or inflammation in their prostate that made their PSA go. Sometimes we don't know why, often we don't know why, but if you track it, you can see that. So whenever somebody in general comes to see me with an elevated psa, the first thing I always do is just recheck it because there can be transient rises in the psa. Now, as you know, we have very similar practice. I don't just recheck the psa. I always order advanced PSA based testing. What does that mean? That is testing that involves looking at the percent free PSA and then other things like minus 2 pro PSA for the prostate health index test or the 4K score, which basically looks at different calacrines and their ratios.

And you and I discussed these tests in great detail in the first podcast, so we can also refer people back to those so that I won't make you re explain them. It does surprise me that the official screening guidelines for prostate cancer don't make any recommendation on the use of PSA testing other than something benign like every patient should discuss this with their physician. Which is a real cop out in my view of what we should be doing.

Well, it depends on which guideline you're looking at.

This is the US Preventative Task Force and the cdc and there's one other.

Yeah, the American Cancer Society, the American Urology Society, and The National Comprehensive Cancer Network, they're a little bit more progressive. They really suggest that you should talk about the risks and the benefits of screening. They kind of skirt around the idea of, well, how do you properly screen for aua? And American Cancer Society? Don't get into details upfront, they say start the discussion with like, what's your potential risk for developing prostate cancer? You can ascertain that with the family history. Again, if you're reading the AUA guidelines or the American Cancer Society guidelines, you already have a leg up on the average internist, because an average internist is just looking at general things they learned in med School or the U.S. preventative Services Task Force, which is too general and too vague. So I totally agree with you. I like and personally reference everybody to the National Comprehensive Cancer Network's Prostate Cancer screening guideline that basically says that every man at age 45 should have a baseline PSA because as you mentioned, changes over time are key, they're critical. And you want to know where you are in relationship to the median. So a 45 year old man's median PSA between 0.5 and 0.7 somewhere around there. Understand your median PSA and then if your PSA is below one, you can get rechecked in two to four years.

But Ted, the test is free. It doesn't cost anything to do a psa. Why wouldn't we do this every single year?

I guess the argument against it is that there can be natural variations. If you're a smart physician, you're going to pick up that, hey, there's natural variations. And if it goes up from 0.7 to 1.5, I'm going to recheck it and it's still in a safe range.

Isn't that all the more reason to do frequent testing if there's natural variation? Because it also means that if you're testing infrequently, you're more likely in the presence of natural variation to miss what the actual trend is. Think of the following thought experiment. So I love doing the thought experiment. So my thought experiment with colorectal cancer is imagine you had a low cost, zero risk colonoscopy that you could do on somebody every month. Would you eliminate colorectal cancer? Yes, there'd be no such thing as colorectal cancer. The third leading cause of cancer death is gone. If you have that. Now the reason we don't do that is they're not free and they're not risk free. Well, similarly, imagine you had just like we have a continuous glucose Monitor, a continuous PSA monitor, you could slap on somebody's arm and you could for free basically measure their PSA over their lifetime. I would argue there would be no such thing as lethal prostate cancer because provided you had the AI engine and the physician to monitor this, you would know Johnny rode his bike, Johnny had sex, Johnny had a prostate infection. You would very quickly be able to pick up signal from noise.

I don't disagree with you. It's just a matter of how frequent what is considered to be intensive PSA testing.

Right. Let's just say annually. Right.

Well, annual PSA testing is very intensive. So all the trials that showed that screening for prostate cancer with the PSA test, those trials that tested whether or not that reduced deaths, which they showed it did, by 20 to 25%, was PSA testing every two to four years. So that's the baseline.

But can we do better? Is my point to your point, it's still the second leading cause of cancer death.

It is. And the real question is, which we don't know the answer to is, were those men that ended up dying of their prostate cancer offered early screening or not? We don't know that.

And then the other thing is, with a little bit more of an investment in knowing prostate size, if you could now get that prostate density. So now if you have from one blood measurement that costs less than a pack of gum, you know your psa, you know your free psa, you know your PSA density, that's really powerful.

Yeah.

By the way, a 4K test is a thousand dollar test. You don't need to do it if you know psa, free PSA and PSA density, pack of gum, Chiclets, those three things. Chiclets, those three things, they're cheaper than.

A pack of gum. But yes, the PSA density is the more expensive.

But you can get that off an ultrasound.

You can. It's free. Basically, it's free. People would argue that percent free PSA gives you some strong correlation between the size. So yes, I totally agree with you.

I'm just pushing back, Ted, because look, you and I want the same thing, but look, there are certain things that I don't see a clear step on the horizon for the elimination. I don't see an immediate step on the horizon for people not dying of pancreatic cancer. I don't see, sadly an immediate step on the horizon for people not dying, women specifically of breast cancer. But I sure as hell see with the existing technology a reason for people not to be dying of colorectal cancer. And Men not to be dying of prostate cancer.

I mean, the deaths from prostate cancer with PSA screening have plummeted. So that's the one thing.

But it's still 35,000 men died last year. Question is, how many of them would have been saved with traditional screening?

Yeah, and trust me, I'm trying to defend the rule makers that made these rules that I was not involved with. But I would say that this idea of baseline PSA testing at age 40 on a population health level where that all came about was from bank serum out of Sweden. And so they were able to model that pretty well to understand what's your overall lifetime risk for developing or dying from prostate cancer. If your PSA at age 40 or 50 is below the median, then your lifetime risk is very low, remember? So we have some information about it. And the modelers, this is the best that they could come up with. I'm not disagreeing with you. There's no reason in my mind why you should not get your PSA tested at an early age, understand your baseline, and track it over time, which is what I do, and I think you do, too.

The other lesson you and I have both witnessed personally is the patients need to take ownership of this. We have both seen tragic cases where individuals who have no medical training but who listen to this podcast, for example, have diagnosed their own prostate cancer even when their physicians have said, there's nothing wrong with you, based on advanced metrics such as PSA velocity and PSA density. And that, to me, is infuriating and heartwarming at the same time.

Yeah, I agree with you. And it's many of those cases that we share are not like the subtle one in a thousand cases. They're like the ones that are obvious. So I do think that patients can own this, and this is a key part of their overall health. 100% agree with that. It's the mindset of the individual patient that also matters, because there are some patients that don't want to be proactive and progressive about how they monitor their health. Now, those are people who you probably don't take care of at all. But I know sometimes I'll see them. And so, yes, we have to balance knowing early with overreaction and kind of over treatment of a potential issue that may arise. So there's subtlety to it. Can it be done well? I believe it can be done well.

Well, let's now talk about that, because I think that if you look at people on the other side of this discussion who are saying, come on, this PSA test. I mean, there are a lot of people out there saying PSA should never be done. It's an awful test. It leads to a bunch of unnecessary misery for men because they're getting unnecessary biopsies. Now let's squash that nonsense that might have been true 50 years ago, but in the year 2023, in the hands of a competent physician, one step above the parking lot attendant, that's categorically untrue. So today let's talk about what we can do with an MRI to check if we have suspicion based on these other blood based biomarkers. What can we do to increase the probability that if we actually go to the step of a biopsy, the probability is sufficiently high that it was worth it?

You just said it. You order an mri, which is frankly surprising and appalling to me that I see second opinions in my office weekly that they never had any pre diagnostic, I. E. Pre biopsy mri. It's absurd to me. When I leave work, I check on my Google map. If there was an accident on the expressway and I changed my course, if there was, it's a test that's approved by all insurances. It should be done before any biopsy. In my opinion, there's really no case. Sure, if the patient's PSA is 1000 and you just need a tissue diagnosis. Okay, let's not debate that. But for every man who's undergoing routine screening for their prostate cancer, if they have an elevated psa, they should get a reflex test, which includes for sure, percent free PSA, prostate health index or 4K or other tests, depending on the cost.

And by the way, typically insurance will approve those if the PSA is over about 5, right?

PSA over 4 for 4k score. But we get phi testing in our lab. They do it for us. It's covered by insurance at any value. It's well calibrated over two, so we do it over two. By the way, what I'm telling you is based off of a prospective randomized trial published in the New England Journal where they used advanced PSA testing, they did not use 4K or PHI. They used Stockholm 3, which is a European only test. Abnormal advanced PSA testing. Do an mri. If the MRI has a suspicious lesion, we'll talk about that in a second. Perform a biopsy not just of the lesion, but of the whole prostate. Reduce prostate biopsies by 50%. Enhance detection of clinically significant disease by 11%. So, hello. Why are you not doing that? I don't know, but frankly, it happens. All the time. So what is it? Okay, the blood test we talked about that provides more specificity to someone with an elevated PSA who may have a problem. That's all I tell people. It tells us we need to do the next step. That next step is a high resolution Google map of their prostate. That is a typically a 3T MRI.

So 3 Tesla, 3 Tesla moderate power.

Yes. And it doesn't need any endorectal coil or any of that. So a 3T magnet doing a prostate MRI because there's specific sequences and it's multi parametric. The key parameters that we look at T2 images. You look at diffusion weighted imaging and dynamic contrast enhancement. Those are the three components of a multi parametric mri. However, there are grade radiologist scientists you're friends with, one of them, Raj, who have and others have shown that you don't necessarily need the contrast and that on average a T2 and the diffusion weighted imaging are nearly as good. Not identical, but nearly as good at evaluating the prostate for any risky lesions. Now, is an MRI perfect? No. It misses prostate cancers. It will miss small, low grade prostate cancers. But like we'll talk about in a sec, that's not necessarily a bad thing. But that's how the test works. It's done. And it's a screening tool to help us identify bulky, higher grade, higher risk tumors. Now, when you look at your MRI report, because as part of the 21st Century Cures act, every patient can look at their entire medical record. You'll see that they'll give you a good, well done mri. The report should contain the size of the prostate. It's baked into our reports because when I came to Chicago, I said, we're going to do PSA density. So you get the density and then it tells you if there's a suspicious lesion and there's a degree of suspicion. It's called the RAD score, the PI RADs for prostate imaging RAD score. And it goes between 1 and 5. 1 and 2 are considered to be BPH lesions. They're not cancer. So really we worry about RADs 3s, RADs 4s and RADs 5s. And in general, most recommendations would be if you have a rads 3, 4 or 5 lesion in your prostate and you've never had a biopsy before that you should consider a biopsy that samples the spot and systematically, that would be what we call target. And systematically samples the areas around the target, that is the peripheral zone in the area mapped around that lesion.

How easy is it for you? To see this and make this determination. For example, when you look at the MRI and you see the lesion in presumably the peripheral zone, how easy is it for you to then go and actually physically do the biopsy and know that you've hit it as opposed to miss it?

Yeah. There's skill involved with doing an MRI targeted biopsy.

Are you doing it under some sort of ultrasound guidance?

Yes. So, yeah, you have an ultrasound. So you use an ultrasound. And ultrasounds are not great. Traditional standard ultrasounds, which are very high resolution, are not great at identifying lesions with the efficiency that a MRI is. And granted they have time to think about and look at the images. So what we typically do is we take the MRI images and you, either cognitively, that is, with your brain or with a computer assistance, overlay the MRI and the suspicious area on the MRI with the real time ultrasound.

And is this a transrectal ultrasound?

Yes.

And then you're biopsying right beside the.

Well, that is how you overlay and you associate the suspicious area on the MRI is with the transrectal ultrasound overlay. Now you can do the prostate biopsy one of two ways. One way is to again pass the needle right alongside the ultrasound probe. That's a transrectal biopsy. Then you can follow the track of the needle as it goes in alongside the ultrasound probe through the rectal mucosa into the prostate. It's a very effective way to pick up prostate cancers. And the trial I talked about, that's the Stockholm 3 trial, that's the technique that they used. Now, the limitation of doing that is you always introduce a small amount of rectal flora bacteria from your rectum into the prostate. When the needle passes from the rectum.

Into the prostate, do men prophylactically take an antibiotic for that procedure?

To prep for that procedure, you'll do an enema to just decrease the volume of stool and bacteria in the rectum. And then you also will take an antibiotic. And with modern antimicrobial prophylaxis, you can reduce infection after prostate biopsy to around, depending on the series, between 1 and 4%.

Still pretty high.

Yeah, but it can be real. I mean, if you're the one in a hundred or the four out of a hundred guys, it's a real issue. Now that's all types of infections. So urosepsis, where you have, as we talked about before, really severe with bacteria in your bloodstream, that's very rare. But infections in general between 1 and 4%. The other approach that you can use is you can do a percutaneous biopsy. So the ultrasound probes in the rectum, it's looking up at the prostate, but the needle is inserted percutaneously through the skin in the space between the rectum and the scrotum. So that's usually around 4-5 cm of space. And in that space, you can actually place a guide, percutaneous needle guide. And then from that, you can then actually target the biopsy.

So in other words, you're not pulling the needle in and out each time. You are. Oh, you are.

You have a short needle guide, a trocar that goes through the skin, so you can establish your trajectory, and then from there, you can, with ultrasound guidance, put the needle exactly into the suspicious lesion.

The trocar stays in. One time. Yes. Yeah. Okay, so what's the drawback of that approach? Is it more difficult?

Yeah. So one pass on the right and one pass on the left. The original way that we did prostate biopsies was with a percutaneous approach. So back in the old days, over 100 years ago, if you had a suspicious bump on your prostate, you'd make an incision there, and you'd cut it out.

That was the original way that they did prostatectomies as well.

That's right, Exactly. So that approach to the prostate has been long appreciated. However, doing the prostate biopsy in a way that you could systematically sample the prostate with that approach has historically been very morbid, because what they would do is they would place a grid, like every 2 millimeters, 2 millimeter by 2 millimeter grid, along the perineum, and they would make between, let's say, 20 and 30 individual pokes into the perineum and into the prostate. That was how you can deliver radioactive seeds or radioactive pellets. But that approach was also used to do biopsies that results in significant edema and swelling on the prostate and significant bleeding. And urinary retention rates after that approach are very high. 15, 20%. And it's very painful. You can't do it awake.

Okay.

So there's a guy, Matt Alloway. He's a Shaffer family friend. He is a urologist in western Maryland. Very innovative guy. And he said there has to be a better way than doing transrectal bringing bacteria into the prostate. And there has to be a less painful way than doing this grid. So he created this percutaneous approach where you can basically have a single trocar on the right, go through the skin, single trochar on the left, go through the skin and you can navigate and sample all areas of the prostate. So he's been doing this for a decade now. A nod to him. He's an entrepreneurial guy. He created a company with his product and it's the gold standard for how you do that today.

So what percentage of your biopsies are done with the trocar versus transrectaly?

I like the transperineal approach, but in a nod to just not adopting things with closed eyes and saying it's better. We are in the midst of completing a 16 institution randomized trial that explores whether or not transperineal prostate biopsy is actually quote, unquote, better than transrectal prostate biopsy. And the primary endpoint is infection. So as I mentioned, modern contemporary infections with transrectal between 1 and 4%. We think our approach to prevent infections trondorectally is very good. And we're probably more on the 1% range when we do a transperineal approach. And Matt Alloway's published a lot on this. You can do that without any antibiotics and the infection rate is less than one in a thousand.

You're presumably powered to show a difference in that direction.

It's a lot. The power is hard. We had a power calculation, the NCI reviewed our power calculations and they said this is the appropriate power to detect a difference. So I think what will end up happening, and we're looking at the data right now, so I'm not going to say, but my sense is we're going to have 0% infections in TP transperineal prostate biopsy. But will we have done enough transrectals to really statistically show a difference?

Will there be secondary outcomes that look at detection?

Yes. So in my mind, if you have an approach that has 0% infections, I don't care if it's 1% or 2%.

Unless you're losing detection.

Yes. So the other endpoints for the study are pain and side effects. As I mentioned, transperineal biopsy with the old grid approach was 15% retention, meaning a catheter. Terrible. So we're looking at side effects. I think done properly, they're minimal. And then we use a lot of medication to do our blocks.

Like a pudendal nerve block.

Yeah, we do a pudendal nerve block and we use lidocaine and we don't just use any lidocaine, we use buffered lidocaine. Because lidocaine, when it comes out of the vial is a ph of about 5.

You put a little bicarb in.

Yeah, you know how you go to the doctor, they go pinching a burn. Well, what's the burn?

The ph.

Ph. There's no more burn. You buffered lidocaine with the transperineal approach. We're looking at the data now. I mean, there's some discomfort, but it's tolerable in the office, awake. And then the most important thing, of course, is cancer detection. So we have 16 centers. There's two other ongoing trials. Not to just say that we're the only one. There's a trial out of a limited number of centers out of Syracuse. They finished their study. They're looking to get their paper published. And then there's a large paper publication, large study in the uk but we're going to be the first to publish a multi center, large prospective trial. And it'll be interesting. I think that it will show that a TP biopsies is 0%. It will show that they're slightly more uncomfortable. And then the cancer detection we have yet to fully analyze, but excited to do that.

Okay, so let's talk about the different types of results that one gets from the biopsy. You've already mentioned the word gleason. Let's talk about what that means and how the scores are determined and what the implications are.

So who needs a prostate biopsy? Somebody who has abnormal blood testing. They go on to get an MRI now, that's our regular pathway. Who do we say you don't need an mri? Men who have bilateral hip replacements. An MRI is effectively useless. So we don't do an MRI for those individuals. We can calculate PSA density with an ultrasound. It's fast, it's cheap, it's effective. Otherwise we have everyone go to an mri. It's worth it.

Even with a single hip replacement.

Single hip? Our radiologists are really good. And a good radiologist can read an MRI effectively. With a single hip. If somebody has profound anxiety and they need general anesthesia for something, we'll be nuanced about whether or not we think an MRI exists. But for the average person, 99.5% of people, you get an MRI. Now, MRI shows a suspicious lesion. A rads 3, 4, 5.

You need a biopsy independent of PSA density.

Independent of PSA density. If your MRI shows no lesion but a high PSA density. So a young man, let's say under 60, that's a PSA density of more than 0.1 or 0.12 if you're older. I'll give you A little bit more of a longer leash. We'll say 0.15 over 65 or 70. If you have a PSA density that's below that threshold and you have a high psa, low percent free, et cetera, you need a biopsy. In my opinion.

We're going to include Ted, the slide that you shared with me a couple months ago that I still have, I still look at it all the time now, which shows by PI rads, by PSA density, the outcome of biopsies. And it's mind boggling.

Yes. PSA density is a huge variable in terms of impacting probability of having cancer when you sample a suspicious lesion and or the volume or bulk of that particular aggressiveness of that particular lesion. So Rads 3, 4 or 5, you need a biopsy. Unless your PSA density is incredibly low, like 0.02. Yeah.

Which by the way, patient, sometimes they have it. Yes.

So there's never always and there's never nevers in medicine. But in general that was what we would say. If you have a negative MRI and a high PSA density, we will often suggest a biopsy for you. And if you have a negative MRI and a low PSA density, we'll say you're likely can be monitored. We'll put in the show links a nice figure that illustrates that from a large group of about 10 institutions pooling all of their MRI and biopsy data together. However, I have the good fortune of having a partner who's a brilliant guy, Ashley Ross. He analyzed and built a neural network real time predictor for all patients, not just Northwestern Medicine patients. But we used all the Northwestern Medicine patients in our system who had had phi, MRI and a biopsy and looked at all their outcomes. So there's some selection bias because we didn't include people who didn't have a biopsy. But in general we took all these people and we created a neural network real time predictor for what's your absolute risk for having prostate cancer in general, but more specifically prostate cancers that would require treatment and that we'll put in the show links. This is the model, this is the MYNM risk calculator.

Okay. So we'll make sure we link to that as well.

So the figure is great because it just gives you an idea of a framework. But the actual risk calculator gives the individual patient their individualized risk. So he built it off around 16, 1700 MRI biopsy linked cases. But now that has grown because it's always learning. If you undergo a prostate biopsy the answer's not just cancer. Yes or no. There's a lot of subtlety, and a lot of things have changed about how we think about these different cancers. So I always explain to patients that it's basic. Effectively, when a pathologist looks at a biopsy sample under the microscope, they're describing the pattern of the cancer gland. We talked about this at the beginning. The prostate is an exocrine gland that produces semen. And there's an architecture of the gland or the duct that a normal prostate has. So think about, like a branching tree. When you develop a cancer, it's an abnormal developed branch. And so the pathologist will score how abnormally developed that duct or that branch is. And that score is what ends up being the Gleason score. Now, the pathologist tells us, if you have a cancer, what does the individual branch look like? What's the pattern? That would be the Gleason pattern. And in the patterns today are pattern three, pattern four, and pattern five. But what we get in the summation report is, well, how much pattern 3 cancer do you have, how much pattern 4 cancer do you have, and how much pattern 5 cancer do you have? And that's the Gleason sum was also referred to as a Gleason score. So the common ones would be three plus three equals six. That means that the pathologist only saw abnormal glandular patterns that were pattern three.

So the pathologist is always reporting the highest scores that they see.

They're reporting the most common pattern they see first. That's the first number. And then the second most common pattern of cancer that they see as number two.

And this is on both sides.

Every single sample, they tell you the score.

Okay. Typical number of samples that should be done in a decent biopsy.

It's 12. Systematics. So that's right side, left side, kind of every 5 millimeters approach. Plus you sample the target. And the recommendation number of samples of a target is usually 3. So 2 is inadequate because the needle can bend, it can deflect. Sometimes the needle is going in 20 centimeters beyond your hand. So you have to account for the deflection, and you can track it. But the idea is you do it three times.

I mean, talk about user error potential, right? Like, think about the difference between you and me doing a prostate biopsy.

I know you could do it better than me. It requires skill.

Even within the field of urology, there has to be a difference in skill.

Yeah, and that's what the training is part of. And Ashley and I actually host a course where we Put on and train anybody who's interested in how to do a proper, good transperineal prostate biopsy, for example.

Hopefully this is just limited to physicians.

Yeah, it'll be helpful. And obviously there is a skill involved with. And you can tell there's a skill involved with doing the biopsy, and there's a skill involved by the pathologist when they report it out. So the requirements or the recommendations are that you declare the Gleason score. That's the sum of the. The most common and the second most common cancer.

Now, presumably some of these core samples come back with no cancer in them. Is that just reported as nothing?

They report no cancer.

Okay, got it. So it's no cancer. Or at best, three. Three.

Yes. There's some rare variants that are not cancer and they're not benign. They'll tell us about them. That would be like prostatic atypia, but that's uncommon, especially in the era of MRI targeted biopsies only I wouldn't worry about that too much.

And you're biopsying only the peripheral zone?

Well, we biopsy where the lesion is, but most prostate cancers originate in the peripheral zone.

But the 12 systematic biopsy spots are peripheral zone. How thick is that, by the way?

It depends on the size of the prostate. So in a young man, it's about 4 to 5 millimeters thick. In a guy who has a big prostate, let's say 100 gram prostate, the total peripheral zone volume does not change in a man over time.

Does that mean it actually gets thinner?

It gets compressed and thinned out. Particularly if you have benign prostatic overgrowth.

Wow. So it makes it harder to biopsy?

It makes it harder to biopsy, absolutely. So that's where skill definitely plays a role. So you have to really understand what you're doing.

Not to take away from breast biopsies and things like that, or a thyroid biopsy. But this is a totally different. Totally different. This is much more complicated, in my opinion.

Yes, for sure. Sure. A thyroid or breast, you're trying to target abnormal. But yes, there's a lot of subtlety to it. You have to know what you're doing. And, yes, the total peripheral zone volume remains the same over time. So if your prostate size increases, the thickness of that peripheral zone goes way down.

Another way to just get this back to our analogy is you're having to biopsy the skin of the orange. If it's a small orange, the skin is a certain thickness, which is relatively thin. The bigger the orange gets, you have to preserve the Amount of skin. So the skin gets thinner and thinner and thinner.

That's right.

Okay, so now what do you do with these Gleason scores?

So you take a look at them, and you say, what is the score? And then what's the distribution? And that's the volume of the score. Because the two things matter in terms of determining what the next steps for the patient are. In general, the way I talk through this with patients is, did your biopsy demonstrate prostate cancer? And if it demonstrated prostate cancer, is it the kind of prostate cancer that we need to treat right now, or is it the kind of prostate cancer that we can safely follow or monitor over time?

Okay, so let's start with. Patient comes in. Both the lesion and the periphery are 3 3.

So Gleason Prostate 6 prostate cancer. That's Gleason 33 6. Prostate cancer is the least aggressive type of prostate cancer. When you look at it under the microscope. And it has a very favorable prognosis, meaning those prostate cancers, the thought process should be, I need to find some data that will convince me that this cancer requires treatment, because the recommendation, on average, is that these cancers can be monitored. Now, what are the variables that affect whether or not we think someone should have their cancer treated?

Sorry. Just to make sure I understand that, Ted, does that mean a 3:3 can't spread or metastasize unless it progresses to a 3:4, for example?

Excellent question. And that's been explored with one major caveat, that is that it's been explored in surgical series.

There's a bias already introduced there.

Huge bias. But if you look at radical prostatectomy series in men who had Gleason 6 prostate cancer, there's a large series by John Epstein at Hopkins and also Scott Egner at University of Chicago. They both showed that there was no lymph node metastasis in men with Gleason 6 prostate cancer.

Just make sure we understand that any man who underwent a prostatectomy with a Gleason 3.3had lymph node negative disease, and therefore, by extension, presumably, they never went on to get metastatic. They never had a recurrence at the.

Time of their surgery. Never had.

So what's the longitudinal data on those folks? Do we know that they're free of disease?

Well, they do very well. The probability that they would die from prostate cancer is very, very low. But they could have a local recurrence, for example, and that could result in subsequent problems and need for additional secondary therapies. But on average, we know that a Gleason 6, prostate cancer that is of low volume can be safely monitored.

But hang on a second. Why did those men have cancer surgery then?

Because we have evolved how we manage them.

I see. So based on those data, we now would be less.

That was the person that I operated on. We operated on Hopkins when I was training, where one core Gleason 6. We thought because they had a cancer that they required immediate treatment.

So this is now very different from the colorectal cancer model. In colorectal cancer, you have an adenomatous polyp, it comes out. You have a carcinoma in situ, it comes out.

Yeah. The difference is because in the colorectal model, you can easily resect the adenomatous polyp with minimal or no side effects. Done with a colonoscopy.

It's the morbidity of the prostatectomy. Similarly in the breast. Right. Dcis. It's coming out debate whether we should radiate or not, but we treat pre cancer so aggressively in these other organs.

In that way, in the positive light of things. Urologists have been very progressive and have been at the forefront of doing surveillance for tumors that have not yet established or declared that they have lethal potential.

So how often do you get a man, Ted. Or maybe. Let me reframe it this way. For every hundred men who you see who have a Gleason three plus three, how many say, Dr. Schaefer, I understand what you just said about the data. I don't want this thing in me. Take it out.

Yeah. I mean, it's rare that I will offer my surgical services to that person, because sometimes the patients don't fully understand what the potential ramifications for their side effects may be.

Meaning the surgical risks.

Yeah. Or radiation risks. So what I will do is I will jump through a lot of hoops to look for reasons to reassure that that patient that they do not have an aggressive, lethal situation. And most of the time, we're successful. Now, a man is diagnosed with Gleason 6 prostate cancer, if it is of low volume, let's call that between one and four cores, which is the most common thing that we would find. One or four samples of a systematic biopsy, or if you target a lesion on the mri, we consider that just to be one region. So if you did five samples of an MRI, suspicious RADS4 lesion, and all five samples came out Gleason 6, we would just call that one area of visible cancer. In those situations, we generally would say you are somebody who is a candidate who can have their prostate cancer Followed because at this time, your tumor does not have the lethal potential to spread to your lymph nodes or other parts of your body. And all kinds of therapy to treat it carry more morbidity than just leaving it in place and just monitoring it.

Yeah, it's amazing. And you're right. It's really precision medicine. But you have to be both as the patient and the physician. You have to have a very high degree of certainty that you didn't miss a four, that that wasn't a three plus four.

Patients will often say that to me. I will tell them. For the average patient, look, we don't just assume that you only had six. Although, remember, with MRI targeted biopsies, we know the chances of reclassification or change in the grade of the tumor at the time of prostatectomy is low. Like 10%. Historically, when you and I are residents at Hopkins, you'd have a guy like the Gleason 6 and he'd come out with the Gleason 8. Because there was no MRI and there was no MRI targeting. So the precision of the biopsy today is much better. And therefore we can provide much better assurance to the patient that, hey, the biopsy shows a six, we got a pretty good idea. You just got a six again. Doesn't mean that patients. We just assume that they're going to be fine for the rest of their life. We do active intensive monitoring. That's PSA testing every six months. I still believe that. Like you were mentioning before, following that PSA and if it changes closely is helpful.

Do you repeat the MRI independent of a change in PSA in those patients? Once they're a three plus three?

I do. My general frequency would be that if they've had an MRI pre biopsy, then I'll track them. If they're PSA stable, I will not repeat the biopsy. And we recommend a confirmatory biopsy at one year. So you have low volume, low grade prostate cancer. We check your PSA at six months, it's stable. Everything looks good. Your MRI was not concerning. We'll do a biopsy for you at one year. If you come in with low grade prostate cancer like the patients we took care of 25 years ago at Hopkins, and you have not had an MRI before your biopsy, you immediately get an mri because I want to know what else is going on in there. I want to know your density and I want to know if there's a lesion that was missed. If on that MRI that I get after your initial diagnosis has a rads 4 or 5, you go to immediate biopsy. If the MRI shows that you have a rads 3, but let's say a really, really high PSA density, like, again, I have concerns that the biopsy quality was poor, you go to immediate biopsy. So again, you want to do confirmation to establish your north as your true north before you tell a patient, yes, 100%, I endorse active surveillance. So we do a lot, a lot of testing in these individual patients to make sure that when we're recommending surveillance, we're recommending it for low volume, low grade prostate cancer.

If you can answer this all things equal, for 100 patients who show up with suspicious enough PSA that they buy a MRI, suspicious enough Rads 345 that they buy a biopsy, but now, high degree of confidence, they're three plus three, meaning they're down the active surveillance pathway. What percentage of those men, and I'm sure it's age dependent, will go the rest of their life without a prostatectomy?

I can't tell you the answer to that, but I can tell you data that's 10 or 15 years out and 5 years out. So if you have Gleason 6 prostate cancer and you enroll in active surveillance, the question of course is, well, what would be the trigger to recommend a treatment? So it's effectively like your cancer is becoming more aggressive or your tumor becomes bulky. So think about it those two ways. The chances that you would have a more aggressive cancer develop in the first five years of surveillance is 12.5%, by the way.

Is that independence of whether you were rads 345? We didn't really talk about that.

It's all comers. All comers. This is Valentine Carter's active surveillance cohort from Johns Hopkins. From Hopkins, 1996 he started it. 12.5% chance that you'd have a change in the grade of your cancer. Overall, about 30 to 35% of men in the first five years of entering surveillance will go on to subsequently have definitive treatment. About 12.5% of guys, it's because there's a change in the grade, it becomes more aggressive looking. And the other guys, a variety of factors, they have increasing bulkiness of their tumor, they may develop concomitant urinary symptoms, and they want it all addressed at one time, et cetera, et cetera. In general, I tell people it's 12.5% chance that you have a really need to do something because there's a change in the grade. That's pretty Steady and pretty consistent. It's around 2, 3% risk annually. That holds for 10 years as well.

Meaning you add 2 or 3% per year after five.

Yeah.

So you're up to 22, 25.

But overall, if I told people there's a one in five chance that your tumor would become more aggressive over the next 10 years of your life and you need treatment.

Yeah, they'd sit on that. Especially because you're not saying, go away and we'll only see you again when you're in trouble. It's like we're going to watch that progress.

That's right. And what's the chance that a cancer progresses in surveillance to be uncurable? It's 0.1%. So one in a thousand guys who you're monitoring would have a Fisherian event.

Wow.

That's Bal Carter's data. Ballantyne Carter out of Johns Hopkins. It has changed how we treat and think about prostate cancer from when we were training there to now.

So let's talk about the Gleason 7s.

A pathologist will tell us what they see under the microscope. How much pattern three do you have, how much pattern four you have? And if you have pattern five, do you have it? So a Gleason 7, as you said again, the Gleason score is a Gleason sum, and it tells how much pattern three and how much pattern four do you have? So it is a blended Scotch, not a single malt or whatever they call it. And the blend is what matters the most. How much pattern four you have particularly is the most important factor. So you can have as little as less than 5% pattern 4 and as much as 99% pattern 4. If you have 100% pattern 4, you don't have a Gleason 7, you have an 8. So when I look at a pathology report, I look at what is the Percentage of Pattern 4 There tells me two things. One, how good was the pathologist who read it? Because if he's not telling me percent pattern four, I don't believe anything he's telling me. And two, if it's there, how much percent pattern four you have? Not just by percentage, but millimeters. So I'll look at how long is the tumor? Remember, our biopsy needle is 15 millimeters long.

What gauge?

It's a true cut biopsy. Around 18, 16 gauge. It's not small. It's a decent sized sample length of the tumor. And then I translate well, how much of that length is percent pattern four. So if I have a patient who has A single biopsy core that has 10% prostate cancer. That's 1.5 millimeters of prostate cancer. That and he has 5% pattern four. Think about how little disease that is that has potential issues with lethality. What I do with that sample is I send it off to Vericite for decipher testing. And I have them look, because about 70% of the time, those small volume Gleason 7 tumors genomically are minimally aggressive. I want to delineate that.

So they behave more like the sixes.

They behave like a six. But if you have more millimeters of pattern four, the more millimeters of pattern four you have on your biopsy in total in some, the more that would push you to do treatment. So, big picture, if they're exclusively a pattern 3 disease, on average, we think surveillance until proven otherwise. If you have a smidge of pattern four, I'm talking about one millimeter, two millimeters in total, we think, okay, maybe surveillance would work for this person. We have a very thorough, detailed discussion. Age, other issues in their life, et cetera, et cetera. We determine, okay, life expectancy. So if you're 75 and you have 2 millimeters of pattern 4, and you're an average US male, maybe you don't need to aggressively treat at that time, you need to aggressively monitor, but don't need aggressive treatment. That's the subtlety to it. But the higher the percentage of pattern four you have, and therefore, on average, the more millimeters of Pattern four you have, the more you're going to be talking about active treatment. So that's the essence of how much prostate cancer management has changed in the last five years.

A Gleason 7 that needs treatment is a perfect surgical candidate.

Yes.

What about a Gleason 8? Now, by definition, every single thing that is looked at is 4. Is there such a thing as a 3 5?

There is a 3 5. The science geeks have looked at it effectively. It behaves like a 4, 4, 8. You treat them all the same, and you treat anything that's an 8 or higher the same way. So you can have a only pattern four. You can have a only pattern four. You can have a pattern four plus pattern five. That would be a Gleason nine. Okay, you can have a ten. That's pretty rare, but pretty bad. And actually, if you're pattern four, three seven. So if you're more than 50% pattern four, you're Gleason. Four plus three equals seven. We generally bundle those together with the eights and the nines. You Have a lot of pattern four, you need treatment. And then the discussion becomes whether or not single modality treatment is effective at treating and curing that individual man of their prostate cancer.

We're talking about the Gleason 8 on average?

Yes. Why? Because the analogy I always use is like a dandelion weed on your front lawn. The higher the Gleason score, the higher the probability that that person can have deep roots in their tumor extending outside the prostate, potentially into the perirectal fat and beyond. And additionally you have a higher probability that that dandelion can go to seed and those seeds can float off to the lymph nodes. When you have a higher grade prostate cancer, you need to do a couple different things in your workup. The thing that you need to do, the one key thing is to do a PET PSMA scan. PSMA is a prostate specific antigen, prostate specific membrane antigen particularly, that is enriched in its expression in prostate cancer cells. And it is the most sensitive and specific way to determine the extent of a person who has high grade prostate cancer disease.

So in other words, it's a PET scan, but instead of using fdg, it.

Uses PSMA specific radioligand because prostate tumors are not FDG avid.

So it's a functional metabolic test as well.

You stage somebody's prostate cancer with a PSMA scan and then from there you develop a treatment plan. On average, if you have prostate area only, let's just call it prostate only, could be extra prostatic, but prostate only or prostate plus lymph nodes, then you have to start thinking about your initial definitive therapy and potentially multimodal therapies to aggressively treat an aggressive lesion. So depending on the patient, their age, the bulk of their tumor, et cetera, I will talk to people about radical prostatectomy as an option for them. There are a select group of people, let's call it 20 to 25% of my surgical practice that presents with very bulky, potentially super bulky, aggressive lesions in those individuals. I'll have an upfront conversation that I don't think that surgery alone will be effective at completely curing you of your prostate cancer, but vis a vis breast cancer treatment, colorectal cancer treatment. Surgery is an important component of your initial therapy. And we'll do surgery and we'll follow that up with the radiation based approach.

And that patient that you're describing, they have bulky tumor, but the PET scan doesn't reveal any activity in the bone. Correct. Does prostate cancer metastasize to places outside of the bone besides local invasion?

LYMPH nodes is the most common place.

It would metastasize within the basin.

Yes. It follows a Halsteadian trajectory most of the time.

But does it follow para aortic lymph nodes the way testicular does?

Yeah.

So it can go to lungs.

It can be in the thoracic cavity. Yes. Mediastinum supraclavicular. So. Yeah. And then it will go to bone.

Why bone?

The microenvironment of the bone is thought to mimic the microenvironment of the prostate.

Are there androgen receptors there?

No, but the milieu that the other growth factors that prostates may need to grow are there, number one. Number two, as you know, the bone marrow filters all your blood, so if you have circulating tumor cells, they're going to be trapped.

But isn't it interesting how few cancers do that besides breast and prostate? Think about colon cancer, pancreatic cancer. I mean, all these other cancers.

Yeah. I mean, the colon one, I think, is that we just pick up advanced colon cancers while they're, you know, they're trapped in their kind of mesenteric blood spread. Right. So you're picking them up regionally more.

Yeah, you're right. It might just be that the colon is so concentrated towards the liver.

Yeah. I mean, the load of circulating tumor cells in colon are filtered by the liver.

Yeah. But again, it's not uncommon to see colon go to lung.

Yeah. Prostate goes to lung. Prostate goes just everywhere else. But yes, it is true. Lymph node is the most common cytometastasis. And then effectively equivalent or just in a close second is bone.

From a staging perspective, do we use typical TNM staging for prostate cancer? And if so, if it's only in the lymph nodes, is it considered.

It's considered stage four for ajcc, that would be stage four at diagnosis. If it's in pelvic lymph nodes, is.

That considered M0 or M1?

We call that regional.

Yeah, but it's stage four.

Yeah. It's scary to have someone have stage four, but prostate cancer in the pelvic lymph nodes is still curable.

How curable?

The devil's in the details. The big differences in prostate cancer Overall for the listeners, 96, 95, 96% of prostate cancers are diagnosed when they're localized. Okay. Then there are people who have N1 disease and M1 disease, and you can have M1A, M1B. It's just the extent of the metastasis. If you have lymph node only disease, it's rare, but if it's picked up at the time of your initial diagnosis, it's less curable than if you subsequently develop lymph node disease. In your follow up and your survivorship monitoring in general, I would say that vast majority of people who have lymph node only disease can live 10 years. And are they cured or not? That's debatable. We have this blood test that tells us exactly what's going on, but they can live 10 years.

And the treatment is prostatectomy plus radiation the best treatment?

If you look at the data, there's never been a randomized trial that explores which one's better. But the best way to control lymph node disease is probably with radiation. Now, I think about what's the role of surgery in this space. The role of surgery is to debulk the bulky tumor. As we talked about, a lymph node Met is probably 40 or 50 million cells at a minimum. And so why not enable the radiation to be more effective by just debulking it? On average, radiation is more effective at controlling that local disease extent than is surgery.

The morbidity of radiation is not trivial, not just from the nausea and the sickness that can come from the treatment, but at least in the few cases I've seen of patients many years out. The rectal bleeding that normally gets better but not always, right?

Yeah. The main side effects when you're considering treatment with radiation would be urinary, sexual, and then kind of GI and GI meaning rectal, rectal irritation, rectal bleeding. The urinary side effects with radiation on average are kind of burning the prostate. So you're going to have these lower urinary tract symptoms that we talked about at the beginning of the podcast. They're always intensified and amplified. They typically persist for the duration of the treatment, plus about a two month lag after that. The rectal side effects that you're describing I think are mostly historical. Why? There's a lot of new technologies that have been used to really minimize that. So you can put in place with the percutaneous approach for like we talked about for the biopsies, you can percutaneously deposit gel hydrogel. When it warms up, it thickens. You put it in the plane between the prostate and the rectum and you elevate the prostate between 5 and 10 millimeters off the rectal wall and it gives the radiation oncologist this window to radiate the prostate effectively without damaging the rectum and it reduces side effects substantially. Now, the other newest and Most exciting kind of way to deliver radiation is with MRI guidance. So remember historically, you were placing fiducial little gold seeds and you'd line up the radiation and you just assume it was gonna hit the prostate most of the time. And then we've developed CT guided radiation where you do a quick CT scan and for that day, you line up the radiation fields with the CT scan, but it's not real time. Now there is MRI guided prostate radiation. So again, we do MRIs to see prostate cancers because it's way more resolution, not CT scans. So you can theoretically resolve to the prostate much better. And now there's a single MRI guided linear accelerator that does intrafractional modifications of the dosage based on subtle movements. So if you take a deep breath or there's a little rectal gas, it will capture it within between the fractions of radiation delivered and alter the trajectory of the beam. There's a trial called the Mirage study. It was done at ucla and they showed that there was almost zero rectal side effects from it. The other really, really cool thing about radiation is that when you have an MRI and you have a big rads lesion, let's say you got a rads four, rads five, you theoretically can boost that lesion with tremendous precision if you have MRI guided linear accelerator.

Because it's so visible on mri.

Yeah. The field of radiation oncology is evolving and they're doing a lot of spectacular things. One, this kind of real time gating is huge. Two, using and boosting the MRI visible lesions is, I think, huge from a cancer control perspective. And then from a patient morbidity perspective, because the MRI linear accelerators are very expensive. We have one, but they're not widely available. You can do this space oar, that's the gel that basically separates the prostate from the rectum. And that's been shown to reduce the toxicity of radiation treatment a lot. It's good. You know what, it raises the field and the competition for us to think about ways to do better, less morbid prostatectomies, I guess.

To close the loop on that, let's talk about systemic therapy. The mainstay of this is androgen deprivation therapy. We've already talked about the morbidity of that. Are there other synthetic agents? Are there any things that are looking promising on the immunotherapy front? We're seeing an enormous surge of that on the side of other epithelial tumors.

Let's talk about the first thing, which is when you're doing localized therapy, we do think about Utilizing androgen deprivation therapy as a radiation sensitizer. So it is known that when you have a higher grade tumor, let's just say you have a Gleason 8 or 9 like we talked about, that radiation alone is not going to effectively cure that patient of their prostate cancer. You need to deliver, and we know you can deliver radiation sensitization with androgen deprivation. Androgen deprivation induces double strand DNA breaks. That's the whole purpose of radiation itself is to induce those breaks.

So in other words, androgen deprivation makes the cells even more susceptible to the radiation.

So we use that routinely. And one of the things that the rad ons have to work on and they're doing, there's a series of trials right now exploring this is either intensifying the androgen deprivation in cases that are very aggressive, or de intensifying androgen deprivation in cases that maybe that the patient would not benefit from it. And the way that they're determining that is with the decipher test. So we use androgen deprivation therapy typically in two spaces, one, to augment and enhance the results of radiation based treatments and two, in individuals who have more advanced prostate cancers. So for individuals who are considering are going to have radiation for their localized or locally aggressive prostate cancers, they will often get that with a course of androgen deprivation. And the course of androgen deprivation typically ranges between 6 and 24 months, depending on the bulk of the tumor and the aggressiveness or Gleason score of the tumor. That ADT was typically delivered with an LHRH agonist. So you would give an LHRH agonist first you get a surgeon testosterone, then it shuts the system down. The problem with that is that it is given as a depot that lasts a long time. It's helpful for the patient, but the probability that the patient would ever recover normal testosterone is very low.

Why is that?

Because of the long term effects on the hypothalamic pituitary axis. It just gets shut down and or because as you know in the aging.

Male that it's fragile to begin with.

It's fragile to begin with. The good news for men who are getting ADT short course is that there are oral LHRH antagonists that are out there and so they're a pill. So their half life is much shorter and they have been shown to effectively suppress testosterone to the same levels as the LHRH agonist. But their half life is so short that people can have a rapid testosterone recovery and they do so for people who are going to get radiation treatment who need a radiation sensitizer. With adt, we will typically use an ORO LHRH antagonist because it's rapid on and rapid off. So good news for those individuals, for individuals who are diagnosed with prostate cancer that progresses to a metastatic state, or individuals who are diagnosed with prostate cancer that's metastatic, at the time of diagnosis, those individuals need to go on systemic therapy. And the mainstay of systemic therapy is androgen deprivation or adt, that is based off of Nobel prize winning work from Charles Huggins out of University of Chicago. That mainstay of therapy has not changed. What has changed is the synthetic molecules that we use in addition to traditional LHRH agonists or antagonists to further suppress testosterone levels. And the two main classes of those are CYP17 inhibitors. That's a molecule called abiraterone. So as you alluded to, androgens are made from cholesterol molecules and you can inhibit a specific enzyme in the anergenic pathway, CYP17, and you can then prevent production of not just testosterone, but other androgens, not just in the testicle, but within the adrenal glands and systemically. And it results in a more profound deeper suppression of testosterone androgen production that is now recommended as first line therapy for people with metastatic prostate cancer.

What's the median survival for men diagnosed with metastatic cancer to bone? Let's talk about distant metastases with and without adt. What I'm really getting at is, given the morbidity of adt, are there men who say, okay, my median survival if I do nothing is 12 months versus my median survival is 16 months if I do ADT, it might not be worth an extra 4 months of life if I have to live sans androgens.

The median survival for someone with newly diagnosed prostate cancer that refuses treatment is probably on the order of two to three years. The median survival for somebody who goes on traditional ADT only LHRH agonist antagonist is between 48 and 50 months. So you can double it.

You can add a year to two years of life.

Yes, but it's also the quality of the life of the individual. There are effects that occur in terms of the impact on metabolic syndrome and overall health. But remember, when prostate cancer is metastatic, it starts taking over your bone marrow. You can develop aplastic anemia. I mean, it's brutal. So if you can mitigate that, how do men die?

What are the final stages of life?

Pathologic fracture, aplastic anemia because of bone marrow replacement. So it's other Organ dysfunction because the tumor takes over for it. Renal failure is a classic one, too.

From local tumors and tumor lysis and things like that.

Yeah, ballpark. You can effectively extend the life of a patient if they're diagnosed with metastatic cancer by about two to three years by going on adt. The new agents, meaning abiraterone or this other class of agents, which are competitive binders of androgen receptors. So they will bind androgen receptor, tether it in the cytosol, and prevent it, the ligand binding domain, from binding the DNA in the nucleus, among other mechanisms. Those are things like Enzalutamide, Apalutamide and Darolutamide. They're related. They're much more evolved cousins to finasteride and Dutasteride, but they're very potent. So there's abiraterone and then there's another class of novel hormonal therapies, the Amides, Enza, Darrow and Appa. They will effectively extend the life of a patient an additional 24 months on average, compared to just traditional ADT alone.

And they're done in concert.

They're done together. Correct. So now if you have someone with newly diagnosed metastatic prostate cancer, median survivals are seven to eight years, which is good. Now, it depends a little bit on the situation that they're diagnosed with cancer in. So if you're newly diagnosed de novo metastatic versus you had your prostate cancer treated and then you develop metastatic. Those two men have different outcomes. The men who are newly diagnosed de novo, they have a much shorter life expectancy, three to five years, compared to somebody who already had their cancer treated, it progressed to the bone or the lymph nodes, they have a much longer life expectancy on average, probably because of bulk of disease and somewhat lead time bias in terms of the detection. So those are traditional androgen deprivation. Then you have novel hormonal therapies. They're always evolving. Newer ones, the amides, they have some toxicities. Enzalutamide and Apalutamide, they have issues with seizures. They have issues with overall sleepiness and kind of alertness. And so they're real. Darolutamide, which is the newest agent in that family, is much cleaner. There's less cognitive effect of it since it doesn't cross the blood vein barrier very well. No seizure side effects. Abiraterone is pretty well tolerated, but it has an effect on aldosterone production. So you have to monitor people's blood pressures while you have them on those drugs. So there are toxicities with the treatment, but on average, people can have a longer lifespan and a relatively good health span while on these medications.

Okay, so let's talk a little bit about surgical therapy. Last time we spoke, we spoke in great length about the evolution of this operation from the way you learned it, which was an open procedure, to the way you did it at the very, very tail end of your residency, which was transitioning to a robot. When was the last time you did an open procedure?

2016.

Okay. So it would be almost unheard of today that a patient would have a prostatectomy that is done anything other than through a robot.

Correct.

What is different today in the surgical practice, your surgical practice, than, say, four years ago? How has it evolved? What are you doing today to make that operation better?

Lots of things. Surgery is always this balance of maximal exposure so that you can see everything with minimal exposure to preserve all the structures around whatever you're removing, whether it's the heart, the colon, the lung, whatever. And so prostate cancer surgery has evolved in a similar way. Historically, the robotic procedure was developed and really mimicked the open surgical procedure, which basically maximally exposed the prostate within the deep pelvis. It's in a very small tube. So for the tennis players out there, the deep pelvis is like the inside of a tennis ball case, the kit where you get the three balls. It's very narrow, very small space. And you enter that space at the top of that case, and you're operating at the bottom. That's why it's such a hard procedure to do. Now, we used to expose all the structures around the prostate to see it and delineate it from those structures. The way that my technique has evolved is that now I maximally preserve all those structures around the prostate and basically operate in an even smaller hole. What do I mean by that? Well, there's fascia, which for the average listener is effectively like the Kevlar or the Gore Tex of our entire body. It provides resiliency and strength to the structures and keeps them in place. And the prostate is surrounded by a tremendous amount of fascia. And when fascia gets really, really thick, we refer to that as a ligament or a tendon. So the prostate has fascia. It has ligaments. They support the prostate in the deep pelvis. And we historically open and robotically always would open up and disassemble that fascia, take it apart to expose the prostate, and then we would just sew it back together and hope that people were okay. We would preserve the structures around the prostate, but we'd hope they were okay since that time, we now have evolved, not just me, but, you know, I think the elite prostate surgeons in the world, in the country, have developed techniques to do pelvic fascial sparing surgery, leaving all the fascia that surrounds the prostate, top, bottom, right, and left alone.

And again, the purpose for this is not to enhance the removal of cancer. It's to mitigate the very real side effects of this surgery, namely around erectile function. Incontinence.

Yes. So you have to always balance and weigh, are you getting all the cancer out? Because you can maximally preserve all these structures in the fascia and the tissues, but leave a lot of cancer behind, and then what's the point of the procedure? So you're always balancing your outcomes functionally with your outcomes from a cancer control perspective.

And a hundred years ago, getting all the cancer out was doable. The problem is the morbidity of the operation was you were guaranteed to be incontinent and impotent.

Yes, I would say 60 years ago, that was the case. 100 years ago, we were not picking up early enough anyway. But remember, 100 years ago or 100 plus years ago, the first prostatectomy was a pelvic fascial sparing prostatectomy. It was done in the perineum, where all the fascia that supports the prostate was left in place. It was bloody. You couldn't see what you're doing. So the robot enables you to have no bleeding. It enables you to see what you're doing very, very well.

And remind us just where the ports are. Where do you gain access?

You gain access to the prostate, typically through the abdominal compartment. So you have a central port at the belly button, and then typically a couple ports around at the level of the belly button, more lateral to it that you insert your instrumentation. Usually the procedure's done transperitoneally, meaning you put the ports into the peritoneum where the intestines live, and then you kind of exit the peritoneum and you do the procedure extraperitoneally outside of the peritoneum, outside of the peritoneum. And the deep pelvis is where all the fascia is there, supporting the prostate and the structures around it. So now when I do the procedure, I do pelvic fascial sparing. I've been doing it for two and a half years now. When I look at my results, I have not impacted at all my cancer control. So some of the early surgeons who did pelvic fascial sparing, they left a lot of Cancer behind. You don't want to do that. That's the whole point of the procedure. When I track my data, I am able to have excellent cancer control numbers or data margin rates, et cetera, while maximally preserving the structures around the prostate. So, as we mentioned before, you have your orange. The pulp of the orange is not cancer, but the outer peel is cancer. And just adjacent to that outer peel are nerves for erectile function, nerves for innervation of the urethral sphincter, and the urethral sphincter itself. All of those structures are supported by pelvic fascia. We now leave all those structures in place and do the procedure through an even smaller space. Requires a learning curve to adapt to it, but with that approach, you can really effectively eliminate urinary incontinence in almost everybody. And more importantly, the rapidity with which urinary control comes back is outstanding.

So what do you tell a patient today?

I tell the patients my data. So I tell them that there's about a 4 to 5% chance that if we do your procedure, you'd have a positive margin if the cancer's contained within the prostate, which is what I was doing beforehand.

So, meaning there's a 95 to 96% chance that this operation will be successful. From a cancer perspective, 4 to 5% chance we'd have to go back in to get some of the cancer out.

I tell patients that it's a little bit more subtle than that. So a measure of surgical skill is are you taking out the prostate and all the prostate cancer? If the cancer is contained within the prostate, because you can see the prostate, you should take it out. So about 4 to 5% of the time I make a little nick or I poke a little hole in the side of the prostate and expose some cancer. It doesn't mean that they're going to have recurrence, but it's a sign of technical skill. In an average surgical series, it's more like 15 or 20%. So we do a good job. Then I tell patients it's 55% chance that when I take your catheter out after the procedure, which is around 10 days, that you'll be dry, no leakage. I tell them that at one month, it's a 66% chance you'll be dry with no leakage. And at three months, and your first kind of in person follow up, 95% chance you'll be dry, no leakage. Now, when we're doing that, I always tell patients that's no leakage, but you can still wear a pad or liner a day because people will often just do that for insurance or for protection. So that's what anterior fascial sparing surgery has done.

What about on erectile function?

Yeah, it's transformed that space urinary recovery substantially. Now, when you do anterior fascial sparing, you can also damage the nerve tissue less when you do it, meaning you're not just fully moving and dissecting it free. You kind of can leave it in situ. It kind of stays attached to the rectum and the fascia around it. There's still neural trauma. And the biggest hurdle that we have in urology and in urologic oncology is really optimizing our neural preservation. So we really are reliant on our neuroscientists to help us find those neuroprotective agents that we could deliver pre surgery to minimize that trauma. The nerves that we use, that are utilized for erection are unmyelinated and they don't really exist in a cable or bundle. They're kind of individual nerve fibers. So they're very sensitive to stretch, pulling and tugging. So that's what I explain to people. Now, the likelihood or probability that that people would recover erectile function is much better when you do anterior fascial or pelvic fascial sparing surgery. But overall, the probability that they recover erectile function is highly dependent on the Gleason score, that is the aggressiveness of the tumor and the extent of the tumor. Because if you have a high grade prostate cancer, there's a 60 to 80% chance that that cancer is growing into the nerve tissue on the side that the tumor exists on already. So we don't often think in absolutes like 100% resection of nerve or 0% resection of nerve. But we have to titrate the dissection surgically to incorporate any potential nerve tissue that may have cancer in it. The nice thing and the exciting thing is that we are moving into a space where there are going to be imaging agents in real time. So think about PET psma. They are now linking PET PSMA to near infrared based tracers. So you can actually flip a switch and do near infrared imaging in real time during a prostatectomy to look for residual cancer, maybe. So if you maximally nerve spare, you can look at the tumor and look at the nerve and say, hey, is there any tumor left behind? So lots of things that are evolving in surgery that will help advance us in identifying precisely where the tumor is and where it is not. Those trials are kind of evolving and starting soon, which would be really exciting stuff.

So If a Gleason 3/4 patient comes into you and it's a high enough 4 that you're going to operate on him, what are you telling him? Is his on Cialis erectile? Because I assume most of these patients will be on Cialis postoperatively.

Age of the patient, what's your sexual function before you start the procedure?

So 65 year old guy who doesn't even require Cialis before surgery, I would.

Tell him it's a 65 to 75% chance they recover erections sufficient for intercourse with Cialis on board, within how long? 24 months. Because that neuropraxia is a 24 to 30 month process. Wow.

So for the guys who don't get it back, they're gonna be looking at other therapies for erectile function, pumps and things of that nature.

Well, there's injectable medication, so prostaglandins, they're very effective. They bypass the nerves and or implantable devices.

Now, 65 year old guy who's on Cialis before surgery, what's his recovery?

On Cialis, it's going to be 10 or 20% less.

Good. Okay. Same guy, but he's a Gleason four plus four.

It depends on where the tumor is. So the nerve bundles are in the kind of posterior lateral portions of the prostate. Let's think about like 5 and 7 o', clock, the bulk of them. So if you have an anterior tumor at one o', clock, then we can do full nerve sparing.

So this is the kind of nuance that again comes into the diagnosis prehinned. Yeah. So the prostaglandins have also been a game changer here because it sort of lessens the need for perfect recovery of erectile function postoperatively.

Well, we use prostaglandins and injectable medication in that kind of one to two or two year period of time where the nerve function is recovering.

And this is an injection at the base of the penis, right at the vascular bundle at the base of the.

Penis into the cavernosal.

Right into the cavernous?

Yeah.

Okay.

And that will trigger an erection.

What prevents that patient from getting priapism?

The dosage of the medication. So you start out low and you titrate high so that reoxygenates the penis, helps maintain penile length. If you're attempting intercourse, it would prevent any kind of potential micro fracture like you had talked about with Mokira, with potential scarring and Plaque formation. So I strongly advocate for it for all the patients. It helps with their recovery and helps them with their sexual function, sexual activity in the meantime.

Obviously, a lot of people listen to this podcast and some of them at some point in their lives are going to maybe require prostate surgery. Not everybody can come to see you. What are the questions that they should be asking their urologists as they're considering prostatectomy for cancer?

A lot of key points we talked about through the whole thing. So when the urologist did their biopsy, did he do an MRI beforehand? Because that means he's just up to date with modern medicine. When the pathologist read the specimen, did they do things like percent pattern four? That means that the pathologist at that institution is up to date. And then frankly, what is the urologist's practice that's offering them a radical prostatectomy? I firmly believe, and there's strong data to suggest that if you are a prostatectomy only practice like mine, that you're dedicated to and focused and thinking about the operation and all the subtleties we've talked about over the last couple hours that are related to the surgical outcome. So if you're a jack of all trade, then I don't recommend that you go to that person for their prostatectomy. So when my patients have kidney stones, I don't treat them. I send them to my partners because they do a better job. All I do is prostatectomy. So for me, it's what's the scope of your practice? Are you prostatectomy only or you do everything and then on top of that, what are your outcomes? So what's your surgical margin rate and what's your rate of functional recovery and just understanding what that numbers are. Sometimes I tell people numbers that they're not happy with. I try to set appropriate expectations for them after their procedure. They'll say, well, like, that's not what my physician told me. Some physicians will say 100% chance of erectile recovery. Well, that's not accurate. So that just tells me that they're trying to oversell having the procedure with that particular person.

You mentioned that there's maybe only a dozen people that are doing the fascial sparing procedure. Did I hear you correctly?

Certainly is a limited number. I mean, it's always evolving in terms of how many people are out there doing it. There is a learning curve.

Yesterday when you and I went for a ruck, you mentioned to me it's added time to your procedure. It's a harder procedure and it takes longer to do?

Yeah, there's a new learning curve. So if you can do a prostatectomy, you can't just suddenly flip and do a fascial sparing.

How long did it take you to do it without fascial sparing? And how long does it take you now?

It takes me about 45 minutes longer with fascial sparing. So my average surgical time was maybe 90 to, to 120 minutes before and I add 45 minutes. You know, it's worth it to do that. We have a bunch of videos on our Northwestern Medicine Urology YouTube channel that show.

We'll link to these as well, how.

You can learn the procedure for those surgeons out there. And then there's other approaches to doing anterior fascial sparing than my approach that I show. But there are numerous videos for those as well.

All right, one last question, Ted. What are you most excited about in the next five years in the field of prostate cancer? And this could be anything from the diagnostics to the surgical treatment to the post operative care and management, anything. What are you most excited about?

Integration of precision medicine. I've been passionate about and incorporated in my practice for over a decade, precision medicine. But like we talked about, understanding the molecular subtypes and phenotypes of an individual's tumor is going to be incredibly powerful. And I think it's going to change how we think about and manage these individual patients, not only recommending treatment for the local licenses, like I think we're going to discover that they're exquisitely radiation sensitive tumors and those that are radio resistant. And we know that there are tumors that are exquisitely sensitive to androgens and those that are inherently androgen resistant. We've never ever looked or thought about it before, but now we have in our hands the power to do that. And that's going to change everything, in my opinion. It's changing now and we'll see the benefits of those studies in the next five years.

Awesome. Well, I think that means we'll probably have to sit down again in five years and talk about it.

Sounds good.

All right, Ted, thanks so much. I really appreciate it.

Thanks for having me.

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