The Peter Attia Drive - #273 ‒ Prostate health： common problems, cancer prevention, screening, treatment, and more

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:16.580 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

00:00:21.580 into something accessible for everyone. Our goal is to provide the best content in health and

00:00:26.780 wellness, and we've established a great team of analysts to make this happen. It is extremely

00:00:31.720 important to me to provide all of this content without relying on paid ads to do this. Our work

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00:00:42.760 and benefits above and beyond what is available for free. If you want to take your knowledge of

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00:00:53.260 of the subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.060 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Dr. Ted Schaefer.

00:01:06.640 Ted is an internationally recognized urologist and prostate cancer oncologist, author, and speaker.

00:01:11.740 He is the chair of the department of urology at the Feinberg School of Medicine, the urologist in

00:01:17.320 chief at Northwestern Memorial Hospital, and the program director of the GU oncology program at

00:01:23.780 Northwestern as well. Ted has published more than 400 peer-reviewed publications emphasizing at-risk

00:01:29.020 populations, diagnoses, treatment outcomes, and the molecular biology of lethal prostate cancer.

00:01:34.360 He is also the co-author of a new book, Dr. Patrick Walsh's Guide to Surviving Prostate Cancer,

00:01:40.260 which is available on October 3rd of this year. In addition to his work at Northwestern University,

00:01:46.520 Ted is also a consultant to a variety of individuals who are going through various aspects

00:01:51.840 of prostate cancer and prostate care, and you can learn more about these services on his website,

00:01:57.940 which we'll link to. Ted was a guest way back on episode 39 in February 2019, and a lot has changed

00:02:04.140 since then, and I wanted to have him back on to pick that up. In this episode, we talk about all

00:02:08.700 things related to the prostate. We discuss the problems that can arise with the prostate as you age,

00:02:13.880 including urinary symptoms, and an increase in frequency. Going to the bathroom at night,

00:02:18.760 we talk about prostatitis, pelvic pain, and prostate inflammation. We talk about the very

00:02:23.020 popular drug finasteride, used both to shrink the prostate and prevent hair loss, and something

00:02:27.800 called post-finasteride syndrome, along with concerns that people have around this controversial

00:02:33.740 diagnosis. We then move on to talk about prostate cancer. We talk about how androgens work,

00:02:39.200 how testosterone and DHT work, how they relate to prostate size, how genetics and non-genetic factors

00:02:45.220 factor into prostate cancer, and its pathogenesis. We discuss the blood-based screening tools that are

00:02:50.580 at our disposal for prostate cancer, including PSA, free PSA, PSA density, PSA velocity. Then talk about

00:02:56.660 how MRI works and how we use it to facilitate biopsies, and then of course, what biopsies mean.

00:03:02.140 How do we interpret a biopsy, and how does that tell us about which patients should and shouldn't

00:03:06.860 undergo prostate removal? And lastly, we talk about prostate cancer treatments that involve not just

00:03:12.740 surgical intervention, but also things such as androgen deprivation therapy. Lastly, I just want

00:03:17.220 to highlight that prostate cancer is the second leading cause of cancer death in men, and it's not

00:03:22.080 only the second leading cause of cancer death, I believe it's also one that is highly preventable.

00:03:28.860 And as such, I think it is very important for everyone to listen to this, because unfortunately,

00:03:32.680 it's very unlikely that you'll go through your life not being touched by this or knowing someone

00:03:37.680 who is. So without further delay, please enjoy my conversation with Dr. Ted Schaefer.

00:03:47.620 Ted, awesome to be sitting down with you to talk about all things prostate related. It's been

00:03:52.960 probably four years since we did this. Yeah, thanks for having me. So I think probably it's worth

00:03:58.120 assuming that there are a lot of people who didn't hear that first podcast, and those that did probably

00:04:02.440 don't remember much anyway. Also, a lot has changed in four years. So I think never a bad idea to start

00:04:08.200 from the beginning. So let's start with talking about what the prostate gland is, what it does before

00:04:14.560 we get into any of the pathology associated with it. Yeah, so the prostate's an exocrine gland,

00:04:19.880 and it's part of the reproductive system. It sits just below the bladder in men. So it's a dimorphic

00:04:26.560 organ. It does not exist in women. It develops in utero in response to fetal androgens. And so

00:04:33.580 it produces basically most of the components are about 50 to 60% of the components of semen.

00:04:40.280 So it's used in reproduction in all mammals. And we're mammals, so we use it too.

00:04:46.700 I guess when you sort of think about things that start to go wrong in the prostate,

00:04:50.460 I'm guessing that most men listening to this, the first thing that they might think of is

00:04:55.780 prostatitis, certainly age-wise before you get into prostate cancer, which of course we're going

00:05:00.720 to talk at length about. Just as a lay person thinking about the prostate gland, I sort of

00:05:04.820 think about inflammation infection. I think about benign enlargement that leads to obstruction. And

00:05:10.180 then obviously we'll talk about neoplasm. Is that how you sort of think about the problems

00:05:14.220 associated with it? Yeah. It's an organ that sits in line with the urinary tract. And so the urinary

00:05:20.960 tract in men has a dual purpose. The general urinary tract is a dual purpose. One is used for

00:05:25.760 reproduction. The other is used to kind of eliminate all the urine. And so because of that shared

00:05:32.220 functionality, you can develop problems in one or the other of those two disease systems, and they

00:05:39.900 result in symptomatic issues. And a lot of the problems that men, even at a young age, but

00:05:45.380 particularly as they age, will experience are related to the prostate. So in some ways, it's kind of the

00:05:50.880 nexus of the lower urinary tract. So yes, it's absolutely true that in younger men, you can develop

00:05:56.860 infections in the urinary tract. They can be very problematic and difficult to solve and address if

00:06:02.340 it's involving the prostate. Additionally, if you develop an infection, classic bacterial or potentially

00:06:09.020 viral or other kinds of causes, you can get inflammation in the prostate, which can result

00:06:14.100 in long-term pain. So that's one of the things I see when young men come in with prostatitis.

00:06:20.660 Then as men evolve in age, as the prostate evolves and changes as we get older, different issues arise,

00:06:28.340 and they can result and impact your urinary function because it's a shared system of elimination

00:06:34.800 of semen and of urine. And so as we get older, 50 to 60% of men at age 50 and older will have

00:06:42.240 issues with lower urinary tract dysfunction. And those almost always directly relate to the prostate

00:06:48.240 in some way or another. Some of the stats are pretty staggering. So at age 50, it's probably 50 to 60%

00:06:54.380 of men have lower urinary tract dysfunction. But by age 60, it's 75 to 80% of men will have lower urinary tract

00:07:00.160 symptoms. So let's talk about what those are. Lower urinary tract symptoms, weak stream, hesitation

00:07:06.040 or slowness in getting your urinary stream started, urgency to go to the bathroom, increased frequency

00:07:11.660 to go to the bathroom. And they're related to two things. One, functional obstruction of the urethra.

00:07:16.920 That's the tube we urinate through, the tube that comes out of the tip of the penis. And that tube,

00:07:23.480 the first part of it passes right through the middle of the prostate. So as the prostate enlarges,

00:07:28.280 it can compress that channel and that can result in weak stream. It can result in dribbling and

00:07:33.760 straining. Additionally, the muscle behind above the prostate is the bladder. The bladder is a bag,

00:07:40.360 a storage device that is muscular. And so that muscle, as the diameter of the tube narrows with

00:07:47.280 increasing size, for example, that muscle will have to work harder. Compliance will go down.

00:07:52.760 And when the compliance of the bladder goes down, the capacity can go down.

00:07:55.920 And the increased urgency to go to the bathroom will go up because it's less stretchy.

00:08:01.760 So again, as we get older, the prostate, parts of the prostate will grow. Oftentimes that growth

00:08:07.920 of the prostate results in narrowing of the channel. That can commonly lead to thickening of the bladder

00:08:13.720 wall. And then that results in a whole constellation of urinary symptoms, which can be managed, but many,

00:08:20.400 many men have them. And it's certainly something that we talk a lot about with almost all of our patients.

00:08:25.920 Maybe let's talk a little bit about what the medical management is for those things, because

00:08:29.780 this is an area where the surgeon does both the medical management and the surgical management,

00:08:35.160 right, typically?

00:08:36.300 Yeah. Urologist, it's one of the more unique specialties in that we do a lot of diagnosing

00:08:41.360 and then managing medically and treating surgically and then survivorship for almost all the conditions

00:08:46.460 that we take care of.

00:08:47.380 So what are the first steps in the medical management of lower urinary symptoms?

00:08:54.620 Behavioral modifications. If you're an executive at a water company and all you do is drink water

00:08:59.600 all day long, you're going to urinate a lot. A lot of it is just education and behavioral

00:09:04.140 modifications. Educating people that a lot of what you take in will come out. The idea that the kidneys

00:09:10.640 are designed to maintain our body's fluid status and a kind of homeostasis. If you increase your

00:09:16.660 fluid intake, you're going to have increased urinary output. And so just basic educational

00:09:21.900 things about that is really, really helpful. In addition to regulating what you drink, it's when

00:09:28.760 you drink it and what's in what you're drinking. So a lot of people come in with symptoms of nighttime

00:09:34.360 urinary frequency. And a lot of that is just, you can modify with education saying, hey, don't drink

00:09:39.720 two glasses of water right before you go to bed. And if you get up in the middle of the night because

00:09:44.160 you have to urinate, don't drink another glass of water right when you get up to urinate. So

00:09:47.840 that component of the education timing of when you take in those fluids and then what's in the fluids,

00:09:53.040 specifically caffeine. And there are some fluids that have natural diuretic properties. And so if

00:09:58.480 you are taking or drinking something that's a diuretic, you're going to produce more urine and that will

00:10:03.320 result in more urinary symptoms within two to four hours after taking that fluid in. So caffeine,

00:10:08.360 for example, is a natural diuretic and it will cause you to produce more urine over a certain

00:10:13.580 amount of time than you would if you took an iced tea with no caffeine in it, for example. So a lot

00:10:18.520 of educational things, a lot of education about what to do, when to do it. We often will have people

00:10:24.280 do voiding diaries. Really, it's a diary of what you're drinking and then when you're urinating. And

00:10:30.360 actually just having the patients just walk through that with them will be quite helpful.

00:10:35.020 So they're measuring their input in timing and volume and output in timing and volume.

00:10:40.000 Yeah. And that simple task, which is easy, easy to do, will result in A, a realization that,

00:10:47.300 hey, I'm drinking 130 ounces of water a day. Like it's all excessive. It's unnecessary because you can

00:10:53.820 show them that, yeah, you're urinating out the same basic amount of volume. Because we also get in our

00:10:59.320 foods, obviously water too or fluids. So mapping out behavioral modifications is the first step I

00:11:05.000 always do. If it persists and they're bothered by it, then we'll talk about doing avoiding diary,

00:11:10.400 particularly if their symptoms are a little bit unusual. For example, if you're sensing that there

00:11:14.860 may be urinating much more at night than you would anticipate after they've done these different

00:11:20.080 behavioral modifications. There are hormonal deficiencies that can result in increased urinary

00:11:24.600 production at night, for example. So if we're suspicious of any of those things, or if patients

00:11:29.320 are still bothered by their urinary symptoms and they want to not go on a medication, we'll do avoiding

00:11:34.900 diary. We'll map out when they're drinking, when they're urinating, and then we'll kind of go from

00:11:39.300 there. What if a guy comes to you and is sort of upset about the frequency with which he's waking up

00:11:43.920 to pee at night? The medical term for that, of course, is nocturia. Is there a norm?

00:11:47.680 So you and I are 50 years old. I would say five nights a week I don't get up to pee. Two nights

00:11:55.640 a week I get up to pee once. And obviously that's probably more tied to the timing of my fluid intake

00:12:01.780 and what it was than necessarily prostate-specific symptoms. But what's normal if there's such a thing

00:12:08.600 as normal for a 50-year-old, a 60-year-old, etc.? Yeah, great question because there's a lot of

00:12:14.060 variability in terms of what you can expect based on the age of the individual. So there's a

00:12:19.200 naturally secreted hormone, anti-diuretic hormone, and it, in younger decades of life,

00:12:25.800 it has a surge of release around 7 or 8 o'clock at night. Anti-diuretic hormone prevents you from

00:12:32.340 diuresing or producing more fluid. Alcohol, by the way, inhibits this hormone, which is why alcohol

00:12:38.440 before bed is a great recipe for having to get up and pee for two reasons. You get the fluid

00:12:44.460 in the drink and then you get a molecule that inhibits the release of anti-diuretic hormone.

00:12:51.060 Absolutely. And so the classic one for that is beer because it's a high volume intake. So we have

00:12:56.440 natural diurnal release of anti-diuretic hormone and that diurnal variation is attenuated per decade

00:13:05.080 as we get older. So that peak of anti-diuretic hormone goes down per decade. And that can then

00:13:11.880 kind of normalize your 24-hour urine production, whereas when you're in your 20s or 30s, you would

00:13:19.860 produce, let's just say, 80 or 90% of your urine during waking hours. During the nighttime when you

00:13:25.720 have high levels of anti-diuretic hormone, you're not going to produce as much urine and your kidneys

00:13:30.700 in your body will save that extra fluid for the morning when you get up. Is there a biologic

00:13:35.280 explanation for the attenuation of that hormone as we age? I don't know the answer as to why that

00:13:40.920 could be, but certainly we see it in general in aging populations, men and women. After we had got

00:13:47.240 through this, I wanted to ask the exact same set of questions around female symptoms. So right now

00:13:52.260 you're saying there's an equalizer. Both men and women experience this reduction in anti-diuretic hormone

00:13:58.240 as we age. And then there are other factors that are also similarly consistent among aging

00:14:04.120 individuals, male or female, like the resiliency of the tight junctions in your capillaries, your

00:14:09.960 vascular system. So it's less resilient and less tight as we get older. Even if it's subtle and not

00:14:16.540 fully appreciable, you have some capillary leak. And as you lie down when you're sleeping at night,

00:14:22.640 that fluid will leave the extracellular space, enter the intravascular space, and your kidneys will

00:14:27.400 read that as increased fluid. I have a very focused urology practice, but when I have people with

00:14:32.460 urinary symptoms, I try to do a full body assessment because one of the main drivers

00:14:36.300 of nighttime urinary frequency, or one of them that's particularly tracks with age is just

00:14:41.680 peripheral edema. So are you developing edema and so forth? So meaning people who have a lot of

00:14:46.180 peripheral edema, in nighttime you get basically reversal of some of the third spacing? Yes. It's

00:14:50.800 almost like they have an IV drip that's taking fluid from their interstitial space into their

00:14:55.240 vascular space. It's like they're drinking at night. Yeah. So one of my behavioral modifications,

00:14:59.760 it's not really behavioral, but non-medical modifications is knee-high Ted stockings for

00:15:03.820 people who are having symptoms who, if I see them at eight or nine or 10 o'clock in the morning,

00:15:08.400 they had any edema, any kind of wringing around their socks or something like that, then I definitely

00:15:13.720 strongly encourage them to do that. I tell people, if you're getting up twice a night and you have a

00:15:19.680 little bit of edema, you do some behavioral modifications. We can reduce your nocturnal urinary

00:15:24.880 frequency by kind of one. So you can go from two times at night to one time at night just by

00:15:29.240 changing when you drink and wearing Ted stockings. Maybe not true for everybody, but it certainly

00:15:33.800 encourages people to do simple things without doing the polypharmacy. The other thing that

00:15:39.380 is a main issue related to nocturnal urinary frequency is sleep apnea. And I'm sure you've

00:15:45.300 talked a lot about sleep apnea on your shows. It is a driver of a lot of just bad pathology. And one

00:15:51.820 of them is nocturnal urinary frequency. And we'll talk about it later, but in the post-prostatectomy

00:15:56.780 space, it can actually result in profound nighttime urinary incontinence. But it will produce

00:16:02.600 symptomatic, profound urine production and nocturnal urinary frequency in individuals.

00:16:08.440 And why is that?

00:16:09.460 I think it's also related to the regulation of your anti-diuretic hormones. And really there's profound

00:16:14.820 whole body side effects from it. So there's a subset of men who this is a good way to encourage them to

00:16:21.740 get their sleep apnea A diagnosed and then treated. So that's behavioral.

00:16:25.960 So then let's talk about the pharmacologic tools. So you've already kind of alluded to one,

00:16:30.340 and it's one that we use in our practice, which is when we have a guy who otherwise we don't have a

00:16:38.960 clear explanation for why he's getting up to pee, and he doesn't appear to have a particularly enlarged

00:16:45.220 prostate. And we're going to talk about, of course, all those things. A very low dose of desmopressin,

00:16:50.740 which is this synthetic version of the anti-diuretic hormone, typically 0.2 milligrams

00:16:55.360 before bed, has profound effects. So talk a little bit about that and then maybe some of

00:17:01.320 the other things. And also, are there any contraindications to the use of that? I know

00:17:04.420 certainly theoretically a contraindication or a concern would be hyponatremia as you would sort of

00:17:10.240 increase plasma volume and therefore dilute sodium. But maybe just talk a little bit about

00:17:15.340 how you would use that. There are very straightforward, frontline medical management

00:17:20.860 pharmacologic agents to manage lower urinary tract symptoms. And generally speaking,

00:17:25.940 frontline ways that we manage it would be with an alpha blocker. That's a class of compounds that

00:17:32.100 are nowadays very, very specific to prevent activation of a set of smooth muscles that are

00:17:38.900 really isolated, mostly in the prostate and somewhat in the seminal vesicles.

00:17:42.360 So if you just take a step back and look at the embryology of the prostate, it develops from

00:17:47.300 the uratinal sinus and there's mesenchymal and epithelial components of that. So there's a lot of

00:17:52.980 smooth muscle within the prostate. The smooth muscle exists within the prostate in part to help with

00:17:58.700 ejaculation. It's like a pump.

00:18:00.660 It's a pump. When you're having an orgasm and the pump squeezes, the prostate will squeeze

00:18:05.080 and that will result in emission of the fluid. So what you can do for individuals who have lower

00:18:10.560 urinary tract symptoms is that while you have this channel, this tube going right to the middle of it,

00:18:15.560 that's the urethra, you can relax the smooth muscle within the prostate and that will relax a little

00:18:21.860 bit. Theoretically, it enhances the diameter of the prosthetic urethral channel. That's the thought

00:18:28.080 for how it works. And that could then result in relaxation and improvement in urinary symptoms.

00:18:33.960 And it works quite well for most people. Now, originally this was noted because of the first

00:18:39.900 class of alpha blockers were used for blood pressure control. And so one of the side effects

00:18:44.740 of the first generation of these medications was just profound hypotension until you've titrated

00:18:49.720 up the dose and so forth.

00:18:50.960 So they're selective in that they relax those muscles without dropping blood pressure.

00:18:55.800 Yeah. And the newest generation of ones are even selective to the smooth muscle within the

00:19:00.360 prostate and not the seminal vesicles. So the seminal vesicles and the prostate grow up right

00:19:05.580 next to each other. For example, when you do a radical prostatectomy, you take out both organs

00:19:10.480 that are attached to each other. The seminal vesicles dump into the prosthetic urethra. So the second

00:19:18.160 generation, third generation alpha blockers would paralyze or prevent contraction of the prosthetic

00:19:25.560 smooth muscle. So you would have improved urinary symptoms.

00:19:29.840 But doesn't impede ejaculation.

00:19:32.440 The first more targeted ones would.

00:19:34.640 Yes.

00:19:34.800 Because they would in fact...

00:19:36.240 Paralyze both.

00:19:37.020 Paralyze both. The newest classes of these medications really focus only on prostate. And so the impact on

00:19:42.800 volume of seminal emission or semen is actually much less impacted. And so I usually will just

00:19:49.440 reach for those. They're great.

00:19:50.660 Typically today, you would only use these third generation alpha blockers. What do they call it?

00:19:56.840 What are the names of these drugs?

00:19:58.020 So alfuzicin is the one I usually go to, but there's another 3.5 generation medication called

00:20:04.580 sildenafin. Alfuzicin and sildenafin are the two newest medications that are third generation that

00:20:10.900 result in less impact on sexual dysfunction, specifically less impact on semen production,

00:20:17.940 but have really, really outstanding efficacy in terms of relaxing the prostate and improving

00:20:23.640 urinary symptoms.

00:20:25.200 Got it. Now, when I was in med school and I remember doing urology rotations and even in

00:20:31.240 residency doing urology rotations, a common drug that was used to treat this was a drug that blocked

00:20:39.940 the conversion of testosterone to DHT. So Proskar was the name of that drug. The brand name of that

00:20:45.500 drug finasteride was the generic name. I want to come back and talk about finasteride specifically

00:20:51.400 so we can punt on the discussion of that syndrome that we're going to discuss. But strategically,

00:20:56.720 whether we're talking about finasteride or dutasteride, drugs that block the conversion of

00:21:01.780 testosterone to DHT, which again, we'll bracket for a moment that we'll come back and explain why.

00:21:05.940 Are those drugs still in use today to treat this particular condition?

00:21:09.740 Yeah. So there are specific indications where you would think about utilizing a 5-alpha reductase

00:21:15.780 inhibitor for men with low urinary tract symptoms. It's second line. So if you have urinary symptoms,

00:21:22.900 you've failed behavioral modifications, then we would do an alpha blocker. If an alpha blocker

00:21:29.520 is working, but not to the extent that the patient's satisfied and the individual patient has a large

00:21:36.820 prostate over 70 or so grams. You can easily diagnose that on an ultrasound or MRI?

00:21:42.580 Yes. You would typically be able to size that no problem.

00:21:46.240 Can a good urologist size that on a rectal exam?

00:21:48.780 A good urologist can. I personally kind of think about things like small, medium, large.

00:21:53.900 In general, for people in a relatively high quality urology practice, you're going to know the patient's

00:21:58.800 volume of their prostate based on a variety of things you're kind of monitoring for. But

00:22:02.360 if you have a large prostate and you're having progression on an alpha blocker, you can reach

00:22:07.260 for a 5-alpha reductase inhibitor, finasteride or dutasteride, and they have been shown to reduce

00:22:14.300 the likelihood of urinary retention and reduce the need for surgical procedures in prospective

00:22:21.980 randomized trials. But in general, they're recommended for really the big, beefy prostates.

00:22:27.540 But remember, the symptoms that they would treat, that is, they result in the decrease in the size

00:22:34.380 of the prostate by between 20% and 30% over the long haul. It doesn't happen immediately. When you

00:22:39.600 take an alpha blocker, you feel better within a week. When you take a 5-alpha reductase inhibitor,

00:22:45.740 it will take six plus months to A, feel better, B, see the size reduction in your prostate, and then,

00:22:52.820 of course, most importantly, you'll have an impact on the PSA levels in the serum. And so it's critical

00:22:59.120 that patients are aware that your PSA numbers will...

00:23:02.620 It's artificially depressed. You could be masking pathology potentially. Is that the concern?

00:23:08.200 Yes. The PSA value will decline because PSA is a androgen regulated product. And so when you reduce

00:23:15.920 the amount of that potent androgen, you'll reduce the value of PSA, it goes down by about half. So

00:23:22.360 it's that useful drug, but it is not something that I usually reach for because it requires a lot of

00:23:29.520 very active monitoring, has limited effect, limited efficacy, in my opinion.

00:23:34.160 And there's a downside we'll talk about.

00:23:35.620 There's a lot of potential issues that one can experience while taking it. So I'm very cautious

00:23:39.940 about doing that. So for me, I reach for an alpha blocker. If the alpha blocker is working in

00:23:45.760 terms of improving the kind of outlet obstruction symptoms, that's strength of the stream, how fast

00:23:52.200 can you empty, but patients still have a significant urinary bother, increased urinary frequency,

00:23:59.200 urgency to go to the bathroom, then you can either do an anti-muscarinic or an M3 agonist,

00:24:05.000 which is the newest class in that category, which really helps relax the muscles in the bladder

00:24:08.960 and really significantly impact the symptomatology for people with those kind of predominantly what we

00:24:14.600 would call storage symptoms. You can have obstructive symptoms. Alpha blockers are great

00:24:18.740 for those. You can have storage symptoms.

00:24:21.320 And storage symptoms are frequency?

00:24:23.400 Frequency, urgency. Just think about it. If you have a thick bladder, the compliance is poor.

00:24:29.240 It doesn't stretch well. It's just always kind of feels full. Then those are things that can be

00:24:34.020 very nicely addressed with these agents. The anti-muscarinics are dangerous or you need to be

00:24:41.120 careful when using those because in aging individuals, they are associated with worsening

00:24:46.960 of dementia and other kinds of neurocognitive acuity. So the M3 agonist has the same net effect,

00:24:54.620 are much cleaner, much less side effects.

00:24:56.880 And the anti-muscarinics were just older drugs?

00:24:59.740 They were.

00:25:00.120 So we kind of put those in the same category as maybe the five alpha reductase inhibitors.

00:25:04.000 That's right.

00:25:04.820 You always look for a better option first. Are women as susceptible to urgency and frequency

00:25:12.640 from the same underlying pathology? Obviously women, when they go through menopause,

00:25:18.000 estrogen withdrawal alone can produce those symptoms. And there the treatment is clear.

00:25:23.040 It's estrogen replacement. So given that women don't have a prostate and therefore don't have

00:25:27.680 something abutting their bladder in the same way, is there a role to use these M3 agonists in their

00:25:36.580 frequency and urgency symptoms?

00:25:39.680 Yeah. I mean, most of those medications and the prescription frequencies is much,

00:25:45.000 much higher in women. So that would be the classic overactive bladder. Women will have

00:25:49.700 bladder symptoms that are also similar in men. The men have thousand to one more often obstructive

00:25:58.080 symptoms because the urethra in a woman is very short. It's four centimeters long. The urethra in a

00:26:02.760 man is 25 centimeters long on average or something like that. So the obstructive symptoms are much

00:26:08.460 more prevalent in men. And so that's why frontline is always an alpha blocker. But if they're having a

00:26:13.960 good response with an alpha blocker, but still bothered, you can reach for an M3 agonist. For me

00:26:20.560 personally, though, it's always a balance because at some point you have to start saying, well, okay,

00:26:25.380 how old is the patient? How significant are their symptoms? Because there are highly effective ways to

00:26:31.240 manage these issues surgically. These days, they can most of the time be done just as a simple

00:26:37.240 outpatient. I usually begin to introduce the idea of, okay, well, if you're still bothered,

00:26:41.700 we have outpatient surgical procedures that can basically fix this for life with no medications.

00:26:47.420 That's kind of my stepwise process that I lead patients through in terms of thinking about their

00:26:52.340 urinary symptoms. Let's talk about the surgical procedure. So again, just kind of going back to my,

00:26:57.480 what I learned about 25 years ago, the TURP, the transurethral resection of the prostate,

00:27:03.480 kind of a Roto-Rooter job. Yeah. The prostate develops from the urodentinal sinus.

00:27:08.380 The prostate, as we mature in response to androgens and estrogens too, for that matter,

00:27:15.020 it develops into different zones or different regions. The peripheral zone, which is outlining

00:27:19.480 the prostate, think about a orange and the orange peel. And the pulp of the orange is a transitional

00:27:25.940 zone of the prostate that gets bigger. Actually, it's not just a testosterone driven thing. It's

00:27:31.260 actually when there's more estrogens around that actually with testosterone that can result in

00:27:35.720 hypertrophy increasing in the size of the transition zone. That is what causes all the

00:27:40.900 urinary symptoms in individuals. With rare exceptions with an aggressive cancer, that's

00:27:45.300 what's causing it. In those situations, you can do what they call, there's a variety of missed

00:27:50.440 procedures. So minimally invasive surgical procedures that can address these urinary symptoms.

00:27:57.280 So you can do a variety of things. You can introduce steam into the transitional zone tissue that can

00:28:04.600 then kill that and effectively kill all the smooth muscle and reduce to some extent the kind of

00:28:10.180 hypertrophy of the epithelial cells. You can surgically resect it. Transurethrally.

00:28:15.860 Transurethrally. So no incisions. A natural orifice procedure. You could suspend it surgically. So

00:28:22.880 there's kind of tethers that you can put in place that tend to open the urethra. But the mainstay,

00:28:28.040 the gold standard is to remove the tissue, which can result in profoundly improved urinary symptoms.

00:28:34.220 And is that done with laser, electrocautery? I mean, what is the gold standard today for the means by

00:28:40.560 which you remove the tissue? So the gold standard has always been the TERP procedure, which is what you

00:28:46.380 described. Now, that procedure itself has evolved in that it can now be done with irrigation that is

00:28:53.400 with normal saline. Traditionally, to maintain a monopolar current, you had to use water because

00:28:58.980 you would not want the sodium to disrupt that current. So now a modern TERP is a bipolar TERP.

00:29:06.520 Explain to folks why you need an irrigant when you're doing this procedure.

00:29:10.040 As you described it, this is a kind of roto-roto procedure, but you're technically removing bulky

00:29:14.900 tissue in the urethra that's circumferentially surrounding the prosthetic urethra.

00:29:20.460 You've got this thing here. Using the natural orifice of itself, you have to expand the diameter

00:29:26.960 of this thing by actually getting rid of prosthetic tissue in the transitional zone.

00:29:31.440 Yeah. So you scrape out small portions, usually one or two gram-sized little scoops of tissue.

00:29:36.980 You do that with effectively a hot knife. It's shaped like a loop. So you core out little loops of

00:29:41.840 tissue. And when you do that, you A, have bleeding and B, the tissue collapses on you. It's like a

00:29:47.880 cave. So it keeps falling in on you. So you have to suspend it open with the irrigant and you have

00:29:52.500 to use the irrigant to better visualize what you're doing. That's a traditional TERP. That was always done

00:29:58.260 with water. And when you did it with water and you were tenting open the tissue, putting it under

00:30:03.400 pressure, you could have water move into the intravascular system. And you could get something called

00:30:09.300 post-TUR syndrome, which is basically where you made the patient profoundly hyponatremic.

00:30:13.880 You diluted their sodium too much, and that's very dangerous.

00:30:17.080 Yes. And you'd have significant neurologic issues and so forth. So that particular procedure,

00:30:21.780 and there's lots of advances in urology in this particular space. That procedure,

00:30:26.020 15 years ago, they started basically redesigning the devices so you could do it with saline.

00:30:31.240 So therefore, if there was flow of fluid from the procedure into the intravascular space...

00:30:38.220 It's just like giving them intravenous fluid that's isotonic.

00:30:41.160 Exactly. So that really prevented issues that you could have with this TUR syndrome.

00:30:46.900 And TERP is a very effective, and it remains the gold standard that all these new MIST,

00:30:51.400 these minimally invasive surgical techniques compare themselves to in terms of efficacy.

00:30:56.940 Now, I have the pleasure of having a partner at Northwestern, Dr. Amy Krambeck.

00:31:00.740 We've actually sent a couple patients to her.

00:31:03.360 Amy does a procedure called HOLEP, which is a homeum laser enucleation of the prostate. So the

00:31:08.340 TERP basically is effectively scraping out little one gram chunks of tissue. So if you have a hundred

00:31:13.620 gram prostate...

00:31:14.780 Your goal is to get that down to 50?

00:31:16.700 Your goal is to get it down to 15.

00:31:19.100 15. So even less... Normal, we would say, might be 30, right?

00:31:23.260 Yeah. Normal prostates increase in size as we get older. A normal prostate for a man who's 40

00:31:29.140 or 50 is between 20 and 30. But people can have profound urinary symptoms with prostates that are

00:31:35.520 as small as 35 grams. So people often assume because you have urinary symptoms that you actually

00:31:41.280 have this gigantic and large prostate. That's not always true. But the smaller prostates typically can

00:31:47.180 be well-managed with medications. And only will we be moving to surgical treatment when the

00:31:51.620 prostates get larger.

00:31:52.680 So you've got sort of a selection bias going on.

00:31:55.940 You do. So frontline, gold standard, historical is TERP. It's now a bipolar TERP, so it can be done

00:32:01.980 safely.

00:32:02.720 And the reason you go from a hundred, if you're starting there, down to 15 as opposed to 30 or

00:32:09.320 40 is you want to be one and done. You never want to be back again.

00:32:12.620 Yes. A good surgical procedure is effective for life. Now, they're not all like that. And so the ones

00:32:18.480 that the less tissue you remove, if you don't remove any tissue, for example, you're more likely

00:32:22.540 to have a secondary treatment. My partner, Amy Cranbeck, is really one of the pioneers in modern

00:32:28.660 whole-lep surgery. So this is different. So again, if you think about the orange analogy,

00:32:33.920 a TERP or any of those other procedures is basically trying to scrape out the pulp

00:32:37.800 one little chunk at a time. Amy will go in and she'll get in the plane between the peel or the rind of

00:32:45.620 the orange and she'll take it all out in one piece. She pushes it into the bladder and then

00:32:50.720 there's a morselator that then chomps it into little tiny pieces that you then remove through

00:32:54.360 the urethra.

00:32:55.240 Let's make sure people understand that because I love that. I think your orange analogy makes

00:32:58.480 this so much easier to understand. If you're doing a TERP, you've got a pencil hole going through the

00:33:03.080 orange. You've got to put a hollow pencil into that pencil hole and literally one tiny, tiny

00:33:09.360 thimble at a time pull out little sacks of pulp one by one by one by one by one by one by one.

00:33:15.320 Yes. Additionally, remember that when you're doing that, you're disrupting the kind of

00:33:19.980 architecture of the orange. And there's lots of blood vessels that exist within the transition zone

00:33:24.860 itself.

00:33:25.820 Now it's bleeding like a sieve.

00:33:27.400 Bleeds a lot. When Dr. Cranbeck, when Amy does her procedures, she gets in that natural tissue

00:33:32.960 planes.

00:33:33.480 She shaves into that natural plane and it's not bleeding as much. And she somehow manages to take

00:33:39.300 that whole pulp minus the peel, shove it into the bladder. And when it's in the bladder now,

00:33:45.560 isolated, you can break it apart.

00:33:47.460 She'll morselate it apart. So she is spectacular.

00:33:50.640 Holep was a procedure developed originally described in New Zealand, I believe by a New

00:33:54.320 Zealand urologist. And it was limited for a long time based on the technology that existed within

00:33:59.380 the lasers. But the laser technology and Amy really helped develop the latest versions of these

00:34:05.320 lasers that are just higher energy, more precise. Take that and then you can then couple that with

00:34:11.320 an experienced surgeon and the outcomes for it are spectacular.

00:34:14.380 What are the patients who would not be considered candidates for that procedure? Is there a

00:34:18.740 contraindication to that?

00:34:20.180 No. If you're talented enough, you can do it in anybody, which she can. Now, the smaller the

00:34:25.700 prostate, the less distinct the differentiation is between the peripheral zone, the skin of the

00:34:33.300 orange, the peel of the orange and the pulp. And so it actually requires more skill to do a holep in a

00:34:39.040 smaller gland than in a bigger gland. When the prostate's really, really big, the adenoma is very

00:34:44.580 well formed and it's easier to get into that plane. So a large prostate would be something over 80

00:34:52.560 grams. That's where you'd really say, in let's say a general urologist practice, the threshold for doing

00:34:57.860 a TURP-like procedure goes down. It's really long to do a TURP. It takes a long, long time to do it.

00:35:04.000 If you're a talented whole lab surgeon, Amy can do a 200 gram prostate in about 20 minutes. I mean,

00:35:10.440 she's spectacular.

00:35:11.920 Tell me about what that patient goes through post-procedure. They go home that day,

00:35:15.560 obviously. It's an outpatient procedure. They have a catheter in place?

00:35:18.420 No.

00:35:19.080 No catheter?

00:35:20.040 Yeah.

00:35:20.340 Because that's the other thing I remember, Ted, from when we were little spring chickens is the

00:35:26.820 catheter management on that patient with a blood bag full of bloody water and urine coming out for

00:35:34.220 days and days and days. And again, it's a relatively small price to pay, I think, for the ultimate

00:35:39.040 relief you're going to get. But how is it that this patient just literally leaves the office without a

00:35:44.400 catheter?

00:35:45.380 So it has to just do with what you do at the end of the procedure. So how well you're controlling the

00:35:49.620 bleeding? And I think the big difference in whole lab, as I mentioned, is when you're in that

00:35:54.140 distinctive plane between adenoma and peripheral zone, it's just the vessels are much more discreet,

00:36:00.200 whereas in a terp, there's these sinuses and so forth.

00:36:03.500 The analogy, again, to the orange is perfect. If you try to peel an orange from the inside,

00:36:08.940 ripping apart, you're going to get orange juice all over your hands. Whereas if you're taking the

00:36:13.320 skin off, it's actually...

00:36:14.500 It's less elegant. You remove less tissue. It's bloodier, et cetera. So big picture,

00:36:19.620 if people are on medication and they have progression, you can start talking about minimally

00:36:25.220 invasive surgical procedures. There are in-office minimally invasive procedures. They're quick.

00:36:31.760 In general, a take-home message, though, is the less you do, the less durable and the less

00:36:36.720 effective it is over time. So there are procedures where you can tent up the prosthetic urethral channel.

00:36:42.840 They work with basically temporary relief. I would only even consider those in individuals who could

00:36:48.500 not tolerate the medications.

00:36:50.520 If you're going to go to the trouble of actually putting a probe in the urethra to go through the

00:36:56.460 tenting up procedure, why wouldn't you just do the procedure Amy does?

00:36:59.880 I do. I'm just saying for your general audience that may be offered for somebody, I never recommend

00:37:04.360 it because it never works. It can cause a lot of pain. You put these clips and you're tethering

00:37:08.040 things up. It prevents effective, high-quality MRI. There's lots of limitations, but people may,

00:37:13.660 who listen to your show, may be offered these things. It's called Urolift. Next step up would be

00:37:19.120 to basically use steam to ablate the prosthetic cells. When you do steam, you're desiccating the

00:37:26.180 cells, and that can result in pretty good symptomatic relief. Do patients require general

00:37:31.500 anesthesia for this? I've forgotten. No. For the Urolift, you can do it in the office. For this

00:37:36.600 procedure called Resume, you can do that in the office with local anesthesia. It's uncomfortable

00:37:41.640 for patients, but it can be done there, or it can be done under like twilight. That works. It is a

00:37:47.600 step more in terms of intensity and what you feel. Those individuals go home with the catheter. There's

00:37:53.240 lots of edema and lots of swelling when you do that procedure, so they require a catheter for

00:37:57.620 several days to a week. Right, because that steam creates inflammation, even though it's

00:38:03.380 cauterizing, and if you don't leave that catheter in, they're going to get urinary obstruction. They're

00:38:06.860 going to close their urethra. Resume would be the next step up in terms of invasiveness. Then you

00:38:12.480 can always go to this traditional terp or bipolar terp. Those are all effective therapies to think

00:38:18.880 about or talk about with the patient when your prostate's less than, let's say, 70 or 80 grams.

00:38:23.420 HOLEP was originally developed to just handle the bigger prostates, which traditionally, you and I,

00:38:27.620 when we were training at Hopkins, we would do an open, simple prostatectomy. That's where you open the

00:38:31.940 patient up from above, just below their belly button. You open up the bladder, and then you

00:38:36.620 manually, with your finger, carve out that inner pulp of the orange, leaving the peel of the orange

00:38:42.680 behind. And the reason you leave the peel behind in that procedure is because it's not a cancer,

00:38:48.840 you don't need to risk injuring the neurovascular bundle on the outside. You see what we're going to

00:38:54.880 talk about when we get to prostate cancer. Everything around the outer peel of the orange is all the

00:39:01.140 important real estate. So the urinary sphincter muscle and all the nerve tissue that goes to the

00:39:06.160 sphincter and also goes to the cavernosal bodies that trigger erections. So that was what we used

00:39:11.060 to do. Now that procedure has evolved. That can be done minimally and basically with a robotic

00:39:14.860 procedure. And that was really emerging as a standard of care. And then the super talented surgeons like

00:39:20.900 Amy Cranbeck came along and can do a 200, 400, 600 gram prostate.

00:39:27.440 First of all, can you just show me what a 400 gram prostate looks like? Like physically.

00:39:33.820 400 gram prostate's a large grapefruit.

00:39:36.800 I mean.

00:39:37.980 Massive. Whereas a normal prostate is a golf ball. So a normal prostate's a golf ball.

00:39:43.300 An orange would be 100 grams. A big grapefruit's 400 grams. That used to be a procedure that was

00:39:49.540 technically very difficult to handle with an open, simple prostate, robotic, simple prostatectomy.

00:39:55.180 Amy Cranbeck can do three of those in a day and be done by noon. Spectacular stuff.

00:40:01.300 A couple of other just questions on the size of that prostate. So when a guy has a 200 to 400 gram

00:40:07.080 prostate, how much of that is genetic? Is that virtually all genetic?

00:40:12.920 Yes. You see that a lot where it's runs in families. So what it is that is underlying that

00:40:18.660 overgrowth, not well studied. Frankly, should the NIH be putting their research dollars behind like,

00:40:24.340 why do men get big prostates? Probably not.

00:40:26.680 Is there any correlation with prostate size and cancer?

00:40:29.900 Yes.

00:40:30.720 Talk about those extremes.

00:40:32.280 So the bigger the prostate, the less your chance of developing aggressive cancer is.

00:40:36.780 Why is that?

00:40:37.820 Not sure. It may have to do with variations in the balance of hormones. Large prostates grow

00:40:45.180 in response to not an increase in testosterone, actually, but more of an even ratio of T to E.

00:40:51.800 So testosterone and estrogens. So actually, as your testosterone declines, as you know,

00:40:57.580 as you get older, the T can go down. Estrogens remain pretty stable or can go up.

00:41:01.600 Especially if you have metabolic syndrome, estrogen will rise.

00:41:05.420 As men age, their prostates grow. And I believe that that's more hormonal.

00:41:09.180 Well, you're saying that, again, classic thinking that has clearly been proved false is that

00:41:14.340 testosterone is causing prostate cancer. You're saying it's way more nuanced than that.

00:41:18.460 And if the endocrine component of prostate cancer may be more related to the relationship

00:41:23.300 of testosterone and estrogen, and a declining testosterone in the presence of a rising estrogen

00:41:28.360 would be a more favorable endocrine milieu for prostate cancer than the younger phenotype,

00:41:34.760 which is higher testosterone to estrogen. Yeah. Well, let's just take that back a second. So

00:41:40.880 as you're aging, and if you have metabolic syndrome, your testosterone levels will go down,

00:41:46.400 your estrogen levels will go up, and that can result in prostatic growth, but it's typically more

00:41:52.940 adenoma growth in the transition zone causing lower urinary tract symptoms.

00:41:57.360 Benign growth.

00:41:57.960 Benign growth. That somehow is protective, either the size or just the ratio. That difference in

00:42:04.820 ratio of T to E is somehow protective for developing kind of later onset prostate cancer. Remember, in

00:42:10.780 my mind, you're locked in and your code is effectively set in stone in your 30s and 40s,

00:42:17.580 in my opinion, for prostate cancer. Wow.

00:42:20.460 Right. When your estrogen levels are very low, your T levels are higher. Now, we'll talk a lot

00:42:25.600 about testosterone and what it's doing in prostate cancer later, but in my opinion,

00:42:31.540 it's the T to E ratio that is responsible for prosthetic enlargement much more than the development

00:42:37.980 of any prostate cancer. Just to close the loop on the surgical procedures for lower urinary tract

00:42:44.520 symptoms, two final thoughts. One is, what is the floor for what's it called? The whole...

00:42:50.720 HOLEP. Homeum, laser enucleation of the prostates.

00:42:54.200 In the hands of someone as talented as Amy, what is the smallest prostate she would do that

00:42:58.960 procedure on? Well, somewhere on, let's just call it 25 or 30 grams.

00:43:04.860 Oh, wow. So basically, there's no limit in the hands of a talented surgeon.

00:43:09.280 Anybody who needs a surgical procedure, that's her go-to technique. Now, below that,

00:43:15.000 there's not a lot of transitional zone tissue. So the other key take-home message for the listeners

00:43:20.140 are if you're developing profound urinary symptoms and you have a small prostate, you have to start

00:43:26.180 looking for other sources. And by definition, you're not responding to two classes of drugs.

00:43:31.620 Yes. You have to worry about cancers, not prostate cancer, but you have to worry about

00:43:36.620 urethelial carcinoma. Urethelial carcinoma, which is a cancer in the lining of the bladder,

00:43:42.140 but also... Can you even get into the urethra?

00:43:45.080 The urethra has urethelial lining. Oftentimes, people, particularly young women will... It's a

00:43:51.380 classic board exam. Younger woman comes in with urgency, frequency. You neglect to look at their

00:43:56.500 urine for cancer cells, and they can have a cancer in the lining of their urethelium that's causing

00:44:01.620 all those urinary symptoms. So small prostate, unresponsive to medical management, persistent

00:44:07.200 symptoms, you better be doing urinary cytology.

00:44:09.920 In my opinion, you need to do a workup to rule that out for sure. And there can be other

00:44:14.520 central nervous system diseases that can result in urinary symptomatology. But in general,

00:44:20.760 as a urologist, you have someone coming in with those symptoms. You really want to start

00:44:24.240 understanding, well, what else could be going on? Because as we mentioned, those individuals may

00:44:29.140 have had a history of prostate infection, like a bacterial infection, or may have had a viral

00:44:33.780 infection. They can result in prostatitis and inflammation in the pelvic floor itself. And

00:44:41.020 that can result in all those symptoms. And so yes, you can have as your canary in that coal mine that

00:44:47.020 you have urgency, frequency, but it's not at all attributed to a large prostate. It's not attributed

00:44:51.220 to drinking too much fluid. If you take away the attribution of a urethelial carcinoma, then you have

00:44:56.500 to start saying, well, what are the other causes? And there's a lot of potential issues that can be

00:45:00.940 addressed that can cause that inflammation that has an unknown etiology to what incited it,

00:45:06.280 causing that urgency, frequency, urinary bother. Now, given the success of this procedure,

00:45:11.680 obviously Northwestern is probably top five urology institutions in the United States.

00:45:16.600 Does every city have an Amy? What's the frequency of surgeons of that skill?

00:45:21.480 I would say that in the U.S., well, I'm biased. I think there's only one Amy out there,

00:45:26.120 but there's very few people who are as talented as she is. I would say that there's probably 10,

00:45:31.800 whole lab surgeons that are on her par. At her level. That could basically go all the way down

00:45:35.640 to a 20, 30 gram. It's not the small prostates. Yes, it requires a lot of skill to do the small

00:45:39.840 prostate, but handling these very, very large prostates in individuals who are incredibly

00:45:44.820 frail and older who were told, look, you're too old for a surgery. I was just on call a couple weeks

00:45:49.960 ago. And we had a 95 year old gentleman came in from another major hospital in our city who was

00:45:57.640 having bleeding from their prostate. That was more than one unit of blood a day transfusion.

00:46:02.820 What? Yes. And was told, we can't do anything for you. You're too old and you're too frail.

00:46:09.020 So I go around in this guy on a Saturday, Amy had done a hole up. It was a hospital, a hospital

00:46:13.580 transfer, quaternary care to quaternary care center hospital, right? Just speaks to her skill level.

00:46:19.280 Transfer in. She does the hole up. It was a 450 gram prostate. She takes out 400 grams of tissue.

00:46:25.920 And the guy, we left a catheter in him because, you know, we just weren't sure. We took his catheter

00:46:30.460 on a Saturday morning. He went back home at age 95. So amazing. Like really a talented surgeon like

00:46:36.440 Amy, and there are other Amys out there, but talented surgeons like Amy, which are hard to find,

00:46:41.760 really can transform people's quality of life. Yeah. Okay. Before we get into some of the

00:46:47.720 pathophysiology of how the hormones impact the prostate, which is a good lead in, I think,

00:46:52.640 to cancer. Let's go back and talk a little bit about prostatitis because I would guess that for

00:46:59.220 many men, that is their first brush with pelvic floor discomfort and a symptom associated with

00:47:08.380 this gland. So I remember, you probably don't remember this, but I remember having a brush with

00:47:12.500 this about six years ago. And of course you helped me out. This is part of the problem when you start to

00:47:16.540 play doctor to yourself. So all of a sudden I start having some discomfort when I'm peeing.

00:47:23.000 And I do all the usual stuff. I check, was it an infection? None of the above. So it's not like

00:47:29.160 I have a urinary tract infection or, you know, an STD or anything like that. And boy, and it's not

00:47:34.280 unbearable pain. I don't want to over-dramatize this. It's not like razor blades are coming out,

00:47:39.640 which I've heard people describe. That might be certain infections. No, no, it's none of that.

00:47:43.760 It's just not comfortable. It's really uncomfortable to avoid. And I gave you a call. I remember exactly

00:47:50.380 where I was when I called you, by the way. And you were the one that said, no, no, no. Look,

00:47:54.080 you started asking me a bunch of questions. Hey, you've been traveling a lot. Are you a little

00:47:56.780 constipated? And one thing led to another. And the diagnosis in your mind was playing doctor over

00:48:01.920 the phone, at least. I'm actually more likely thinking this is prostatic inflammation. So walk

00:48:06.800 us through the pathology of that. I wish I could tell you in the next five minutes what the pathology

00:48:11.940 was, because the short answer is we do not know. We call this constellation of symptoms,

00:48:16.380 chronic pelvic pain syndrome. What that really ends up meaning is it's a bucket. We put a lot

00:48:22.080 of different things into. So you can have pelvic pain and discomfort if you have a large prostate

00:48:29.500 and it's obstructing your urinary tract. Okay. That one we talked about, you can manage that. That's

00:48:33.500 pretty easy to do. But there are other things that can cause pelvic pain and discomfort. One would be

00:48:38.400 acute bacterial infection. And that's a classic. Frankly, if we find that, I feel good because I know we

00:48:44.460 have a solution. We can address it and so forth. You can address the infection. Now, the inflammation

00:48:49.360 and the discomfort and pain that results after that may take much, much longer to resolve. You can

00:48:56.260 have a non-bacterial inflammation that could be viral, although no one's really ever isolated specific

00:49:02.380 viruses that are individual man tracks with that pain, but viral. And then there's pelvic floor

00:49:08.980 dysfunction that is outside of the urinary tract. That pelvic floor function could be in the anus

00:49:15.680 and in the rectum having to do with dysfunctional voiding or elimination in the rectum. It could have

00:49:21.720 to do with dysfunctional elimination between the bladder and the urinary or urethral sphincter.

00:49:27.020 Those are common in kids. The other thing anatomically that maybe we failed to mention was the proximity

00:49:32.360 of the rectum to the prostate. Yeah. The rectum and the prostate are adjacent to each other. The rectum and

00:49:37.600 the prostate effectively developed from the cloaca. Cloaca is the embryonic sewer. That's where all

00:49:43.900 the waste in a fetus would go into and out of. And then it's divided anteriorly and posteriorly into

00:49:50.200 the urogenital sinus and then what becomes the anus and the rectum. And so, yes, they're intimately

00:49:56.060 associated with each other. And the innervation between the two of them is actually, there's a lot

00:50:01.300 of cross innervation. So if you have inflammation in the gut, in the rectum and the anus, you can result

00:50:06.540 in irritation and inflammation in the prostate. There also can be translocation of bacteria between

00:50:12.740 the rectum and the prostate. So when we are talking about your individual situation, I said,

00:50:17.300 are you traveling? Are you constipated? We think that that can result in maybe some increased

00:50:22.220 transmural translocation of bacteria. And by the way, to this day,

00:50:26.520 we don't really know what it was. Yeah. But that said, I go to great lengths to make sure my bowel

00:50:31.540 habits are regular when I travel. It's still difficult. I'm out of routine. I don't know if

00:50:35.840 it's dehydration. I don't know what it is. It also might be parasympathetic, sympathetic balance. I

00:50:40.380 think there are lots of reasons. Most people I talk to as patients, obviously, I don't have this

00:50:44.140 discussion at parties, but we'll say, yeah, I just get constipated when I travel a lot.

00:50:48.320 That almost always seems to produce some change in voiding quality.

00:50:53.360 A hundred percent. So there's a huge correlation. Number one, it's just physically

00:50:57.600 the pressure on the prostate and so forth can just make it much more difficult. So the classic

00:51:02.920 presentations for a man with urinary retention, obviously post-procedural. So if you have a hip

00:51:09.960 or a knee, anesthesia can shut your gut down and you can get constipated and you can do that. Or

00:51:15.120 some of the different cough and cold medications can do the same thing. But in general, I think of

00:51:20.060 travel, constipation from changing in your bowel function, that will be a big one. And even if you

00:51:24.940 doesn't make you frankly go into urinary retention, it affects how you urinate and so forth.

00:51:30.340 So let's say you rule out the common stuff. Your father wrote a very important paper in the New

00:51:36.720 England Journal of Medicine. Has it been 20 years now?

00:51:39.560 15 years ago. Yeah.

00:51:41.100 I refer back to that paper quite a bit. And it was actually following the algorithm of that paper that

00:51:46.820 when I got back to New York from back in whenever this was going on, circa 2016,

00:51:51.620 that we went through that diagnostic procedure. Walk through that procedure, which again, I think

00:51:56.980 for most people, it's a long run. But when you're dealing with something so complicated,

00:52:02.080 it is important to get some diagnostic specificity because the treatments do differ. Once, in my case,

00:52:08.400 the treatment was identified, the fix was on. There's a workup that you can do and you implement

00:52:15.520 if you're concerned about or worried that someone has an infection in their prostate or potentially

00:52:20.340 their seminal vesicles that you would have to go through to distinguish that type of infection from

00:52:25.540 an infection in the bladder, which is right next to the prostate. And so that is basically was

00:52:31.380 described by a Stanford urologist, Tom Stamey. And that effectively was that you would capture urine

00:52:38.400 as it comes out the urethra in different phases. And therefore, you could track where that urine came

00:52:43.300 from. So it's actually a four-step process. So the first step would be to capture urine immediately

00:52:49.200 after you start voiding. That would then capture and wash out any bacteria within the urethra,

00:52:55.720 the long channel between the bladder and the tip of your penis.

00:52:59.020 So that first few cc of urine that

00:53:01.380 it gives you a sense for, is there any bacteria growing in the urethra, urethritis?

00:53:06.440 Then the second phase would be, you would wait a couple seconds and then capture urine

00:53:11.620 midstream coming out from the bladder. And then you could then determine,

00:53:15.980 is there an infection in the bladder? Then what you would do is you would tell the patient to pause.

00:53:20.700 You would do then a rectal examination and you would press on the prostate,

00:53:25.860 pressing on the prostate vigorously so that you could effectively in some ways replicate what

00:53:31.020 happens in an orgasm. That is where the smooth muscle squeezes the fluid out of the prostate.

00:53:35.560 When you do a vigorous rectal exam, you're trying to push the fluid into the urethra.

00:53:39.940 You can sometimes just actually capture that prostatic secretion by itself.

00:53:44.300 We call that EPS or expressed prostatic secretion. You can send that off for an evaluation for any

00:53:50.960 bacteria in it. It's not always the case that you can get that fluid out. So then what you would do is

00:53:56.640 send the patient back to the washroom, have them capture urine coming out of the urethra,

00:54:02.120 the beginning of the flow, right after a vigorous exam. That will capture the fluid that may be still

00:54:07.240 in the prosthetic and the other parts of the urethra, but it was in the prostate. And that would

00:54:12.100 be the kind of essence of the step. And then you can just complete the void. So then therefore,

00:54:16.540 what you can do is look for where are the cultures showing any bacteria. And the cultures that would be,

00:54:22.840 let's say, for example, clean in the initial void, that would be VB1, the initial void. And clean in

00:54:28.840 VB2, that would be the bladder. But having bacteria in the EPS, the prostatic fluid itself, or VB3,

00:54:36.520 then that would tell you that there's an infection within the prostate. Now, the key thing is that

00:54:41.660 standard labs will call an infection if they see bacteria that's growing more than 10 to the fifth.

00:54:46.860 So more than 10,000 plus bacteria in that sample. But if you're worried about having an infection in

00:54:53.540 the prostate, for example, you need to lower that threshold. Are you having hundreds or thousands

00:54:57.880 of bacteria? So it's 10 to the two or 10 to the three. Because that should be a completely sterile.

00:55:02.840 It should be completely sterile. The prostate is a hostile environment for bacteria to persist.

00:55:07.800 It's very acidic. It's actually thought when people say like, well, what's the point of the

00:55:12.800 prostate, right? It's used for reproduction. But it's also thought that it can be somehow a barrier

00:55:18.360 to developing an infection in a man in the bladder. So the hostile acidic environment of the prostate

00:55:25.640 is thought, people speculate, to somehow prevent a bladder infection. Because remember, pre-modern

00:55:32.340 medicine, if you as a man would develop an infection in your bladder, it's life-threatening.

00:55:37.840 Yeah, especially if it goes up to the kidneys.

00:55:39.460 If it goes into the kidneys or it goes into the blood, you get urosepsis and you often will die.

00:55:44.740 So people think, okay, what's the prostate for? Well, it's used for reproduction,

00:55:48.360 but it's also maybe used for helping to prevent as a natural barrier for bacteria to go all the

00:55:54.820 way into the bladder. Do women have any such thing? I mean, women are so much more susceptible

00:55:58.860 to UTIs because of the short urethra. Yes, they're susceptible to UTIs. But remember,

00:56:03.900 if you have an infection in the bladder of a woman, yes, it can also track to the kidney,

00:56:09.100 but in general, there's limited stasis of urine in a woman's bladder because the urethra is so

00:56:15.180 short and you can evacuate or empty the bladder so effectively in a woman. Whereas in a man,

00:56:20.320 as you get older and your prostate gets larger, you get more stasis of urine in the bladder.

00:56:26.100 If you retain urine that's infected with bacteria.

00:56:29.780 So all things equal, women are less likely to develop urosepsis kidney infections based on the

00:56:35.540 fact that it's easier for them to evacuate the bladder if there's an infection.

00:56:39.000 It's by decade. So young men, they're the least likely to get any urinary tract infection, period.

00:56:45.820 But as men get older, their chances of developing a urinary tract infection equal that of a woman.

00:56:51.640 But you could argue because of the urinary stasis, et cetera, that that infection in a man is much more

00:56:57.160 life-threatening early on in their disease course than a woman. The probability that you would develop

00:57:04.080 an infection in the kidneys is probably the same between a man and a woman. But remember, if you

00:57:08.720 have a man who's older, who has a bladder infection, that can go into the blood, but it also can go into

00:57:14.300 the prostate. And as we were alluding to in our discussion of working up somebody for a prosthetic

00:57:18.600 infection, clearing an infection in the prostate is very, very difficult and very challenging.

00:57:23.300 So you have to do this specific STAMI for glass test. That's the different phases of the urinary

00:57:30.160 voiding. You have to rule out that there's any infection in the prostate. It's rare that we would

00:57:35.880 pick that up, but it's possible. And the other place that you want to look for in the kind of very

00:57:40.720 unusual cases is in somebody who has maybe an infection in their seminal vesicles. Maybe we can

00:57:45.960 put a picture up for the audience, but the seminal vesicles, they produce about 50% of your semen.

00:57:52.260 You can get a bacterial infection in your seminal vesicles. And unless you're looking for that

00:57:57.020 infection, you'll never clear that person because it's kind of very isolated from any continuity of

00:58:02.360 the urinary tract, but it can result in pelvic pain, can result in persistent issues of the

00:58:06.660 infection. In general, we do that very specific test to rule out infections in the urinary tract

00:58:15.660 that are related to the prostate or the seminal vesicles. The other way you could do it, a poor man's

00:58:20.680 version is to actually send off a semen for a bacterial testing. We like to do this express

00:58:26.960 secretion kind of setup, but you could do that too. If you have an infection in the prostate or in the

00:58:32.540 seminal vesicles or the genital tract, then yes, we know how to treat that. It's with directed

00:58:37.320 antibiotics. That in many ways will address the infection and most of the time address the pain

00:58:42.740 and discomfort that's associated with those symptoms. Now, the issue is that there are many

00:58:48.480 people who have discomfort that is not associated with bacterial infection. It could be viral. It

00:58:53.840 could just be inflammation. And it's not necessarily within the urinary or genital tract. So I see a lot

00:58:59.960 of patients. And when I do a rectal exam on somebody who's complaining of prosthetic pain, I always want

00:59:04.760 to feel the muscles in the pelvic floor. And how do you do that on the rectal? Is it just a broader

00:59:10.260 exam? So when you do a rectal exam and you feel kind of straight posterior, you're feeling just the

00:59:14.580 prostate. If you just move your finger laterally. You're into the pelvic floor. You're in the pelvic

00:59:18.660 muscles for sure. And so oftentimes you won't feel much of anything. But in a man who has pelvic pain

00:59:24.780 syndrome. Meaning it's just locked up. It feels like a guitar string. You'll feel bands of muscles. So

00:59:31.420 think about when you tweak your traps. You have those bands of muscle that you can feel with your

00:59:36.760 hands. But the good thing about that is you can go get a massage and you can work it out. And that

00:59:41.560 same thing happens in the pelvic floor muscles. So when I'm dealing with the patient who has chronic

00:59:46.080 pelvic pain syndrome or pelvic pain, I should say, maybe not chronic, but oftentimes we'll see them

00:59:51.680 after a while, this discomfort and pain, I try to treat their symptoms based on where the pain is

00:59:56.480 coming from. So is it prostatic? If it's prostatic, I try to do things like alpha blockers, potentially

01:00:03.700 Cialis is another one to treat symptoms that are associated with that discomfort. If I pick up that

01:00:10.140 they have a lot of tightness in their pelvic floor, I send them for myofascial release. So it's

01:00:15.020 transrectal myofascial release. It sounds barbaric.

01:00:19.380 I've seen this change a guy's life.

01:00:21.780 100%.

01:00:22.260 And the same for women.

01:00:23.380 Yes, true. So I feel great if I'm examining somebody and they have that, it makes me feel

01:00:28.640 good because I have a solution. The ones that are difficult are the ones that we just don't

01:00:31.880 know what's causing it. It can be related to food too. So if somebody has pelvic discomfort or pelvic

01:00:36.900 pain, you do a very thorough diary of what they're eating. And it's more classic in women with the kind

01:00:42.920 of female equivalent of this would be interstitial cystitis, where you'd say, well, what foods trigger it

01:00:48.480 for you? Because it can be triggered and irritate the bladder and that's causing the pelvic

01:00:52.760 discomfort. So again, you take a thorough history. The NIH has a very good online questionnaire to

01:00:58.420 help you kind of tease out where the symptoms are coming from.

01:01:01.760 That's under NIH's website or is it under specifically?

01:01:04.620 If you Google NIH chronic pelvic pain syndrome questionnaire, you'll get it. You can take it

01:01:10.560 and you can delineate that. And so, yes. Is it common in young men? No. But it's more common for

01:01:17.260 if a young man's seeing a urologist to have that than let's say BPH or something. Obviously, the most

01:01:22.000 common thing for a young man to come see us for is ED. But yes, it's definitely something that we can

01:01:26.460 address. And I've seen a number of men who go through the diagnostic workup. There is no infectious

01:01:34.040 agent whatsoever. But simple prostatic massage, just like you described a massage to an ailing muscle,

01:01:41.020 alleviates the problem. It's a very anti-inflammatory process.

01:01:45.320 Yes, that's a great point. So A, why that works for some people, we don't know, but it works and

01:01:49.860 hey, we'll take it. The other classic thing I hear about and you'll hear about in medicine is,

01:01:55.600 well, I have chronic prostatitis. Again, that's a very specific diagnosis. It's a bacterial infection

01:02:01.940 that you can't clear. So it's almost impossible to have that. But I have chronic prostatitis and I take

01:02:06.520 an antibiotic and I'll go on 30 days or 60 days of this stuff and it makes me feel better.

01:02:11.640 That scares me a lot because as you know, going on anything like a potent antibiotic has a lot of

01:02:17.840 downstream consequences that you just got to be careful of. Changing your gut, flora, all these

01:02:24.060 different issues. Why is it that they work? And if you ask the patient, they'll say, as soon as I get

01:02:28.140 this discomfort, I'll take a Cipro, I'll take a Levoquin, I'll take a Bactrim and I feel better.

01:02:33.140 It's because these powerful antimicrobial agents, these antibiotics, they are profoundly

01:02:39.780 anti-inflammatory too. So if that's what they're telling me, I try to transition them out of popping

01:02:45.240 these month-long runs of antibiotics and get them on an anti-inflammatory.

01:02:49.900 Is there a particular NSAID that you find works better? Does Celebrex even work? I don't find it

01:02:57.380 to be necessarily as potent. I try to stick with the more potent ones and I think naproxen is what I

01:03:02.880 like. It's BID dosing. It can be a little hard on your stomach. Ibuprofen is incredibly potent,

01:03:08.360 but it taking the right dose three times or four times a day can be hard.

01:03:12.420 What about meloxicam? I haven't gone to it, but it theoretically should work. And people,

01:03:17.100 you know, they have different sensitivities or efficacies with these different ones. So I start

01:03:20.800 generally with naproxen and I'll do that with a little bit of an anxiolytic because some of the

01:03:26.100 anxiolytics, they relax a lot of your muscles and they'll help relax the pelvic floor muscles. Because

01:03:30.340 although you want to treat that particular symptom, it's causing inflammation in all the structures

01:03:35.700 around it, rectum, bladder, prostate, and pelvic floor muscles. So I usually will try to do that

01:03:41.000 for a limited time. I don't like people taking long-term antibiotics for it unless they have a

01:03:45.200 difficult infection to clear. I have a friend who I sent to you recently in that boat, right, where

01:03:50.560 kind of has prostatitis believed to be bacterial prostatitis once a year. And that triggered my

01:03:57.220 thinking that maybe that's not what this is. And maybe we need to go down a different path.

01:04:00.980 Now there are individuals who we can't put our finger on what's causing the symptoms,

01:04:05.480 but my father still has an active research lab. He is the worlds of Florida on prostatitis and pelvic

01:04:10.640 pain. And one of the things he's- And he's still at Northwestern.

01:04:12.900 He's still at Northwestern. He has an ongoing clinical trial for people. He believes that a lot

01:04:18.100 of discomfort and pain has to do with mast cell dysfunction. He has a clinical trial where he'll

01:04:23.540 actually see individuals. He'll do an EPS. He'll look at their voided fluid. He'll assess them for

01:04:29.400 different markers for mast cells. If they're high, he'll put them on mast cell inhibitors in a clinical

01:04:35.300 trial. And it's quite effective. So if folks are interested listening to this, presumably this is a

01:04:40.500 trial only for men, of course, where can they find more information about the trial?

01:04:43.860 Yeah. On the Northwestern Feinberg School of Medicine under the Department of Virology's webpage,

01:04:48.100 my father, Anthony J. Schaefer and Praveen Tumbakat. He's my father's scientific partner. They are

01:04:54.640 working on this. We'll link to that as well for folks who are interested in that trial.

01:04:58.260 There is hope for these individuals because there is a subset of men. We do see that.

01:05:02.520 It really is sad because it has a huge impact on the quality of our life.

01:05:06.440 We've talked now at length about two of the big problems associated with the prostate.

01:05:12.300 And while both of these can be an enormous threat to the quality of a man's life, they're not often

01:05:20.420 a threat to the length of life though. I guess one point I'd make before we leave these is one of the

01:05:24.200 questions I get asked a lot is, how does somebody actually die from Alzheimer's disease? What I

01:05:29.640 usually explain to people is they usually don't die from Alzheimer's disease. They usually die from

01:05:33.960 something else that is brought on by the Alzheimer's disease. And one of the classic sad,

01:05:39.200 tragic cases you see is urosepsis. So you see a man with Alzheimer's disease. So one,

01:05:45.040 he might have a catheter in him because he's unable to void on his own and that dramatically

01:05:48.620 increases his risk. But even if he doesn't, he's simply less responsive to the signs of an infection.

01:05:54.660 He's not attentive to the fact that it's burning when he pees. And because of his age and his

01:06:00.680 immunologic reserve, what starts out as a urinary tract infection on day one is a lethal case of

01:06:07.740 urosepsis on day four. And so I do think of this as kind of one of the grim reapers of older men.

01:06:14.180 Yeah. I mean, as men age, and particularly if you have concomitant other significant medical issues,

01:06:19.820 your frailty goes way up. And so any little insult to your body can do it. And obviously,

01:06:25.520 classic things are aspiration, aspiration pneumonia.

01:06:29.080 Smallest cellulitis if you're not moving around.

01:06:31.100 Exactly. And so I think it's a lack of awareness. It requires a very astute caregiving family or

01:06:38.000 cohort of individuals to notice subtle changes. Because obviously, if you can pick up an infection

01:06:43.100 early, then it doesn't necessarily have to spread and it won't be so symptomatic.

01:06:47.940 If you could speak to someone listening to this who's caring for an elderly patient, male or female,

01:06:55.900 who is in the throes of dementia, what can a caregiver do on this particular front? Is there

01:07:03.380 anything they can do to minimize the risk of a kidney infection or a bladder infection turned into

01:07:10.680 systemic sepsis?

01:07:12.640 Good hygiene is obviously key. In general, if you're monitoring the individual,

01:07:18.560 they're voiding history. So we obviously would prefer for people to void on their own.

01:07:23.460 And many people can. Many times people have catheters in place for convenience of the caregiver.

01:07:29.660 And so if you can keep hardware out of somebody, that's obviously very effective. And if the

01:07:34.540 individual can't void and they're having trouble with that, then intermittent catheterization

01:07:40.020 is what we obviously endorse and recommend, where you just place a catheter temporarily.

01:07:45.680 Intermittent catheterization poses less of an infectious risk than constant catheterization.

01:07:50.940 A little counterintuitive, right? You would think, gosh, if three times a day you have to cath somebody,

01:07:55.600 that's three times you're introducing it. But you're saying if it's done with perfectly sterile technique.

01:08:00.220 Dwell time, right? So three times a day for 60 seconds each. So that's 180 seconds versus 24-7

01:08:07.220 for the bacteria to be there. And we know if you leave a catheter in place by 48 hours,

01:08:12.160 the bacteria has crawled up the tubing and is in the bladder. So yes, if you can minimize the dwell

01:08:18.140 time of the foreign body, the better. So yes, it is a little counterintuitive, but for men and for

01:08:23.800 women, if you can do intermittent catheterization, that's a profound way to reduce the chances that

01:08:29.020 you develop any urosepsis. Will you develop or will you have bacteria in the urine if you do

01:08:34.400 intermittent catheterization? It's possible. Does that mean that you've failed with that technique?

01:08:38.420 No, because if you're continuously emptying the bladder, you never can get overgrowth and you can

01:08:43.920 never get enough urine with bacteria in it to cause or pose a problem. That leads to another point,

01:08:49.420 which I often see, which is in individuals, as they're aging, dehydration is a key underappreciated

01:08:56.760 contributor to all these medical conditions. Especially because older people lose their relationship

01:09:02.340 between thirst and hydration status. That's another one of those things that deteriorates

01:09:06.100 as they eat. Yeah. And if you have Alzheimer's, you forget to drink, frankly. And so if you have

01:09:11.420 bacteria in the urine, but you keep the concentration at 10 bacteria per ml, well, that's not going to be

01:09:16.440 a problem. But if you're dehydrated and you have more concentrated urine and there's the same amount

01:09:22.120 of bacteria with less urine, you couldn't really have significant issues. So as we age and you have

01:09:27.640 these comorbidities, a good caregiver is critical. Oftentimes in medicine, they're paid the least.

01:09:33.960 It's really an important role that you have. So I think if you can maintain any kind of hardware in

01:09:38.740 an individual, get them out walking around and just remind them to drink. If they have a catheter,

01:09:43.380 you want to get that catheter change every month or three weeks. And generally, a good caregiver and a

01:09:49.220 good urology practice, we have a whole team of nurses that do this for our cohort of patients.

01:09:53.840 They'll get an idea of the cadence for that individual. But we try to stay away from it if

01:09:59.080 at all possible. Okay. Now let's talk about the third big pathologic issue associated with the

01:10:06.400 prostate, which is prostate cancer. Prostate cancer is the second leading cause of cancer death for men

01:10:12.440 behind only lung cancer. And so in order, it goes for men, it's lung, prostate, colon, pancreas.

01:10:21.100 The thing that stands out to me is we have great tools of detection for prostate cancer. Based on

01:10:31.140 that, I guess it's a little surprising to me that it is still the second leading cause of cancer death

01:10:35.520 in men. So one of the things I hope to be able to do by the end of this final part of our discussion

01:10:41.040 is get a better sense of what an individual can do to flip the odds in their favor. Because you've

01:10:47.300 probably heard me say this before, I don't think anybody should ever die of colon cancer for the

01:10:51.000 same reason. We have remarkable tools of detection and we also have a very predictable pathogenesis

01:10:58.360 where we must go from a polyp. We must go from an adenoma to a carcinoma and we can detect the

01:11:06.200 presence of the adenoma because it is outside the body effectively. So just to bring it back old

01:11:11.580 school to where we first met, obviously that would be the Halsteadian theory for how cancer would

01:11:17.760 spread. And that would be a stepwise from a localized non-invasive to an invasive tumor to a

01:11:24.140 regionally advanced and then metastatic lesion. And colon follows that algorithm pretty well. There are

01:11:30.080 obviously always the cases that are outliers. Sure, there are sessile polyps that are very difficult

01:11:35.540 to detect. In general, I would say that yes, I agree with everything you're saying and I would

01:11:40.600 agree that on average, prostate cancers follow a similar Halsteadian theory of spread as opposed

01:11:47.040 to Bernard Fisher and the Fisherian spread. Which is the breast cancer model. Exactly. So yes,

01:11:53.180 100% agree with you that prostate cancers on average, 250,000 to 260,000 new diagnoses this last year,

01:12:01.800 so a lot, will follow more of a Halsteadian spread. Now remember, if you keep that in mind and you're

01:12:08.800 the math guy, not me, if you do, just model it. 250,000 to 260,000 new diagnoses, 34,000 deaths.

01:12:17.380 So yes, on average, we are picking up cancers. But on average, if you look at the ratio of cancers

01:12:24.120 diagnosed to cancer deaths, that ratio is pretty favorable. It's much better than the other cancers.

01:12:30.740 Conversely, to put pancreatic cancer in terms like that, of the people diagnosed with adenocarcinoma

01:12:37.360 of the pancreas, about 95% of those people will experience lethality within five years.

01:12:43.960 We have that in our favor. And so yes, what keeps me up and gets me up in the morning and excited is

01:12:49.260 to understand and identify what it is about the individuals who develop prostate cancer that is

01:12:55.780 localized and doesn't have a lethal potential and how do we better attack those subset of

01:13:01.480 individuals that will ultimately die from their prostate cancer. So lots of progress, even since

01:13:06.380 when we last talked. But yes, big picture, it is still a real issue.

01:13:10.000 Okay. We've already touched on testosterone. We touched on estrogen, peripherally discussed

01:13:18.340 dihydrotestosterone. Let's explain how androgens work. Where are androgen receptors? What are these

01:13:26.340 hormones doing? And for the purpose of this discussion, how do they factor into the pathogenesis

01:13:32.640 of this condition?

01:13:33.780 If you go back, and I actually think it's a really good exercise for an individual to go back and

01:13:39.360 understand where the prostate actually comes from. It comes from the urogenital sinus. This is a

01:13:44.240 sexually dimorphic organ. And in the response to androgens around week 10 or 11 in a developing

01:13:51.780 fetus, human fetus, there's a surge of testosterone from the gonad. And that surge of testosterone results

01:13:58.820 in the development of this ductal network. It's an extraconglant and it develops out of the structure.

01:14:04.940 By the way, how big a surge in testosterone? I know that it's much more significant than the levels

01:14:09.120 that a little boy is born. A little boy is born with very low testosterone, but he did experience a lot of

01:14:13.940 it in utero, right?

01:14:15.140 Lots in utero, lots at birth, and then puberty. Those are the three peaks. And they're similar.

01:14:20.600 I think obviously puberty is the highest, but it's enough to impact a change. And we'll talk a little

01:14:25.380 bit about that because it's not just testosterone levels, of course, that matter, but it's what the

01:14:29.940 intracellular dihydrotestosterone levels are. So in the urogenital sinus, the mesenchyme,

01:14:36.320 those are the things that eventually turn into muscle and connective tissue. They contain androgen

01:14:42.020 receptors that then send a paracrine signal to the epithelium.

01:14:46.260 Let's even back up for a moment and make sure people understand this. So testosterone,

01:14:49.800 complicated molecule derived from cholesterol. So picture a cholesterol molecule with all of its

01:14:54.580 rings. Testosterone is very comparable. What is an androgen receptor? Explain what it is and where it

01:14:59.360 sits. The androgen receptor is a very fluid molecule that basically sits in the cytosol of a cell.

01:15:06.420 So outside the nucleus. Outside the nucleus. And the androgen receptor is a transcription factor.

01:15:12.680 So it turns on a variety of different genes within a cell. So think about in your house,

01:15:18.840 if you have a circuit breaker and you turn on the circuit breaker and every light in the house goes

01:15:23.960 on. That's what a transcription factor does in my mind. That's how I think about it. I explain it to

01:15:27.800 patients. Androgen receptor is a transcription factor. It needs to be in the nucleus of the cell

01:15:32.880 to flip those switches. And it sits in the cytoplasm. It needs to translocate to the nucleus and then

01:15:40.200 bind to the DNA of our cells. And it only does that once testosterone or dihydrotestosterone binds

01:15:46.700 to it in the cytoplasm. That's right. So its signal, it has a conformational change that permits it to

01:15:52.540 enter the nucleus when it's bound to testosterone or dihydrotestosterone. Now dihydrotestosterone has a

01:16:00.320 much stronger, higher affinity for the androgen receptor and enables it to be, it's about 10 times

01:16:06.520 more potent. So one molecule of DHT is the equivalent of 10 molecules of testosterone. Now that conversion

01:16:12.560 of testosterone to dihydrotestosterone does not occur anywhere in your body. And just for the listeners,

01:16:19.000 by the way, women have an equal distribution of androgen receptor as do men, but they don't

01:16:24.500 typically have androgens around. I guess let's do the math. A woman will have probably 5% of the

01:16:31.960 androgens. Yes. She'll have about 5% of the testosterone that a man will have. But theoretically

01:16:37.000 at birth or in utero, they have the equal distribution of androgen receptor, but they don't

01:16:42.200 have dihydrotestosterone. So men have five alpha reductase in their hair follicles and in their

01:16:48.700 prostatic tissue predominantly. Those are the two main areas where it exists. So if you have the same

01:16:53.660 amount of testosterone floating around in your blood, it will have one effect, let's say on your

01:16:59.160 skin, it's never converted to DHT. But if that same testosterone molecule hits a hair follicle or

01:17:06.440 hits the prostate, it's converted into a very potent androgen DHT through 5-alpha reductase. And that can

01:17:13.260 then have a much more potent effect in terms of the subsequent effect of the androgen receptor.

01:17:19.420 So just to make sure I understand, if a male has a normal testosterone level,

01:17:24.640 but he's taking a 5-alpha reductase inhibitor, I want to talk about that now, which lowers the

01:17:32.160 conversion of testosterone to DHT. Young guys will take this all the time to prevent hair loss. These

01:17:38.440 are the most common drugs that are used to prevent hair loss. Part of the story, I guess we didn't finish

01:17:42.760 here, was DHT in the hair will damage the follicle. It's leading to baldness. Early death, yeah.

01:17:50.400 So it seems to me like he's shortchanging his androgen receptor potential. He's shortchanging

01:17:55.980 the ability to experience testosterone. It's almost like he's taking a testosterone haircut

01:18:00.540 without taking the testosterone haircut. Yes. What you end up with is less intraprostatic

01:18:06.300 DHT, more intraprostatic T actually, because you can't convert it. So you're pulling it in there.

01:18:12.080 You normally would convert it. That's true in the hair follicle also, as we'll talk about,

01:18:16.800 because there's significant pathology associated with taking finasteride. We used to think that it

01:18:21.740 was predominantly in those main structures, follicles of your hair, prostate, et cetera. But now we know

01:18:26.040 it actually has profound potential impact of that centrally in your nerve system, right? And it can

01:18:31.400 affect your sex drive. It can affect your sex performance. So let's talk about this because I had

01:18:35.940 never heard of this until a few months ago. Post-finasteride syndrome. So we talked earlier

01:18:42.780 about finasteride. When it's taken in a drug called Proskar, five milligrams a day, it has a cousin

01:18:49.560 called Dutasteride or Avodart. I think that's 0.5 milligrams per day.

01:18:53.660 Yep. That one theoretically is more potent because it blocks five alpha reductase one and two. The

01:19:00.440 efficacy is equivalent in the human body. And then lower dose finasteride, so not five milligrams.

01:19:05.720 One milligram per day is called Propecia, and that's the branded version that's used for hair loss.

01:19:10.320 Yes.

01:19:11.360 The first thing I remember you telling me about this was, it's a little bit of a scam that these

01:19:16.400 drugs are taken daily because their half-life is quite long.

01:19:19.480 They all have a very long half-life. So if you took a single finasteride five milligram dose,

01:19:24.520 it's generic, so it costs nothing anyway. But if you took that, it would hang around in your system

01:19:28.400 for a week or two. The reason it was reformulated at one milligram versus five milligrams was for a

01:19:33.140 new patent, new indication. I haven't worked it out. You could probably just take a single five

01:19:37.260 milligram of finasteride once a week, and that would be the same as one milligram of the other stuff

01:19:41.300 every day. It has a much longer half-life than anyone appreciates. That's the least of the problems

01:19:47.020 that I think is associated with this drug. Let's get to the issues because this is also a very

01:19:51.700 controversial topic. There are people that get up in arms on both sides of this discussion.

01:19:57.620 Describe what post-finasteride syndrome is.

01:20:00.280 It's a variety of symptoms that men will complain of after taking either the BPH dosing or the kind

01:20:09.100 of hair loss dosing of these medications. Decreased sex drive, impotence, and ejaculation.

01:20:16.400 Inability to ejaculate.

01:20:17.820 Inability to ejaculate. Those are obvious and apparent things for any young man trying to do it,

01:20:23.120 but there's a lot of other associated findings with it like depression, change in your affects. So

01:20:29.600 those are harder, in my mind, to attribute to medication, but patients do complain about it.

01:20:34.900 But when you have a patient who's young, healthy, has a great interest in sex, etc., and they take

01:20:40.100 this medication for hair loss and they can't get an erection. They have no interest in sex. They

01:20:44.700 can't have any orgasm. Those are real, and those are directly, in my opinion, definitely related to

01:20:50.400 the drug.

01:20:51.540 What do you think is the approximate frequency of this post-finasteride syndrome?

01:20:57.640 That's probably where there's more debate. Some people would say 5%. Some people would say 15%.

01:21:03.420 Depends on where you look. I think about it like 1 in 10 guys will have appreciable issues with it.

01:21:09.680 And it's not just the young men. It's in older men, too. It's just that they're maybe, on average,

01:21:14.440 less interested in sex or less sexually active.

01:21:17.100 It's less apparent in an older guy.

01:21:18.860 Yes. I definitely see it. So that's why I never really use it in my practice. I mean,

01:21:22.620 it's just such a limited drug. In part because the efficacy is limited, in my opinion, in terms of

01:21:27.360 managing lower urinary tract symptoms. And then the side effects from it, this post-finasteride syndrome,

01:21:31.420 are real. The duration of these symptoms can be highly variable. So some people will stop the

01:21:37.820 medication, and they'll have resolution within a couple weeks once the drug washes out. But there

01:21:43.760 are people that I know who have it permanently.

01:21:46.840 Yeah. There are case reports, and that's the really scary stuff, which is the case report of

01:21:51.100 the guy who goes to see the hair doctor. They put him on finasteride, experiences all of these

01:21:56.440 symptoms. They're horrible, and they're very noticeable because he's 25 or 30. He stops taking

01:22:02.300 the drug, and it never comes back. Those are rare, like you say, but they're real, and they are

01:22:08.040 associated with the drug, and there's no doubt in my mind. I guess the obvious question here is,

01:22:13.500 let's assume that the frequency of this is 1 in 10, and we want to avoid it at all costs because we

01:22:18.340 never know if it's reversible. Is there any sense of what predicts susceptibility to this?

01:22:26.000 It's a good question. You know, it's a post-hoc diagnosis. I haven't seen a great paper that really

01:22:30.440 took 100 or 500 men and really tried to evaluate what it was that would predict it. So I'm not aware

01:22:37.380 of any high-quality study that can help predict that association.

01:22:41.000 Would you be comfortable then, and feel free to say no, but would you be comfortable recommending

01:22:47.420 to a patient who's considering using a 5-alpha reductase inhibitor for hair loss that they might

01:22:54.440 be better off looking at other medical and non-medical therapies for hair loss?

01:22:58.880 Yeah. I mean, I don't recommend it for use in any man.

01:23:02.280 BPH or otherwise?

01:23:03.420 Yeah. Why? If you're taking it for hair loss, which I experienced at a very young age,

01:23:07.820 so I know what that feels like, and it can have a real impact on a young individual's

01:23:11.880 life, there's a lot of really effective therapies that you can do. I mean, hair transplant works

01:23:17.420 very well. It's very precise, and I know people who've done it, and they're very satisfied with

01:23:22.360 it. So I think there's alternatives. I think understanding what that spectrum of alternatives

01:23:27.240 is is really important because when young guys go to these pop-up shop clinics, they're not given

01:23:33.860 the full...

01:23:34.800 They don't have a consent.

01:23:35.620 Yes. And they don't understand what the long-term effects are because in addition to

01:23:40.020 the post-finasteride syndrome, as a prostate cancer biologist and an individual who treats

01:23:46.800 people with prostate cancer, the other big thing has to do with what its effect is on your PSA value.

01:23:52.540 So it halves your PSA value if you take the medication for one to two or two to three years.

01:23:59.060 And after five years of being on the medication, it reduces your PSA number by about 2.5x.

01:24:04.200 And that does not come back?

01:24:06.540 If you stop the medication, your PSA will rise. But the biggest issue is not whether or not it

01:24:11.340 suppresses your PSA or not. It's lack of awareness that it does amongst the patients and the providers.

01:24:20.060 Because if you're going to some men's health clinic for your finasteride or your finasteride for your

01:24:25.160 hair loss, you may not mention it to your internist. And usually when you start that for hair loss,

01:24:29.720 you maintain it for life. The classic case, I see it probably every other week of a guy whose PSA is

01:24:36.140 rising on finasteride. If your PSA begins to rise on finasteride, we're talking about PSA in general

01:24:40.480 a sec. If your PSA rises on finasteride, you have a problem. That is a warning sign that there is a

01:24:45.900 cancer and likely an aggressive cancer growing in your prostate. And guys aren't aware of it.

01:24:50.780 And not just guys. It might be that physicians aren't aware of this.

01:24:53.400 That's right. So if you're a man, you take finasteride starting at age 25, you start at age 25, your PSA is

01:25:01.200 0.5. Think about this. It may begin to rise. Let's say now you're 50. So 20 years later, it goes between

01:25:08.900 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

01:25:17.680 problem before it's even anywhere near being on the radar of the patient or their internist. So in my

01:25:24.000 opinion, it's just, you got to be very, very careful with these medications, particularly taking them that

01:25:28.480 long. And this says nothing about the other issue, which is not having DHT probably isn't a good thing

01:25:38.060 if you're in the business of taking advantage of your androgen receptors. You're taking away the most

01:25:44.900 potent androgen in the body and androgens do really good things.

01:25:50.300 Absolutely. I mean, the extreme examples are those individuals with no testosterone. We induced that

01:25:55.260 in individuals with advanced prostate cancer. And there are rare cases for men who are born with no

01:26:00.240 testosterone at all. But in general, yes. I mean, for a healthy man, it's absolutely imperative,

01:26:06.380 in my opinion, that you maintain a eugonadal state. That's debatable what that means. But I think,

01:26:12.860 in my opinion, you can titrate to a functional eugonadal state in almost all men if their

01:26:19.340 testosterone levels are low. But having testosterone around is just critical for...

01:26:24.100 Everything from metabolic health to structural health.

01:26:26.260 Really for everything.

01:26:27.540 Probably mood and a whole bunch of other things.

01:26:29.760 Exactly.

01:26:30.720 Now let's talk about the relationship between testosterone and DHT and the development of

01:26:37.200 prostate cancer over a man's lifetime. So one of the obvious statements is,

01:26:42.760 when a man has the most testosterone and presumably DHT in his body, so let's just

01:26:49.120 take out the case of guys who are taking 5-alpha reductase inhibitors. So when a man is in his 20s,

01:26:55.420 call it 18 to 20, 18 to 30, his testosterone and DHT are through the roof. We don't see guys

01:27:01.520 getting prostate cancer. Similarly, by the way, we don't see women getting breast cancer when their

01:27:06.300 estrogen is at their highest either. We know that the story is more complicated than the caricature is,

01:27:11.660 which is not to say that these hormones don't matter, because to your point a moment ago,

01:27:16.060 when you have men with metastatic prostate cancer or untreatable prostate cancer, hormone

01:27:21.960 deprivation therapy is a core treatment. So how do we reconcile those two observations?

01:27:28.800 There's a time-dependent co-variable here. There's lots of things that testosterone does at a cellular

01:27:33.980 level, right? It impacts damage to the DNA, repair of that damage to the DNA, all these different

01:27:39.420 things that people, I don't think, really fully appreciate. But I think when you go through your

01:27:45.000 surge of testosterone, whatever that may be, if your puberty peak is age 18 or age 25, wherever your

01:27:51.840 peak is, I think you begin to reset the functional code. So you're born with your DNA, but it's not

01:27:59.420 really, for the most part, what's in your DNA that matters. It's the epigenetic changes that result in

01:28:05.880 the RNA translocation transition that really is the most important thing. So I think that you begin

01:28:13.400 to mark and see differences in terms of the epigenetics of different genes within an androgen

01:28:20.960 responsive organ that then sets the stage for your potential risk for developing prostate cancer.

01:28:26.320 So I think that there's a correlation between testosterone and subsequent future diagnosis of

01:28:33.500 prostate cancer, but it's just one of the many factors that plays a role. So if you don't have

01:28:37.500 any testosterone, you're not going to get prostate cancer because you won't have a prostate. That's

01:28:41.500 the obvious one. But I do think that there's a correlation between T and A, being a healthy male,

01:28:47.460 and part of being a healthy male is a potential risk for developing prostate cancer. Does that make sense?

01:28:52.300 It does. And there's this other very interesting observation, and I don't know if this has been

01:28:55.980 subsequently refuted, but I remember this probably when we were in residency, Ted, that there was that

01:29:01.940 paper that came out that found that men with lower testosterone, this was in the New England Journal

01:29:06.640 of Medicine, were at risk for higher grade prostate cancers. Yes. The sort of teleologic

01:29:13.040 explanation was, at least this was my teleologic explanation, if you are developing prostate cancer

01:29:21.080 in the presence of low androgens, you have a cancer that's very sensitive and therefore is probably

01:29:26.740 much higher grade. Is that still kind of the thinking, or has the thinking evolved significantly?

01:29:31.960 So we just published a paper on this. We looked at 100,000 prostate cancer transcriptomes.

01:29:38.820 Where did you get so much?

01:29:40.260 We did this in partnership with a company, originally it was called Decipher, now it's owned by a company

01:29:45.540 called Verisite. And I did this with the founder, Eli DaVincione. We looked at their database of,

01:29:52.320 they now have 140,000 plus prostate cancer transcriptomes. We just asked a simple question.

01:29:59.460 If you take prostate cancers and you do AI-based hierarchical clustering, just looking for

01:30:06.780 patterns, do you see different types of cancer? Not grade or stage, but different types from the

01:30:13.700 perspective of the transcriptome of prostate cancer? And you do. So you see two general themes. One, you see

01:30:20.700 luminal-like prostate cancers and basal-like prostate cancers. And then within that sub

01:30:27.860 classification of luminal and basal, there are kind of effectively aggressive luminals and then

01:30:34.560 aggressive basals and then less aggressive ones. So where is this all coming from? So if you take a look

01:30:40.720 back at embryonic development, people have done this. I did this in my postdoc study. What happens to the

01:30:46.580 prostate in a mouse or a rat when you begin to take away testosterone and give it back? You can see

01:30:51.840 that the prostate, as we mentioned before, grows in response in part to testosterone and estrogens

01:30:57.120 around. But if you castrate a mouse, all of the luminal cells. Post-maturity. Yes. You develop a normal

01:31:04.340 prostate and you castrate a mouse or a rat with the prostate, it will regress. And think about it like

01:31:10.860 a plant in the middle of a drought. It looks dead, but there's roots that are still alive. Those roots

01:31:17.620 that are still alive in the prostate are predominantly basal cells. If you give that prostate back its

01:31:24.900 growth fuel, testosterone or DHT, then it will regrow a new prostate. And the basal cells can begin to

01:31:33.900 repopulate and you'll get also a proliferation of these luminal cells that will then form the big,

01:31:39.780 bulky, meaty prostate that we think about, let's say, just the BPH portion of the prostate.

01:31:44.520 So you have luminal cells and the luminal cells in development, and we believe in prostate cancer,

01:31:51.640 are exquisitely sensitive to testosterone androgens. The basal cells, the cells that survive

01:31:58.480 the drought, the cells that survive in the absence of effectively any testosterone at all,

01:32:05.080 those are the ones that form more basal-like tumors, which are very, very aggressive.

01:32:10.840 So when I look at somebody with prostate cancer, yes, I look at their grade, yes, I look at their

01:32:16.040 stage, but I also look at the genomics of their tumor and what's the biology of their tumor,

01:32:21.440 because they may have a big, bulky, luminal, proliferating, luminal tumor. But I know,

01:32:27.640 A, it's exquisitely sensitive to testosterone suppression, which is something that I have in my back

01:32:33.340 pocket, and B, it's less likely to start spreading to other parts of the body.

01:32:37.100 Why is that? Because it's on the basal side?

01:32:39.280 No, if it's a luminal-type tumor, think about it, it's more dependent on that testosterone-rich

01:32:44.920 microenvironment with the DHT around. It doesn't do as well, theoretically, living in the bone marrow

01:32:50.720 when it metastasizes to the bone or the lymph nodes.

01:32:53.320 This is very counterintuitive. On the one hand, you're saying it's a more aggressive tumor.

01:32:57.920 Locally bulky.

01:32:58.800 But on the other hand, you're saying less likely to survive metastatic spread.

01:33:03.960 Yeah. If you look, which we've done, the distribution of a luminal-differentiated tumor

01:33:09.240 in a localized state is about 40%. If you look at how many metastatic lesions,

01:33:15.760 so you take tumors that are metastatic, it's less than 10% are luminal-differentiated.

01:33:20.080 They just don't have the capacity to survive and spread to other parts of the body,

01:33:24.880 whereas a basal tumor, which is by nature able to survive in the absence of testosterone

01:33:31.800 and or uses alternate growth pathways to testosterone because it's not dependent on it,

01:33:39.240 those tumors are more capable of spreading to other parts of the body.

01:33:42.800 So this is kind of a great tragedy. It means that the prostate cancers that are most likely

01:33:47.360 to kill you, which by definition are the ones that spread, are also the most capable of thriving

01:33:53.440 in a low testosterone environment and therefore are least hurt by androgen deprivation.

01:33:59.080 Yes. I mean, this is just things that we've been working on this thesis, Eli and I, for

01:34:03.920 now a decade, but we have this data now we just published this year. Lots of other interesting

01:34:10.020 studies coming out that really kind of support this idea. So that's why, in my opinion, I am very

01:34:17.560 comfortable with a patient who has a low testosterone being on testosterone supplementation if they have

01:34:25.420 a low T, either during the process of being diagnosed with their cancer or in their recovery

01:34:31.620 phase. Because I know that if they were to develop a recurrent disease, a recurrence of their cancer,

01:34:38.440 it's most likely a luminal type, and we can exquisitely modulate that tumor with testosterone.

01:34:45.120 So it's a big step. It's a big step in a different direction. It takes a lot to think about. In my

01:34:50.960 opinion, it really helps us understand the biology, not so much of localized prostate cancers, but rather

01:34:57.460 when you have a localized cancer that has the capacity to spread. So a localized cancer with lethal

01:35:02.120 potential. And what's the nature of that tumor? How do you begin to attack it? And understanding

01:35:08.340 the molecular underpinnings of it is key. That's precision medicine.

01:35:11.940 Yeah, absolutely. So you've got these 100,000 transcriptomes. They've given you this insane

01:35:18.060 amount of insight. How often can you now predict based on a man's genetics? Or do you need a tissue

01:35:26.920 biopsy to map to the transcriptome to say, aha?

01:35:31.320 Let's talk about the transcriptome of the tumor. So once a patient has a diagnosis, you can get the

01:35:36.140 transcriptome information. It's provided to the providers. It's not commercially available. It's

01:35:42.000 not provided commercially because you have to be cautious about how you interpret that data and

01:35:47.640 what you advise the patient until we have more information from clinical trials about, well,

01:35:52.780 what does a particular molecular phenotype mean for the, A, how you treat their new diagnosed,

01:35:58.080 localized, or potentially if they have a recurrent disease, how you should better treat it. But those

01:36:02.720 trials are now in process or are just being built based on some of this work.

01:36:08.580 Sorry, just to be clear, Ted, does that mean that someone listening to this who has a biopsy of their

01:36:13.900 prostate, their physician will get this information back but won't necessarily know how to interpret it?

01:36:20.740 If a patient gets a biopsy of their tumor and they have genomic testing with Decipher Verocyte,

01:36:27.800 which I don't have any conflicts with, by the way, they will then get a simple readout of how

01:36:32.860 aggressive is their tumor. It's a molecular Gleason score. But on the back end, in addition to measuring

01:36:39.020 those 21 different genes that consist of the Decipher score, they capture the whole transcriptome of

01:36:45.100 that tumor. And you can get access to what they call the GRID report, which gives you this whole

01:36:50.640 deep dive into what's the biology and nature and phenotype of that particular tumor, which for me,

01:36:57.780 I look at, and I will then look at that and then say, okay, this patient on paper perhaps has an X or

01:37:06.400 Y or Z, but the molecular phenotype of the tumor is favorable or it's not favorable. I'm going to alter

01:37:11.540 what I recommend to the patient based on that. So that's how I interpret it. It's kind of experimental

01:37:16.560 use only, so to speak.

01:37:18.480 But it is the direction of precision medicine.

01:37:20.640 It's the future of it. And so based on these papers and many, many others, not just the one that I did

01:37:25.820 this one, but many, many other papers with really great scientists, they are the platform through which

01:37:32.120 all clinical trials in prostate cancer are now reliant on. So the CIFR score as a entry criteria,

01:37:40.240 as a predictor for intensification or de-intensification of therapy is part of almost all clinical trials

01:37:46.740 going through the National Institute of Health right now, which is exciting.

01:37:50.240 Yeah. So let's talk a little bit more about the pathogenesis. You talked earlier about the transition

01:37:57.260 zone and the peripheral zone, the orange analogy. I'm assuming that most prostate cancers develop in

01:38:03.840 the peripheral zone. Correct.

01:38:05.660 And the reason for that is we didn't state this earlier, but you would think or hope,

01:38:10.940 I suppose, that any man who's undergoing prostate tissue removal for BPH would have a lower risk

01:38:16.180 of prostate cancer because, hey, you just shed 80% of your prostate. That doesn't seem to be the case,

01:38:21.160 correct?

01:38:21.840 It doesn't necessarily change their risk for developing prostate cancers in the future. However,

01:38:27.380 it changes your ability to monitor them for the development of prostate cancer because, remember,

01:38:34.260 the PSA blood test, it's been often criticized, but it's a very powerful tool. And it just depends

01:38:40.760 on how you use that blood test to identify people at risk for potentially having prostate cancer.

01:38:46.320 I want to really talk about this in a minute because there are a few things that annoy me more

01:38:50.340 than people who harp on how bad the PSA is, which to me means, no, it's how bad you are at using it.

01:38:56.440 The PSA is a remarkable test.

01:38:59.240 Yes. So the issue arises from this overlap in the test because it's not prostate cancer specific.

01:39:08.040 It's prostate specific. So the beauty of having my partner, Amy Krambeck, do a hole up and take

01:39:14.400 out 90% of your prostate is that reduces 90% of the PSA producing cells. The PSA should be below one,

01:39:22.240 but it makes the test way more sensitive for me to follow for a future potential risk of developing

01:39:28.680 prostate cancer. So in general, I would say that, yes, the specificity of the tool changes based on

01:39:35.780 how much prostate tissue you have. So the PSA test is actually exquisitely sensitive in young men

01:39:41.480 to their future risk for developing prostate cancer because they have such limited amounts of transition

01:39:46.920 zone tissue. And the bulk of their prostate is just peripheral zone.

01:39:51.080 So why is it that the cells in the peripheral zone are susceptible to becoming neoplastic as opposed to

01:39:58.520 the cells in the transitional zone?

01:40:00.120 Under the microscope, there are some subtle differences as to how they look,

01:40:03.360 but people don't know why that particular zone or that zonal anatomy is such that you have a higher risk

01:40:09.040 of developing it there. It's obviously very unfortunate because as the name implies, it's in the periphery.

01:40:14.920 And what's just outside of the prostate is the high price real estate of the nerves for erection,

01:40:20.320 the nerves for urinary continence and the muscles for urinary continence. So that has a big impact

01:40:25.440 on how we manage prostate cancer and it's been a result. That's what results in a lot of the potential

01:40:29.780 side effects that occur. But in general, yes, in young men, PSA is a very potent way for us to

01:40:35.660 initially screen someone for their prostate cancer risk. And your PSA, if you're young, good numbers

01:40:43.480 remember for the listeners, median PSA for a 40-year-old, 0.5, median PSA for a 50-year-old, 1.

01:40:51.240 So if your number's over those medians, those age-adjusted medians, then you need to just

01:40:56.800 take action. Do you have to have a prostatectomy? No.

01:41:00.240 But then here's the problem. We talked about earlier, a lot of those guys are going to be on

01:41:03.300 5-alpha reductase inhibitors these days. And now those numbers become very difficult to interpret.

01:41:07.920 Yes, they do. They become difficult to interpret and difficult to follow. So if your numbers are

01:41:13.820 over those, then you should just consider a kind of annual or twice every other year intensive

01:41:19.980 follow-up. It doesn't mean that you have prostate cancer, but it means if you're over that median

01:41:24.320 that you have a much higher risk in your future, next 20 or 30 years of developing it. Again,

01:41:30.180 the issue is in young men who are on 5-alpha reductase inhibitors, their PSAs are going to be very,

01:41:35.240 very low and you may miss an early blip. As a somewhat sidebar, there's a great paper published

01:41:40.540 out of the group at UCSD looking at finasteride and dutasteride use in veterans. So it's a closed

01:41:47.840 access system. And they asked the question, is use of dutasteride and finasteride associated

01:41:53.480 with more prostate cancer lethalities? And it's hotly debated about whether or not the drugs actually

01:42:00.040 induce more aggressive cancers and result in that. But if you just take that as a

01:42:05.200 more public health issue, the answer was glaringly, yes, there was a huge increased risk of death

01:42:11.240 from prostate cancer in men on finasteride and dutasteride. Why? For the reason we talked about

01:42:16.820 neglect. You don't realize you're on it. You don't know your numbers are rising. Your internist has no

01:42:21.400 idea that your PSA of four isn't really four. It's 10 because you've been on the meds for 10 years.

01:42:26.380 We certainly don't know if 5-alpha reductase inhibition impacts prostate cancer biology.

01:42:32.240 But to our point about detection, it impedes detection. Yes. I think that there may be an

01:42:38.440 impact subtly on the biology, but that's less of a real general issue. It's really being a lack of

01:42:44.640 awareness of the biomarker that you use to screen for prostate cancer and the effect that dutasteride

01:42:50.940 or finasteride have on that biomarker. How many cases of prostate cancer are associated with

01:42:58.160 germline genes that we know are drivers, for example, the equivalent of a BRCA mutation in

01:43:04.100 breast cancer, or is it virtually all somatic mutation? It is very limited. So there are a class

01:43:11.360 of proteins, molecules that fix homologous recombination defects. And those HRD classes

01:43:20.420 of molecules include BRCA1 and BRCA2. The actual protein complex that fixes double-strand DNA breaks

01:43:27.440 is really, really big. So there's lots of different genes that fit within that protein complex that

01:43:33.060 fixes a double-strand break. That's what BRCA1 and BRCA2 do classically. But the most potent

01:43:38.960 of the different genes in that grouping of HRD molecules is BRCA2 for men. So individual men,

01:43:47.380 it's about 1% or less of the general population have a BRCA2 deficiency, BRCA1, BRCA2 deficiency.

01:43:55.940 Those men are at increased risk for developing breast cancer and prostate cancer. And in the case of

01:44:02.240 prostate cancer, if you develop prostate cancer, it's a more aggressive disease course, and you have to be

01:44:07.740 very, very careful with individuals who have that deficiency and have prostate cancer. But on average,

01:44:14.480 it's very rare, probably less than 2% of prostate cancer cases, localized prostate cancers diagnosed

01:44:22.020 are attributable to a germline genetic alteration. There are mutations in those same pathways

01:44:29.180 somatically seen within the tumor, right? Not in the germline, but in the tumor that are attributed

01:44:34.680 and related to cancer aggressiveness and progression of cancer. The classic one, in my opinion. So the

01:44:41.140 way I think about prostate cancer in very general terms is you can have localized prostate cancers.

01:44:46.580 These are these lower grade lesions on average. Localized prostate cancers with lethal potential,

01:44:52.000 so LCLP. You got a localized cancer with lethal potential. And in my mind, the general genetic

01:44:58.220 trait associated with that transition from localized to localized with lethal potential is something to

01:45:05.000 do with the P10-AKT pathway. And that doesn't mean that you have a lethal tumor if you have P10 loss.

01:45:11.600 In my mind, it begins to open up the book to say lots of other mischief and nonsense can go on within

01:45:17.520 the tumor. We know from lots of studies that if you have loss of P53, for example, that that's

01:45:24.160 associated with lethal prostate cancer. Amplification of MYC. Lethal cancer in general.

01:45:28.520 Yes, exactly. Amplification of MYC is another one.

01:45:31.840 Okay. So it's interesting. So basically between MYC and P53 and all of KRAS, I mean, I'm sure KRAS

01:45:38.020 is associated as well? Less so KRAS, but yes, those are classic markers of lethal cancers. And so

01:45:44.100 prostate is not immune to that as well. Got it. Okay. Let's talk a little bit about

01:45:48.300 non-genetic risk factors, or at least we can include sort of polygenic stuff that's embedded. So

01:45:53.760 one of the things I always remember from training, African-American men at a higher risk. Why?

01:45:58.240 No one knows. There's a great paper published by this scientist at USC, Chris Heyman. And they

01:46:04.800 looked at genomic risk through SNPs for individuals who did or did not develop prostate cancer. It was

01:46:10.940 like 235,000 guys, a ton of individuals. How did they know what SNPs to look at?

01:46:16.600 There's been lots of work in single nucleotide polymorphism and risk for prostate cancer. And then

01:46:21.440 this paper was a refreshed look at saying how many SNPs are actually out there associated with

01:46:26.200 risk of developing prostate cancer. And it's somewhere around 250 or 260. I don't know the

01:46:31.440 exact number, but there's a certain amount. So what they did was they developed a genomic risk

01:46:36.980 score based on how many SNPs you had and your likelihood or probability of developing prostate

01:46:43.380 cancer. And what they showed was that although there's no difference between SNP profiles in

01:46:50.820 men of African ancestry, because they could look genomically where their ancestry was, and

01:46:55.700 Caucasians or non-black men, there was an enrichment for that same group of SNPs in black men and

01:47:06.060 an enrichment in men who were diagnosed with prostate cancer at a young age. So why is it that there's

01:47:12.400 an enrichment of these different portfolio of SNPs in black men? And why is there enrichment in the

01:47:20.340 younger men? We don't know, but it doesn't appear as though the tumors are profoundly different from a

01:47:26.020 genomic perspective. And we've looked ourselves, we had a series of grants to look at, again, somatic

01:47:33.240 alterations in prostate tumors between black and white men with lethal tumors. We found a difference in the

01:47:39.920 cell cycle gene pathway, but again, these are single percentile differences. So what exactly is driving

01:47:46.520 the development of more prostate cancers in black men than white men is thought to be at this point kind

01:47:53.180 of environmental. So what is their exposure to epigenetic changes? What's their exposure to smoking?

01:48:00.700 It's in general in urban populations of black individuals, there's more smoking correlates with the

01:48:07.980 food deserts, all these different kinds of epigenetic factors.

01:48:12.620 I see. So it may not actually be hardwired.

01:48:15.920 It's not hardwired.

01:48:17.240 That's great news.

01:48:18.400 It is good news. And so, yes, I think people would bundle that under this kind of umbrella of social

01:48:23.880 determinants of health, but you can actually begin to really begin to connect those two ends of what

01:48:30.160 are the social determinants and then what is the impact on the SNPs and the epigenetic changes that occur.

01:48:35.900 So I think a great future project would be to take that and look at exposures. Think about it. Your

01:48:41.520 exposures in an environment with high smoke, high pollution, poor foods, and the epigenetic changes

01:48:48.660 that occur when you're having a surge in your testosterone in your 20s. That begins to hardwire

01:48:53.180 that person's cells for future development of prostate cancer. And that's kind of how I think about it now.

01:48:59.000 I spent a decade looking for the smoking gun, the heritable germline change. There are some out there,

01:49:06.180 but they're not very big guns. They're not big enough to be associated with that change. And so

01:49:11.320 this paper that Chris did and his team of, there's like 150 authors, his spectacular work,

01:49:16.660 really begins to provide more insight.

01:49:18.620 This is the UCSD group that led this?

01:49:20.980 USC.

01:49:22.020 Oh, USC.

01:49:22.780 USC. Chris Heyman is the last author and great publication.

01:49:26.920 We'll link to that paper.

01:49:28.260 So it gives you a sense of why are there different subpopulations of individuals

01:49:34.960 that have different risks. It's likely just enrichments for these single nucleotide polymorphism

01:49:41.400 changes, which by the way, if you look at that paper, if you had the highest, let's say,

01:49:47.800 decile or quartile of SNPs, you had about a five-fold increased risk of developing prostate cancer

01:49:54.400 compared to the average man, which is the same fold increase as if you're BRCA2 deficient.

01:50:02.220 So having a poor genomic risk score is just as potent as having deficiency in BRCA2,

01:50:10.180 which we know is not good.

01:50:11.800 And the penetrance of BRCA2 and BRCA1 for prostate cancer are how high? 80%-ish?

01:50:16.760 No, lifetime risk is less than that. A lifetime risk is somewhere on the order of 60 to 70%.

01:50:23.640 We would definitely do intensive screening for them, but it's not a guarantee.

01:50:27.940 Obviously, women that are...

01:50:29.680 Highly penetrant and at a very young age. That's not true for men in average.

01:50:33.800 It's not unreasonable for a woman to undergo a prophylactic mastectomy if she has a deficient

01:50:39.340 copy of the BRCA gene. Are any men considering prophylactic prostatectomy?

01:50:44.640 Not at this point. The difference is we have very powerful screening tools.

01:50:49.060 It gets back to Halstead versus Fisher.

01:50:51.200 And those screening tools work just as well in individuals who are BRCA deficient. So their

01:50:55.520 tumors may be more aggressive when they're diagnosed. But we have very powerful tools to

01:51:00.540 A, identify them early and B, monitor them once they're picked up. And so it doesn't necessarily

01:51:06.800 change that paradigm, which is different for breasts because you have to wait till you have

01:51:10.920 a visible lesion, which a visible lesion on mammogram is 40 or 50 million cells.

01:51:15.840 I would guess it's closer to a billion. A centimeter?

01:51:19.440 Well, we'll try to find something for the show notes. But yes, it's a ton of cells. Whereas we have

01:51:25.140 much better tools to look at that with the blood test.

01:51:27.940 And hopefully with breast cancer, we're going to see liquid biopsies and cell-free DNA

01:51:31.760 adding more to that resolution. As a biomarker, it definitely shows promise. I mean, there's lots

01:51:38.140 of those liquid things. It's not essential for our space because we have a very good one.

01:51:42.280 Another esoteric risk I kind of vaguely remember, and I don't know if I'm remembering it correctly,

01:51:47.320 is there an inverse relationship between the frequency of ejaculation and the development

01:51:52.160 of prostate cancer? Yeah, there's an epidemiologic study that shows that men who are ejaculating more

01:51:57.720 than 20 times a month, that there was a lower risk of developing prostate cancer in the

01:52:01.760 paper. The paper you're remembering is really the paper on that topic. It still exists.

01:52:06.200 How big was the hazard ratio? Is it worth paying attention to?

01:52:09.080 I don't remember because it's so old. To be honest, I've never thought about encouraging

01:52:12.720 increased ejaculation for the... As a preventative strategy.

01:52:16.680 I mean, it's not a bad idea. It's never occurred to me to kind of encourage that.

01:52:20.820 The idea isn't that prostatic stasis in the absence of ejaculation allows something to occur in

01:52:30.040 the prostate that leads to the development, either through the microenvironment or other genetic

01:52:36.620 issues. Point is, we have no further insight than that epidemiologic study that is...

01:52:41.120 But it's not a bad one. I think the converse would be horrific for men. Don't ejaculate because

01:52:45.320 it'll lower your risk of cancer. So it's kind of a win-win, right? That's how I think about it.

01:52:49.380 So let's talk about a couple other risk factors besides ancestry.

01:52:53.600 Which is huge. Bigger than many cancers.

01:52:57.240 Yes. So it's not just African-Americans, but anybody with West African ancestry is really

01:53:02.900 what is the most significant in that risk factor. And then there's other ones. So Ashkenazi Jewish

01:53:08.740 individuals have a much higher chance of harboring foundry mutations in BRCA1 and BRCA2.

01:53:14.780 So I always talk about ancestry and I talk about all cancer risks, right? When I'm taking a family

01:53:20.120 history, I say, what's your personal history of prostate cancer? And if you have a personal

01:53:24.680 history of prostate cancer, you're a father, uncle, or brother. So first degree relative.

01:53:30.180 Father, uncle, brother. Okay.

01:53:32.720 The number of individuals and the age that they were diagnosed, and we'll put a link in the show

01:53:37.420 note for the table, it increases your full risk of being diagnosed with prostate cancer significantly.

01:53:43.320 It doesn't mean you shouldn't have a prophylactic prostatectomy, but you should just have

01:53:47.600 intensive monitoring. What about grandfather?

01:53:50.660 Grandfather is not... If it skips the generation, it doesn't matter. So your grandfather has prostate

01:53:55.180 cancer, but your brother... It's not considered to be a family history of prostate.

01:54:00.220 Okay. What about grandfather and father? Is that worse than just father?

01:54:04.560 Father is the driver for that. Ancestry and then family history, and then individual patients. So smoking,

01:54:11.520 it is classically linked with lung cancer and classically linked with bladder cancer,

01:54:17.620 urothelial carcinoma. But smoking is associated with the development of more aggressive prostate

01:54:24.040 cancer. So not necessarily more prostate cancer, but when you get it, it's worse.

01:54:29.160 Yes. And at a younger age. The correlation is younger age onset, more aggressive cancer with...

01:54:34.640 What's the youngest patient you've ever seen with prostate cancer?

01:54:37.440 34. That is staggering to me. I would have never guessed that.

01:54:42.100 I'll never forget that gentleman. I have his picture in my brain.

01:54:45.940 He didn't survive?

01:54:47.080 We treated him. He's still alive now, but still, when you have a 34-year-old and his wife sitting

01:54:53.760 there going like, what? I've subsequently diagnosed young men with prostate cancer and then subsequently

01:55:00.840 treated their fathers. So they had their cancer before their father, which is also mind-boggling.

01:55:06.280 Tell me a little bit about this guy's case. Was there just some freak gene?

01:55:10.840 The youngest man, the 34-year-old, was early in my career at Hopkins where we had such a lack of

01:55:15.420 understanding of the genetic risks and so forth. So I would love to go back and pull his tumor and

01:55:20.320 just sequence the whole thing.

01:55:21.960 He presented how?

01:55:23.380 He wanted to get a $250 discount on his health insurance for the year. So he got a routine

01:55:27.500 screening through his work and they picked up a PSA that was like 10 and he's 34. And he wasn't from

01:55:33.340 an infection. But anything below what is freakish, 50?

01:55:38.160 So the median age of diagnosis for prostate cancer is 68. We would consider early prostate cancer,

01:55:44.720 which would be a criteria for doing genetic screening at around 50. So hereditary could

01:55:51.000 be young age of onset, so 50.

01:55:53.500 If I'm not mistaken, I believe type 2 diabetes and metabolic disease also increase the risk of

01:55:57.520 prostate cancer as it does breast cancer and endometrial cancer and a number of cancers.

01:56:02.240 And also the aggressiveness and likelihood and probability of recurrence. All the other things

01:56:07.280 really have never been fully supported with any decent follow-up studies. So these different

01:56:12.560 products in the skin of grape, broccoli, tomato.

01:56:16.940 Oh, you mean as preventive things?

01:56:18.960 They really haven't been linked with any real increased or decreased risk for developing prostate

01:56:24.220 cancer. So let's talk about the PSA a little bit because we've alluded to it a number of times.

01:56:29.280 So let's explain what it is, where it comes from, and more importantly, of course, how we use it.

01:56:34.360 Yeah. So PSA is a protein. It exists to aid in the liquefaction of semen. So it's produced by the

01:56:42.240 prostate. And if one were to measure PSA in semen, it would be very, very high. I always tell people,

01:56:49.660 if you looked at PSA in the semen, it would be, I don't know, 100,000 nanograms from a liter of

01:56:54.720 PSA in semen. It's designed to be there and it exists there to liquefy the semen to help in the

01:57:00.100 process of fertilization. It is not designed and it should not exist in the blood, but a certain

01:57:06.720 percentage of PSA made in prosthetic epithelial cells leaks into the bloodstream. And when we do a

01:57:13.960 PSA blood test, we're measuring the PSA that has leaked into the bloodstream from a prostatic

01:57:21.620 epithelial cell. Now, most of the PSA that leaks into the bloodstream is bound to other proteins.

01:57:31.220 Is that albumin mostly or sexoma binding globulin?

01:57:33.760 Alpha chymotryptin.

01:57:35.120 Oh, so it's its own separate binding protein.

01:57:37.300 Yeah. That's the most common protein that PSA binds to, but it can bind to a family of three or

01:57:42.760 four or five different.

01:57:43.980 But these are prostatic proteins.

01:57:45.640 Yeah. It's bound. Now, how much it's processed, because as you know, protein cells don't come out

01:57:51.120 finished. They grow into their final state and they grow by shrinking. They get things snipped off of

01:57:56.440 them as they're maturing and going through that process. As PSA is evolving in the normal kind of

01:58:02.680 development of its exocrine function, it gets snipped into smaller and smaller states. Fully processed PSA

01:58:09.820 can float around in the bloodstream freely. That's free PSA. So if you have a benign prosthetic

01:58:17.400 epithelial cell, a lot of its PSA will be fully processed and ready to go in the ejaculate, let's

01:58:23.580 just say. And if it leaks into the bloodstream, it can float around freely. You can measure it in an

01:58:28.500 assay and it's what we call free PSA. A lot of the unprocessed or incompletely processed PSAs bound

01:58:36.260 to protein. Alpha chymotryptin is the most common one. And that is what we would consider to be when

01:58:42.480 we do a measurement of when we're looking at total PSA, you're measuring mostly bound PSA and some

01:58:48.140 free PSA. And that ratio we use, you and I use in our practices to help discriminate against PSA

01:58:55.360 that's in the bloodstream that may have leaked from a cancer cell or may have leaked from a benign

01:59:02.160 epithelial cell. Now, there are other siblings of PSA that are also produced in prosthetic epithelial

01:59:10.560 cells. Of course, all in response to androgens. They're produced in those cells and they can also

01:59:17.100 leak into the bloodstream. And we use those in some advanced PSA-based blood testing as well. But in

01:59:23.600 general, when we are measuring PSA, we are measuring the amount of PSA, this protein, that's leaked from a

01:59:30.600 prostatic epithelial cell into the bloodstream. We can refine that value by saying how much is there

01:59:39.220 and how much is free. If we have high amounts of free PSA, 30%, for example, then we can have good

01:59:47.920 reassurance that most of the PSA in the blood that you're detecting is from benign cells. When most of

01:59:54.840 the PSA that you have in your blood is bound, very limited amounts of free PSA, that's a strong marker

02:00:02.240 that there's something going on, i.e. that cancer cells are leaking the PSA into the bloodstream.

02:00:08.140 Now, as I mentioned, you can also measure other byproducts, other types of free PSA or other sibling

02:00:15.320 molecules to PSA. PSA is called HK3 or human calocrine 3. You can measure, for example, how much

02:00:23.020 of human calocrine 2 is in the blood. And these are part of a more advanced PSA tests like the 4K score

02:00:29.880 or, for example, the prostate health index. These are both mathematical equations that predict

02:00:35.980 probability of aggressive cancers. But they're built off of looking at not just the PSA itself,

02:00:41.680 but the PSA and how much other types of process PSA exist as well.

02:00:47.460 Let's go back and talk a little bit about the free PSA. Does the amount of free PSA that we would

02:00:54.280 want to see to be more assured of a benign nature of the PSA vary by age and absolute PSA level?

02:01:03.660 Yes, it does. So we begin to use the free PSAs and the free PSA ratios and all those things

02:01:11.680 when PSAs have crossed over a certain threshold. If your PSA is 1, we can't even get a lab to check

02:01:18.040 a free PSA. That's right. Because we know if you're screening someone and your PSA is 1, then the

02:01:22.740 probability of a prostate cancer that's lethal is incredibly low. They don't have the assay set up

02:01:28.460 to check it. And oftentimes, or some labs will not do that secondary default testing unless it's over 4,

02:01:35.460 for example, or over 2.5. Our lab's set up to do everything at levels as low as 2. So you can get

02:01:41.920 them at lower levels. But in general, the idea is, well, if your PSA is below 2, the probability you

02:01:47.540 have a lethal prostate cancer is less than 1 in a million. So we don't have to worry about that

02:01:51.940 individual. And we really want to use the percent free PSA to discriminate individuals who have elevated

02:01:58.260 PSAs and having to discriminate between elevated because of BPH and elevated because of a cancer.

02:02:04.600 So yes, as you get older, your prostate enlarges. As we talked about, metabolic syndrome causes your

02:02:11.180 prostate in large part to grow just because of the T to E ratios. As you get older, your prostate gets

02:02:16.700 bigger. We begin to use that. As you get older and your prostate gets bigger, you can have a proportional

02:02:23.060 rise in total PSA in your bloodstream just because your prostate's bigger and it's leakier.

02:02:29.360 But you can easily tease that out by looking at the percent free PSA. So if the percent free PSA is

02:02:35.120 over 18 to 20, then you can be pretty well assured that that's likely not coming from some aggressive

02:02:42.260 bulky tumor. What about with prostatitis when we see these huge spikes? Everything goes up in those

02:02:47.780 cases. But does the free still remain disproportionately high? I don't use free PSA

02:02:53.220 in people because I'm tracking it. I'm literally looking for trends for coming back down to a new

02:02:57.400 baseline. So yeah. Okay. Let's talk about two other ways we use the PSA, the density and the velocity.

02:03:03.660 How do those work? As I mentioned, as you get older, your prostate on average gets bigger,

02:03:09.000 not for all men, but for many men. And when that happens, your PSA can concordantly rise because

02:03:14.440 it's just your prostate gets bigger and it gets equally leaky. So the PSA can kind of go up.

02:03:20.960 Now, what we look at is the ratio of the prostate, the PSA value to the prostate volume. And that,

02:03:28.080 as you alluded to, is called PSA density. And in general, when I educate patients, I tell them,

02:03:33.020 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.

02:03:42.140 So if your PSA is four and your prostate's 40 grams, which is about average size for a 60,

02:03:50.640 65 year old guy, that's a PSA density of 0.1. We know that that is correlated with a low risk of

02:03:57.080 having an aggressive prostate cancer. When I'm looking at someone's case, I want to know what

02:04:01.700 their PSA density is. If the PSA density in a young man, frankly, is more than 0.1, I get a little

02:04:07.800 worried. If on an average age person, if the PSA density is more than 0.15, I start saying,

02:04:14.000 let's do some additional testing. You put everything together. But yes, PSA density predicts

02:04:18.800 likelihood that you'd ever be diagnosed with prostate cancer. It predicts aggressiveness of

02:04:24.700 a cancer if you're diagnosed with it. And it actually predicts your outcome if you have a

02:04:28.640 prostate cancer. So the higher your PSA density, the more significant your disease will be.

02:04:33.620 So the faster it increases and the faster that your PSA rises, it is a canary in the coal mine

02:04:40.580 to say, hey, you need to do some additional evaluation. Now, it doesn't mean you have prostate

02:04:44.920 cancer because I often have, and we share patients where their PSA went from one to five, but we

02:04:51.500 tracked it and it came back down because they had a flare up or inflammation in their prostate

02:04:55.420 that made their PSA go. Sometimes we don't know why. Often we don't know why. But if you track it,

02:05:01.200 you can see that. So whenever somebody in general comes to see me with an elevated PSA, the first

02:05:06.680 thing I always do is just recheck it because there can be transient rises in the PSA. Now,

02:05:11.620 as you know, we have very similar practice. I don't just recheck the PSA. I always order advanced

02:05:16.580 PSA-based testing. What does that mean? That is testing that involves looking at the percent free

02:05:22.320 PSA and then other things like minus two pro PSA for the prostate health index test or the 4K score,

02:05:30.660 which basically looks at different calocrines and their ratios.

02:05:34.840 And you and I discussed these tests in great detail in the first podcast, so we can also refer

02:05:39.480 people back to those so that I won't make you re-explain them. It does surprise me that

02:05:45.020 the official screening guidelines for prostate cancer don't make any recommendation on the use

02:05:54.080 of PSA testing other than something benign like every patient should discuss this with their

02:06:00.040 physician, which is a real cop-out in my view of what we should be doing. Well, it depends on which

02:06:05.860 guideline you're looking at. This is the U.S. Preventative Task Force and the CDC, and there's

02:06:11.620 one other. Yeah, the American Cancer Society, the American Urology Society, and the National

02:06:16.260 Comprehensive Cancer Network, they're a little bit more progressive. They really suggest that you

02:06:21.520 should talk about the risks and the benefits of screening. They kind of skirt around the idea of,

02:06:26.020 well, how do you properly screen for AUA and American Cancer Society? Don't get into details

02:06:31.300 up front. They say, start the discussion with like, what's your potential risk for developing

02:06:35.640 prostate cancer? You can ascertain that with the family history. Again, if you're reading the AUA

02:06:41.340 guidelines or the American Cancer Society guidelines, you already have a leg up on the

02:06:44.780 average internist because an average internist is just looking at general things they learned in

02:06:49.920 med school or the U.S. Preventative Services Task Force, which is too general and too vague.

02:06:54.340 So I totally agree with you. I like and personally reference everybody to the National Comprehensive

02:06:59.500 Cancer Network's prostate cancer screening guideline. That basically says that every man at age 45 should

02:07:06.180 have a baseline PSA. Because as you mentioned, changes over time are key. They're critical.

02:07:11.440 And you want to know where you are in relationship to the median. So a 45-year-old man's median PSA

02:07:16.960 between 0.5 and 0.7, somewhere around there. Understand your median PSA. And then if your PSA is below

02:07:25.360 one, you can get rechecked in two to four years. But Ted, the test is free. It doesn't cost anything to do

02:07:33.240 a PSA. Why wouldn't we do this every single year? I guess the argument against it is that

02:07:39.260 there can be natural variations. If you're a smart physician, you're going to pick up that,

02:07:44.520 hey, there's natural variations. And if it goes up from 0.7 to 1.5, I'm going to recheck it and

02:07:50.660 it's still in a safe range. Isn't that all the more reason to do frequent testing if there's natural

02:07:54.900 variation? Because it also means that if you're testing infrequently, you're more likely in the

02:08:00.540 presence of natural variation to miss what the actual trend is. Think of the following thought

02:08:05.160 experiment. So I love doing the thought experiment. So my thought experiment with colorectal cancer is

02:08:09.780 imagine you had a low cost, zero risk colonoscopy that you could do on somebody every month.

02:08:18.400 Would you eliminate colorectal cancer? Yes. There'd be no such thing as colorectal cancer.

02:08:22.760 The third leading cause of cancer death is gone if you have that. Now, the reason we don't do that

02:08:28.420 is they're not free and they're not risk free. Well, similarly, imagine you had, just like we

02:08:34.180 have a continuous glucose monitor, a continuous PSA monitor, you could slap on somebody's arm

02:08:39.260 and you could for free basically measure their PSA over their lifetime. I would argue there would be

02:08:45.800 no such thing as lethal prostate cancer because provided you had the AI engine and the physician

02:08:51.680 to monitor this, you would know. Johnny rode his bike. Johnny had sex. Johnny had a prostate infection.

02:08:59.100 You would very quickly be able to pick up signal from noise. I don't disagree with you. It's just

02:09:03.800 a matter of how frequent, what is considered to be intensive PSA testing, right? Let's just say

02:09:08.960 annually, right? Well, annual PSA testing is very intensive. So all the trials that showed that

02:09:14.080 screening for prostate cancer with the PSA test, those trials that tested whether or not that

02:09:19.160 reduced deaths, which they showed it did by 20 to 25%, was PSA testing every two to four years.

02:09:25.620 So that's the baseline. But can we do better is my point. To your point, still the second leading

02:09:30.680 cause of cancer, death. It is. And the real question is, which we don't know the answer to,

02:09:36.280 is were those men that ended up dying of their prostate cancer offered early screening or not? We don't

02:09:42.400 know that. And then the other thing is with a little bit more of an investment in knowing prostate size,

02:09:48.220 if you could now get that prostate density. So now if you have from one blood measurement that costs

02:09:54.160 less than a pack of gum, you know, your PSA, you know, your free PSA, you know, your PSA density,

02:10:00.900 that's really powerful. Yeah. By the way, a 4k test is a thousand dollar test. You don't need to do it.

02:10:08.400 If you know PSA, free PSA, and PSA density. Pack of gum. Chicklets? Those three things.

02:10:16.660 Chicklets? Those three things. They're cheaper than a pack of gum. But yes, the PSA density is the more

02:10:21.880 expensive. But you can get that off an ultrasound. You can. It's free, basically. It's free.

02:10:25.960 People would argue that percent free PSA gives you some strong correlation between the size. So yes,

02:10:33.700 I totally agree with you. I'm just pushing back, Ted, because look, you and I want the same thing.

02:10:38.920 But look, there are certain things that I don't see a clear step on the horizon for the elimination.

02:10:45.080 I don't see an immediate step on the horizon for people not dying of pancreatic cancer.

02:10:50.620 I don't see, sadly, an immediate step on the horizon for people not dying, women specifically,

02:10:56.020 of breast cancer. But I sure as hell see, with the existing technology, a reason for people not to

02:11:04.500 be dying of colorectal cancer and men not to be dying of prostate cancer.

02:11:08.660 I mean, the deaths from prostate cancer with PSA screening have plummeted. So that's the one thing.

02:11:12.920 But it's still 35,000 men died last year. Question is, how many of them would have been

02:11:17.040 saved with a traditional screening? Yeah. And trust me, I'm trying to defend

02:11:20.960 the rule makers that made these rules that I was not involved with. But I would say that

02:11:25.180 this idea of baseline PSA testing at age 40 on a population health level, where that all came

02:11:31.500 about was from Bank Serum out of Sweden. And so they were able to model that pretty well

02:11:36.320 to understand what's your overall lifetime risk for developing or dying from prostate cancer.

02:11:41.200 If your PSA at age 40 or 50 is below the median, then your lifetime risk is very low, remember?

02:11:47.320 So we have some information about it. And the modelers, this is the best that they could come up with.

02:11:52.480 I'm not disagreeing with you. There's no reason in my mind why you should not get your PSA tested

02:11:57.800 at an early age, understand your baseline, and track it over time, which is what I do. And I think

02:12:03.200 you do too. The other lesson you and I have both witnessed personally is that patients need to take

02:12:10.100 ownership of this. We have both seen tragic cases where individuals who have no medical training,

02:12:18.380 but who listen to this podcast, for example, have diagnosed their own prostate cancer,

02:12:23.640 even when their physicians have said there's nothing wrong with you, based on advanced metrics,

02:12:28.740 such as PSA velocity and PSA density. And that to me is infuriating and heartwarming at the same time.

02:12:35.320 Yeah, I agree with you. And it's many of those cases that we share are not like the subtle

02:12:40.020 one of the thousand cases. They're like the ones that are like obvious. So I do think that patients can

02:12:45.540 own this, and this is a key part of their overall health. 100% agree with that. It's the mindset of

02:12:51.720 the individual patient that also matters, because there are some patients that don't want to be

02:12:56.620 proactive and progressive about how they monitor their health. Now, those are people who you probably

02:13:01.680 don't take care of at all, but I know sometimes I'll see them. And so, yes, we have to balance

02:13:06.980 knowing early with overreaction and kind of overtreatment of a potential issue that may

02:13:14.200 arise. So there's subtlety to it. Can it be done well? I believe it can be done well.

02:13:18.740 Well, let's now talk about that, because I think that if you look at people on the other side of

02:13:22.560 this discussion who are saying, come on, this PSA test, I mean, there are a lot of people out there

02:13:27.140 saying PSA should never be done. It's an awful test. It leads to a bunch of unnecessary misery for

02:13:32.140 men because they're getting unnecessary biopsies. Now, let's squash that nonsense. That might have

02:13:37.000 been true 50 years ago, but in the year 2023, in the hands of a competent physician, one step above

02:13:44.260 the parking lot attendant, that's categorically untrue. So today, let's talk about what we can do with an

02:13:51.540 MRI to check if we have suspicion based on these other blood-based biomarkers, what can we do to

02:14:00.160 increase the probability that if we actually go to the step of a biopsy, the probability is

02:14:05.480 sufficiently high that it was worth it? You just said it. You order an MRI, which is frankly like

02:14:11.060 surprising and appalling to me that I see second opinions in my office weekly that they never had

02:14:17.580 any pre-diagnostic, i.e. pre-biopsy MRI. It's absurd to me. When I leave work, I check on my Google

02:14:24.920 map if there was an accident on the expressway, and I change my course if there was. It's a test

02:14:30.520 that's approved by all insurances. It should be done before any biopsy, in my opinion. There's

02:14:35.260 really no case. Sure, if the patient's PSA is 1,000 and you just need a tissue diagnosis, okay,

02:14:41.420 let's not debate that. But for every man who's undergoing routine screening for their prostate cancer,

02:14:46.860 if they have an elevated PSA, they should get a reflex test, which includes, for sure,

02:14:52.120 percent free PSA, prostate health index, or 4K or other tests, depending on the cost.

02:14:57.920 And by the way, typically insurance will approve those if the PSA is over about five, right?

02:15:03.060 PSA over four for 4K score. Okay. But we get PHI testing in our lab. They do it for us. It's

02:15:10.320 covered by insurance at any value. It's well calibrated over two. So we do it over two. By the

02:15:16.940 way, what I'm telling you is based off of a prospective randomized trial published in the New England

02:15:20.920 Journal, where they use advanced PSA testing. They did not use 4K or PHI. They use Stockholm 3,

02:15:26.900 which is a European only test. Abnormal advanced PSA testing. Do an MRI. If the MRI has a suspicious

02:15:36.580 lesion, we'll talk about that in a second. Perform a biopsy, not just of the lesion, but of the whole

02:15:42.780 prostate. Reduce prostate biopsies by 50%. Enhanced detection of clinically significant disease by

02:15:50.760 11%. So hello, why are you not doing that? I don't know. But frankly, it happens all the time.

02:15:58.260 So what is it? Okay. The blood test we talked about, that provides more specificity to someone

02:16:04.960 with an elevated PSA who may have a problem. That's all I tell people. It tells us we need to do the next

02:16:10.760 step. That next step is a high resolution Google map of their prostate. That is a typically a 3T

02:16:18.280 MRI. So 3 Tesla. So 3 Tesla. Moderate power. Yes. And it doesn't need any endorectal coil or any

02:16:26.640 that. So a 3T magnet doing a prostate MRI because there are specific sequences and it's multi-parametric.

02:16:35.580 The key parameters that we look at, T2 images, you look at diffusion-weighted imaging and dynamic

02:16:42.760 contrast enhancement. Those are the three components of a multi-parametric MRI. However, there are great

02:16:49.020 radiologists, scientists, you're friends with one of them, Raj, who have and others have shown that you

02:16:55.460 don't necessarily need the contrast and that on average, a T2 and the diffusion-weighted imaging are

02:17:02.360 nearly as good, not identical, but nearly as good at evaluating the prostate for any risky lesions.

02:17:10.380 Now, is an MRI perfect? No, it misses prostate cancers. It will miss small, low-grade prostate

02:17:17.760 cancers. But like we'll talk about in a sec, that's not necessarily a bad thing. But that's how the test

02:17:23.320 works. It's done and it's a screening tool to help us identify bulky, higher-grade, higher-risk tumors.

02:17:30.360 Now, when you look at your MRI report, because as part of the 21st Century Cures Act, every patient

02:17:37.640 can look at their entire medical record, you'll see that they'll give you a good, well-done MRI. The

02:17:43.540 report should contain the size of the prostate. It's baked into our reports because when I came to

02:17:48.960 Chicago, I said, we're going to do PSA density. So you get the density. And then it tells you if

02:17:53.720 there's a suspicious lesion. And there's this degree of suspicion. It's called the RAD score,

02:17:59.680 the PI-RADS for prostate imaging RAD score. And it goes between one and five. One and two are

02:18:05.600 considered to be BPH lesions. They're not cancer. So really, we worry about RADs 3s, RADs 4s,

02:18:12.460 and RADs 5s. And in general, most recommendations would be if you have a RADs 3, 4, or 5 lesion in

02:18:20.400 your prostate, and you've never had a biopsy before, that you should consider a biopsy

02:18:24.720 that samples the spot and systematically, that would be what we call target, and systematically

02:18:30.760 samples the areas around the target, i.e. the peripheral zone in the area mapped around that

02:18:38.200 lesion. How easy is it for you to see this and make this determination? For example,

02:18:44.060 when you look at the MRI and you see the lesion in presumably the peripheral zone,

02:18:49.460 how easy is it for you to then go and actually physically do the biopsy and know that you've

02:18:55.240 hit it as opposed to miss it? Yeah, there's skill involved with doing an MRI-targeted biopsy.

02:19:01.000 Are you doing it under some sort of ultrasound guidance? Yes. So yeah, you have an ultrasound. So you

02:19:05.340 use an ultrasound, and ultrasounds are not great. Traditional standard ultrasounds, which are very

02:19:11.480 high resolution, are not great at identifying lesions with the efficiency that a MRI is. And

02:19:18.480 granted, they have time to think about and look at the images. So what we typically do is we take the

02:19:23.120 MRI images, and you either cognitively, i.e. with your brain, or with the computer assistance, overlay the

02:19:30.520 MRI and the suspicious area on the MRI with the real-time ultrasound. And is this a transrectal

02:19:37.440 ultrasound? Yes. And then you're biopsying right beside the... Well, that is how you overlay and you

02:19:43.880 associate the suspicious area on the MRI is with the transrectal ultrasound overlay. Now, you can do

02:19:50.860 the prostate biopsy one of two ways. One way is to, again, pass the needle right alongside the

02:19:58.360 ultrasound probe. That's a transrectal biopsy. Then you can follow the track of the needle as it goes in

02:20:05.980 alongside the ultrasound probe through the rectal mucosa into the prostate. It's a very effective way

02:20:10.700 to pick up prostate cancers. And the trial I talked about, that's the Stockholm 3 trial, that's the

02:20:15.640 technique that they used. Now, the limitation of doing that is you always introduce a small amount

02:20:21.780 of rectal flora, bacteria from your rectum, into the prostate when the needle passes from the rectum

02:20:27.700 into the prostate. Do men prophylactically take an antibiotic for that procedure? To prep for that

02:20:32.680 procedure, you'll do an enema to just decrease the volume of stool and bacteria in the rectum, and then

02:20:38.360 you also will take an antibiotic. And with modern antimicrobial prophylaxis, you can reduce

02:20:45.540 infection after prostate biopsy to around, depending on the series, between one and four percent.

02:20:53.540 Still pretty high.

02:20:55.100 Yeah. It can be real. I mean, if you're the one in a hundred or the four out of a hundred guys,

02:20:59.060 it's a real issue. Now, that's all types of infections. So, urosepsis, where you have, as we

02:21:05.620 talked about before, really severe with bacteria in your bloodstream, that's very rare. But infections

02:21:11.900 in general, between one and four percent. The other approach that you can use is you can do a

02:21:18.040 percutaneous biopsy. So, the ultrasound probes in the rectum, it's looking up at the prostate,

02:21:23.000 but the needle is inserted percutaneously through the skin in the space between the rectum and the

02:21:29.400 scrotum. So, that's usually around four to five centimeters of space. And in that space, you can

02:21:36.220 actually place a guide, percutaneous needle guide. And then from that, you can then actually target

02:21:44.020 the biopsy. So, in other words, you're not pulling the needle in and out each time.

02:21:48.320 You are.

02:21:49.020 Oh, you are.

02:21:49.480 You have a short needle guide, a trocar, that goes through the skin so you can establish your

02:21:54.200 trajectory. And then from there, you can, with ultrasound guidance, put the needle exactly into

02:21:59.320 the suspicious lesion.

02:22:00.820 The trocar stays in one time?

02:22:02.860 Yes.

02:22:03.200 Yeah. Okay. So, what's the drawback of that approach? Is it more difficult?

02:22:07.240 Yeah. So, one pass on the right and one pass on the left. The original way that we did prostate

02:22:12.620 biopsies was with a percutaneous approach. So, back in the old days, over 100 years ago,

02:22:17.440 if you had a suspicious bump on your prostate, you'd make an incision there and you'd cut it out.

02:22:22.940 That was the original way that they did prostatectomies as well.

02:22:25.840 That's right. Exactly. So, that approach to prostate has been long appreciated. However,

02:22:31.300 doing the prostate biopsy in a way that you could systematically sample the prostate with

02:22:36.980 that approach has historically been very morbid. Because what they would do is they would place

02:22:42.800 a grid, like every two millimeters, two millimeter by two millimeter grid, along the perineum. And

02:22:50.060 they would make between, let's say, 20 and 30 individual pokes into the perineum and into the

02:22:56.360 prostate. That was how you can deliver radioactive seeds or radioactive pellets. But that approach was

02:23:02.920 also used to do biopsies. That results in significant edema and swelling in the prostate

02:23:07.960 and significant bleeding. And urinary retention rates after that approach were very high, 15, 20%.

02:23:13.700 And it's very painful. You can't do it awake. Okay. So, there's a guy, Matt Alloway. He's a

02:23:21.280 Schaefer family friend. He is a urologist in Western Maryland. Very innovative guy. And he said,

02:23:27.440 there has to be a better way than doing transrectal, bringing bacteria into the prostate. And there has

02:23:33.480 to be a less painful way than doing this grid. So, he created this percutaneous approach where you can

02:23:39.060 basically have a single trocar on the right go through the skin, single trocar on the left go through

02:23:44.000 the skin, and you can navigate and sample all areas of the prostate. So, he's been doing this for a

02:23:48.120 decade now. And nod to him. He's an entrepreneurial guy. He created a company with his product.

02:23:53.560 And it's the gold standard for how you do that today. So, what percentage of your biopsies are

02:23:58.680 done with the trocar versus transrectally? I like the transperineal approach. But in a nod to just not

02:24:05.720 adopting things with closed eyes and saying it's better, we are in the midst of completing a 16

02:24:10.780 institution randomized trial that explores whether or not transperineal prostate biopsy is actually

02:24:18.080 better than transrectal prostate biopsy. And the primary endpoint is infection. So, as I mentioned,

02:24:25.860 modern contemporary infections with transrectal, between 1% and 4%. We think our approach to prevent

02:24:32.640 infections transrectally is very good, and we're probably more on the 1% range. When we do a

02:24:37.880 transperineal approach, and Matt Alloway has published a lot on this, you can do that without

02:24:41.840 any antibiotics. And the infection rate is less than 1 in 1,000. You're presumably powered to show

02:24:48.340 a difference in that direction. It's a lot. The power is hard. We had a power calculation. The NCI

02:24:53.880 reviewed our power calculations, and they said this is the appropriate power to detect a difference.

02:24:59.140 So, I think what will end up happening, and we're looking at the data right now, so I'm not going to

02:25:03.440 say. But my sense is we're going to have 0% infections in TP, transperineal prostate biopsy.

02:25:09.620 But will we have done enough transrectals to really statistically show a difference?

02:25:14.540 Will there be secondary outcomes that look at detection?

02:25:17.480 Yes. So, in my mind, if you have an approach that is 0% infections, I don't care if it's 1% or 2%.

02:25:24.360 Unless you're losing detection.

02:25:26.580 Yes. So, the other endpoints for the study are pain and side effects. As I mentioned,

02:25:31.260 transperineal biopsy with the old grit approach was 15% retention, meaning a catheter. Terrible.

02:25:38.260 So, we're looking at side effects. I think done properly, they're minimal. And then we use a lot

02:25:43.880 of medication to do our blocks. Like a pedendal nerve block?

02:25:49.020 Yeah, we do a pedendal nerve block, and we use lidocaine. And we don't just use any lidocaine,

02:25:53.120 we use buffered lidocaine. Because lidocaine, when it comes out of the vial, is a pH of about 5.

02:25:59.140 You put a little bicarb in?

02:26:00.800 Yeah. You know how you go to the doctor, they go pinching a burn? Well, what's the burn?

02:26:04.740 The pH.

02:26:05.280 pH. There's no more burn. You buffered lidocaine with the transperineal approach. We're looking

02:26:12.200 at the data now. I mean, there's some discomfort, but it's tolerable in the office awake. And then

02:26:17.780 the most important thing, of course, is cancer detection. So, we have 16 centers. There's two other

02:26:23.420 ongoing trials, not to just say that we're the only one. There's a trial out of a limited number of

02:26:27.780 centers out of Syracuse. They finish their study. They're looking to get their paper published.

02:26:33.860 And then there's a large paper publication, large study in the UK. But we're going to be the first

02:26:39.020 to publish a multi-center, large prospective trial. And it'll be interesting. I think that it will show

02:26:45.480 that, A, TP biopsies is 0%. It will show that they're slightly more uncomfortable. And then the

02:26:52.920 cancer detection, we have yet to fully analyze, but excited to do that.

02:26:56.860 Okay. So, let's talk about the different types of results that one gets from the biopsy. You've

02:27:01.860 already mentioned the word Gleason. Let's talk about what that means and how the scores are

02:27:06.160 determined and what the implications are. So, who needs a prostate biopsy? Somebody who has

02:27:11.720 abnormal blood testing, they go on to get an MRI. Now, that's our regular pathway. Who do we say

02:27:19.440 you don't need an MRI? Men who have bilateral hip replacements, an MRI is effectively useless.

02:27:25.460 So, we don't do an MRI for those individuals. We can calculate PSA density with an ultrasound,

02:27:31.340 and it's fast, it's cheap, it's effective. Otherwise, we have everyone go to an MRI. It's worth it.

02:27:37.640 Even with a single hip replacement?

02:27:39.220 Single hip, our radiologists are really good, and a good radiologist can read an MRI effectively with

02:27:44.020 a single hip. If somebody has profound anxiety and they need general anesthesia for something,

02:27:49.680 we'll be nuanced about whether or not we think an MRI may exist. But for the average person, 99.5%

02:27:55.560 of people, you get an MRI. Now, MRI shows a suspicious lesion. A RADS 3, 4, 5, you need a biopsy.

02:28:03.600 Independent of PSA density?

02:28:05.760 Independent of PSA density. If your MRI shows no lesion but a high PSA density,

02:28:14.540 so a young man, let's say under 60, that's a PSA density of more than 0.1 or 0.12.

02:28:19.660 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.

02:28:26.440 If you have a PSA density that's below that threshold, and you have a high PSA, low percent free, etc.,

02:28:34.120 you need a biopsy, in my opinion.

02:28:36.080 We're going to include, Ted, the slide that you shared with me a couple months ago that I still have,

02:28:42.800 I still look at it all the time now, which shows by PI-RADS, by PSA density, the outcome of biopsies,

02:28:52.240 and it's mind-boggling.

02:28:54.060 Yes. PSA density is a huge variable in terms of impacting probability of having cancer when you

02:29:00.660 sample a suspicious lesion and or the volume or bulk of that particular aggressiveness of that

02:29:06.800 particular lesion. So, RADS 3, 4, or 5, you need a biopsy unless your PSA density is incredibly low.

02:29:13.400 Like 0.02?

02:29:14.720 Yeah.

02:29:15.200 Which, by the way, patient...

02:29:16.660 Sometimes they have it, yes. So, there's never always, and there's never nevers in medicine.

02:29:21.360 But in general, that was what we would say. If you have a negative MRI and a high PSA density,

02:29:27.360 we will often suggest a biopsy for you. And if you have a negative MRI and a low PSA density,

02:29:33.480 we'll say you're likely can be monitored. We'll put in the show links a nice figure that illustrates

02:29:39.180 that from a large group of about 10 institutions pooling all of their MRI and biopsy data together.

02:29:46.820 However, I have the good fortune of having a partner who's a brilliant guy, Ashley Ross. He

02:29:52.040 analyzed and built a neural network real-time predictor for all patients, not just Northwestern

02:29:58.440 medicine patients, but we used all the Northwestern medicine patients in our system who had had

02:30:03.300 PHI, MRI, and a biopsy and looked at all their outcomes. So, there's some selection bias because

02:30:10.440 we didn't include people who didn't have a biopsy. But in general, we took all of these people

02:30:14.560 and we created a neural network real-time predictor for what's your absolute risk for

02:30:18.700 having prostate cancer in general, but more specifically, prostate cancers that would require

02:30:24.560 treatment. And that we'll put in the show links.

02:30:27.380 This is the model.

02:30:28.380 This is the MyNM risk calculator.

02:30:30.220 Okay. So, we'll make sure we link to that as well.

02:30:31.920 So, the figure is great because it just gives you an idea of a framework, but the actual

02:30:36.140 risk calculator gives the individual patient their individualized risk. So, he built it

02:30:40.760 off around 1,600, 1,700 MRI biopsy-linked cases, but now that has grown because it's always

02:30:47.300 learning. If you undergo a prostate biopsy, the answer is not just cancer, yes or no. There's

02:30:54.840 a lot of subtlety and a lot of things have changed about how we think about these different

02:30:58.560 cancers. So, I always explain to patients that it's basic effectively when a pathologist

02:31:04.540 looks at a biopsy sample under the microscope, they're describing the pattern of the cancer

02:31:10.680 gland. We talked about this at the beginning. The prostate is an exocrine gland that produces

02:31:16.580 semen. And there's an architecture of the gland or the duct that a normal prostate has.

02:31:22.680 So, think about like a branching tree. When you develop a cancer, it's an abnormally developed

02:31:28.220 branch. And so, the pathologist will score how abnormally developed that duct or that branch

02:31:34.860 is. And that score is what ends up being the Gleason score. Now, the pathologist tells us

02:31:42.220 if you have a cancer, what does the individual branch look like? What's the pattern? That would

02:31:47.500 be the Gleason pattern. And then the patterns today are pattern three, pattern four, and

02:31:52.880 pattern five. But what we get in the summation report is, well, how much pattern three cancer

02:31:59.320 do you have? How much pattern four cancer do you have? And how much pattern five cancer do

02:32:04.680 you have? And that's the Gleason sum, which also refers to the Gleason score. So, the common

02:32:10.780 ones would be three plus three equals six. That means that the pathologist only saw abnormal

02:32:17.800 glandular patterns that were pattern three. So, the pathologist is always reporting the

02:32:22.520 highest scores that they see? They're reporting the most common pattern they see first. That's

02:32:28.300 the first number. And then the second most common pattern of cancer that they see as number

02:32:33.760 two. And this is on both sides? Every single sample, they tell you the score. Okay. Typical number

02:32:39.620 of samples that should be done in a decent biopsy? It's 12 systematics. So, that's right

02:32:45.500 side, left side, kind of every five millimeters approach. Plus, you sample the target. And the

02:32:51.580 recommendation number of samples of a target is usually three. So, two is inadequate because

02:32:57.020 the needle can bend, it can deflect. Sometimes the needle is going in 20 centimeters beyond your

02:33:03.160 hand. So, you have to account for the deflection. And you can track it. But the idea is you do

02:33:08.640 it three times. I mean, talk about user error potential, right? Like, think about the difference

02:33:13.720 between you and me doing a prostate biopsy. I know you could do it better than me. It requires

02:33:19.880 skill. Even within the field of urology, there has to be a difference in skill. Yeah. And that's

02:33:26.300 what the training is part of. And Ashley and I actually host a course where we put on and train

02:33:30.840 anybody who's interested in how to do a proper, good, transparent prostate biopsy, for example.

02:33:35.980 Hopefully, this is just limited to physicians. Yeah. It'll be helpful. And obviously, there is

02:33:40.640 a skill involved with, and you can tell there's a skill involved with doing the biopsy and there's

02:33:45.020 a skill involved by the pathologist when they report it out. So, the requirements or the

02:33:49.080 recommendations are that you declare the Gleason score. That's the sum of the most common and the

02:33:55.600 second most common cancer. Now, presumably, some of these core samples come back with no cancer in

02:34:01.760 them. Is that just reported as nothing? They report no cancer. Okay. Got it. So, it's no cancer

02:34:06.280 or, at best, 3-3? Yes. There's some rare variants that are not cancer and they're not benign.

02:34:13.000 They'll tell us about them. That would be like prosthetic atypia. But that's uncommon,

02:34:18.240 especially in the era of MRI-targeted biopsies only. I wouldn't worry about that too much.

02:34:22.840 And you're biopsying only the peripheral zone? Well, we biopsy where the lesion is,

02:34:27.800 but most prostate cancers originate in the peripheral zone. But the 12 systematic biopsy

02:34:33.460 spots are peripheral zone. How thick is that, by the way? It depends on the size of the prostate.

02:34:38.220 So, in a young man, it's about 4 to 5 millimeters thick. In a guy who has a big prostate, let's say

02:34:45.980 100-gram prostate, the total peripheral zone volume does not change in a man over time.

02:34:53.080 Does that mean it actually gets thinner? It gets compressed and thinned out,

02:34:56.760 particularly if you have benign prosthetic overgrowth. Wow. So, it makes it harder to

02:35:01.280 biopsy. It makes it harder to biopsy. Absolutely. So, that's where a skill definitely plays a role.

02:35:06.280 So, you have to really understand what you're doing. Not to take away from breast biopsies and

02:35:10.420 things like that or a thyroid biopsy, but this is a totally different. Totally different. This is

02:35:13.960 much more complicated. In my opinion, yes, for sure. Sure, a thyroid or breast, you're trying to target

02:35:19.920 abnormal. But yes, there's a lot of subtlety to it. You have to know what you're doing. And yes,

02:35:24.880 the total peripheral zone volume remains the same over time. So, if your prostate size increases,

02:35:31.940 the thickness of that peripheral zone goes way down. Another way to just get this back to our

02:35:36.460 analogy is you're having to biopsy the skin of the orange. If it's a small orange, the skin is a

02:35:43.780 certain thickness, which is relatively thin. The bigger the orange gets, you have to preserve the

02:35:48.520 amount of skin so the skin gets thinner and thinner and thinner. That's right.

02:35:51.680 Okay. So, now what do you do with these Gleason scores?

02:35:54.800 So, you take a look at them and you say, what is the score? And then what's the distribution?

02:36:00.180 And that's the volume of the score. Because the two things matter in terms of determining what the

02:36:04.420 next steps for the patient are. In general, the way I talk through this with patients is,

02:36:09.480 did your biopsy demonstrate prostate cancer? And if it demonstrated prostate cancer, is it the kind

02:36:14.920 of prostate cancer that we need to treat right now? Or is it the kind of prostate cancer that we can

02:36:20.140 safely follow or monitor over time? Okay. So, let's start with patient comes in, both the lesion

02:36:27.660 and the periphery are 3-3. So, Gleason 6 prostate cancer, that's Gleason 3 plus 3 equals 6 prostate

02:36:36.440 cancer, is the least aggressive type of prostate cancer when you look at it under the microscope.

02:36:41.320 And it has a very favorable prognosis. Meaning, those prostate cancers, the thought process should

02:36:50.240 be, I need to find some data that will convince me that this cancer requires treatment. Because

02:36:56.620 the recommendation, on average, is that these cancers can be monitored. Now, what are the variables

02:37:02.780 that affect whether or not we think someone should have their cancer treated?

02:37:06.400 Sorry, just to make sure I understand that, Ted. Does that mean a 3 plus 3 can't spread or

02:37:12.540 metastasize unless it progresses to a 3-4, for example?

02:37:17.860 Excellent question. And that's been explored with one major caveat. That is that it's been

02:37:23.760 explored in surgical series.

02:37:25.560 There's a bias already introduced there.

02:37:27.860 Huge bias. But if you look at radical prostatectomy series in men who had Gleason 6 prostate cancer,

02:37:35.140 there's a large series by John Epstein at Hopkins and also Scott Egnor at University of Chicago,

02:37:39.900 they both showed that there was no lymph node metastasis in men with Gleason 6 prostate cancer.

02:37:46.340 Just make sure we understand that. Any man who underwent a prostatectomy with a Gleason 3 plus 3

02:37:51.840 had lymph node negative disease, and therefore, by extension, presumably, they never went on to get

02:37:58.200 metastatic. They never had a recurrence.

02:37:59.840 At the time of their surgery, never had...

02:38:03.540 So what's the longitudinal data on those folks? Do we know that they're free of disease?

02:38:07.520 Well, they do very well. The probability that they would die from prostate cancer is

02:38:11.260 very, very low, but they could have a local recurrence, for example, and that could result

02:38:15.960 in subsequent problems and need for additional secondary therapies. But on average, we know that

02:38:21.260 a Gleason 6 prostate cancer that is of low volume can be safely monitored.

02:38:26.920 But hang on a second. Why did those men have cancer surgery then?

02:38:30.240 Because we have evolved how we manage them.

02:38:32.540 I see. So based on those data, we now would be less likely...

02:38:35.320 That was the person that I operated on. We operated on at Hopkins when I was training,

02:38:39.200 where one core Gleason 6, we thought because they had a cancer that they required immediate treatment.

02:38:45.560 So this is now very different from the colorectal cancer model. In colorectal cancer,

02:38:50.880 you have an adenomatous polyp, it comes out. You have a carcinoma in situ, it comes out.

02:38:58.640 Yeah. The difference is because in the colorectal model, you can easily resect the adenomatous

02:39:04.100 polyp with minimum or no side effects done with a colonoscopy.

02:39:09.100 Yeah. It's the morbidity of the prostatectomy. Similarly in the breast, right? DCIS, it's coming

02:39:14.320 out. Debate whether we should radiate or not. But we treat pre-cancer so aggressively in these

02:39:20.640 other organs.

02:39:22.060 And that way, in the positive light of things, urologists have been very progressive and have

02:39:26.220 been at the forefront of doing surveillance for tumors that have not yet established or

02:39:32.540 declared that they have lethal potential.

02:39:34.400 So how often do you get a man, Ted, or maybe let me reframe it this way. For every hundred men who

02:39:41.460 you see who have a Gleason 3 plus 3, how many say, Dr. Schaefer, I understand what you just said about

02:39:48.460 the data. I don't want this thing in me. Take it out.

02:39:51.280 Yeah. I mean, it's rare that I will offer my surgical services to that person because

02:39:56.840 sometimes the patients don't fully understand what the potential ramifications for their side effects

02:40:02.580 may be. Meaning the surgical risks.

02:40:04.720 Yeah. Or radiation risks. So what I will do is I will jump through a lot of hoops to look for

02:40:10.740 reasons to reassure that that patient, that they do not have an aggressive lethal situation. And most of

02:40:17.100 the time we're successful. Now, a man is diagnosed with Gleason 6 prostate cancer. If it is of low volume,

02:40:24.600 let's call that between one and four cores, which is the most common thing that we would find.

02:40:29.780 One or four samples of a systematic biopsy, or if you target a lesion on the MRI, we consider it just

02:40:37.660 be one region. So if you did five samples of an MRI suspicious RADS4 lesion and all five samples came

02:40:44.680 out Gleason 6, we would just call that one area of visible cancer. In those situations, we generally

02:40:50.660 would say you are somebody who is a candidate who can have their prostate cancer followed because at this

02:40:57.100 time, your tumor does not have the lethal potential to spread to your lymph nodes or other parts of

02:41:03.100 your body and all kinds of therapy to treat it carry more morbidity than just leaving it in place and

02:41:10.480 just monitoring it. Yeah. It's amazing. And you're right. It's really precision medicine, but you have

02:41:16.020 to be both as the patient and the physician, you have to have a very high degree of certainty that you

02:41:22.400 didn't miss a four. That wasn't a three plus four. Patients will often say that to me. I will tell

02:41:28.000 them for the average patient, look, we don't just assume that you only had six. Although remember

02:41:34.760 with MRI targeted biopsies, we know the chances of reclassification or change in the grade of the

02:41:42.140 tumor at the time of prostatectomy is low, like 10%. Historically, when you and I were residents at

02:41:47.960 Hopkins, you'd have a guy like the Gleason 6 and he'd come out with the Gleason 8 because there was

02:41:52.280 no MRI and there was no MRI targeting. So the precision of the biopsy today is much better and

02:41:59.560 therefore we can provide much better assurance to the patient that, hey, the biopsy shows a six.

02:42:05.880 We got a pretty good idea. You just got a six. Again, doesn't mean that patients, we just assume that

02:42:12.060 they're going to be fine for the rest of their life. We do active intensive monitoring. That's PSA

02:42:17.360 testing every six months. I still believe that, like you were mentioning before, following that PSA

02:42:22.980 and if it changes closely is helpful. Do you repeat the MRI independent of a change in PSA in those

02:42:29.600 patients once they're a three plus three? I do. My general frequency would be that if they've had an

02:42:35.560 MRI pre-biopsy, then I'll track them. If they're PSA stable, I will not repeat the biopsy. We recommend

02:42:42.380 a confirmatory biopsy at one year. So you have low volume, low-grade prostate cancer. We check

02:42:48.000 your PSA at six months. It's stable. Everything looks good. Your MRI was not concerning. We'll do

02:42:53.740 a biopsy for you at one year. If you come in with low-grade prostate cancer like the patients we took

02:42:59.640 care of 25 years ago at Hopkins and you have not had an MRI before your biopsy, you immediately get an

02:43:05.360 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

02:43:11.060 there's a lesion that was missed. If on that MRI that I get after your initial diagnosis has a RADS

02:43:19.340 four or five, you go to immediate biopsy. If the MRI shows that you have a RADS three, but let's say

02:43:26.800 really, really high PSA density, like again, I have concerns that the biopsy quality was poor,

02:43:32.240 you go to immediate biopsy. So again, you want to do confirmation to establish your north is your true

02:43:38.120 north before you tell a patient, yes, 100% I endorse active surveillance. So we do a lot,

02:43:45.060 a lot of testing in these individual patients to make sure that when we're recommending surveillance,

02:43:51.120 we're recommending it for low-volume, low-grade prostate cancer. If you can answer this, all things

02:43:56.540 equal for 100 patients who show up with suspicious enough PSA that they buy an MRI, suspicious enough

02:44:06.200 RADS three, four, five, that they buy a biopsy, but now high degree of confidence, they're three plus

02:44:12.400 three, meaning they're down the active surveillance pathway. What percentage of those men, and I'm sure

02:44:18.320 it's age dependent, will go the rest of their life without a prostatectomy? I can't tell you the answer

02:44:24.820 to that, but I can tell you data that's 10 or 15 years out and five years out. So if you have

02:44:30.960 Gleason 6 prostate cancer and you enroll in active surveillance, the question of course is, well,

02:44:36.720 what would be the trigger to recommend a treatment? So it's effectively like your cancer is becoming

02:44:42.840 more aggressive or your tumor becomes bulky. So think about it those two ways. The chances that

02:44:49.720 you would have a more aggressive cancer develop in the first five years of surveillance is 12.5%.

02:44:55.040 By the way, is that independence of whether you were RADS 3, 4, 5? We didn't really talk about that.

02:44:59.520 It's all comers. All comers. This is Ballantine Carter's active surveillance cohort from Johns

02:45:05.700 Hopkins. From Hopkins. 1996, he started it. 12.5% chance that you'd have a change in the grade of

02:45:13.320 your cancer. Overall, about 30 to 35% of men in the first five years of entering surveillance will go

02:45:21.920 on to subsequently have definitive treatment. About 12.5% of guys, it's because there's a change in the

02:45:29.060 grade. It becomes more aggressive looking. And the other guys, a variety of factors. They have

02:45:33.740 increasing bulkiness of their tumor. They may develop concomitant urinary symptoms, and they

02:45:39.060 want it all addressed at one time, et cetera, et cetera. In general, I tell people it's 12.5% chance

02:45:44.600 that you really need to do something because there's a change in the grade. That's pretty steady

02:45:49.500 and pretty consistent. It's around 2%, 3% risk annually. That holds for 10 years as well.

02:45:56.500 Meaning you add 2% or 3% per year after five.

02:45:59.580 Yeah.

02:45:59.900 So you're up to 22, 25.

02:46:02.040 But overall, if I told people there's a one in five chance that your tumor will become more

02:46:07.120 aggressive over the next 10 years of your life and you need treatment.

02:46:09.960 Yeah. They'd sit on that. Especially because you're not saying go away and we'll only see you

02:46:16.020 again when you're in trouble. It's like, we're going to watch that progress.

02:46:19.340 That's right. And what's the chance that a cancer progresses in surveillance to be uncurable?

02:46:24.840 It's 0.1%. So one in a thousand guys who you're monitoring would have a Fisherian event.

02:46:33.600 Wow.

02:46:34.700 That's Bal Carter's data. Ballantyne Carter out of Johns Hopkins. It has changed how we treat

02:46:40.100 and think about prostate cancer from when we were training there to now.

02:46:44.680 So let's talk about the Gleason 7s.

02:46:47.780 A pathologist will tell us what they see under the microscope. How much pattern 3 do you have?

02:46:51.740 How much pattern 4 you have? And if you have pattern 5, do you have it?

02:46:55.340 So a Gleason 7, as you said, again, the Gleason score is a Gleason sum and it tells how much pattern

02:47:02.740 3 and how much pattern 4 do you have? So it is a blended scotch, not a single malt or whatever they call it.

02:47:10.100 And the blend is what matters the most. How much pattern 4 you have particularly is the most

02:47:15.820 important factor. So you can have as little as less than 5% pattern 4 and as much as 99% pattern 4.

02:47:24.060 If you have 100% pattern 4, you don't have a Gleason 7, you have an 8. So when I look at a pathology

02:47:31.060 report, I look at what is the percentage of pattern 4 there. It tells me two things. One,

02:47:38.520 how good was the pathologist who read it? Because if he's not telling me percent pattern 4,

02:47:43.980 I don't believe anything he's telling me. And two, if it's there, how much percent pattern 4 you have,

02:47:50.380 not just by percentage, but millimeters. So I'll look at how long is the tumor.

02:47:55.880 Remember, our biopsy needle is 15 millimeters long.

02:47:59.340 What gauge?

02:47:59.820 It's a true cut biopsy around 18, 16 gauge. It's not a small, it's a decent size sample.

02:48:07.340 Length of the tumor. And then I translate, well, how much of that length is percent pattern 4?

02:48:12.640 So if I have a patient who has a single biopsy core that has 10% prostate cancer, that's 1.5 millimeters

02:48:22.240 of prostate cancer, that, and he has 5% pattern 4. Think about how little disease that is that has

02:48:30.080 potential issues with lethality. What I do with that sample is I send it off to Verisite for decipher

02:48:36.400 testing. And I have them look because about 70% of the time, those small volume Gleason 7 tumors

02:48:44.460 genomically are minimally aggressive. I want to delineate that.

02:48:48.960 So they behave more like the 6s.

02:48:50.800 They behave like a 6. But if you have more millimeters of pattern 4, the more millimeters

02:48:57.940 of pattern 4 you have in your biopsy in total, in sum, the more that would push you to do treatment.

02:49:03.640 So, big picture, if you're exclusively pattern 3 disease, on average we think surveillance

02:49:11.080 until proven otherwise. If you have a smidge of pattern 4, I'm talking about 1 millimeter,

02:49:17.000 2 millimeters in total. We think, okay, maybe surveillance would work for this person.

02:49:22.040 We have a very thorough detailed discussion, age, other issues in their life, et cetera, et cetera.

02:49:27.960 We determine, okay, life expectancy. So if you're 75 and you have 2 millimeters of pattern 4,

02:49:33.620 4 and you're an average U.S. male, maybe you don't need to aggressively treat at that time.

02:49:39.120 You need to aggressively monitor, but don't need aggressive treatment. That's the subtlety to it.

02:49:43.360 But the higher the percentage of pattern 4 you have, and therefore, on average, the more millimeters

02:49:48.680 of pattern 4 you have, the more you're going to be talking about active treatment. So that's the

02:49:54.140 essence of how much prostate cancer management has changed in the last five years.

02:49:57.940 A Gleason 7 that needs treatment is a perfect surgical candidate.

02:50:04.260 Yes.

02:50:04.960 What about a Gleason 8? Now, by definition, every single thing that is looked at is 4. Is there

02:50:11.020 such a thing as a 3-5?

02:50:12.360 There is a 3-5. The science geeks have looked at it. Effectively, it behaves like a 4-4-8.

02:50:18.040 You treat them all the same, and you treat anything that's an 8 or higher the same way. So you

02:50:23.660 can have a only pattern 4. You can have a only pattern 4. You can have a pattern 4 plus pattern

02:50:31.460 5. That would be a Gleason 9. Okay, you can have a 10. That's pretty rare, but pretty bad.

02:50:36.640 And actually, if you're pattern 4, 3, 7, so if you're more than 50% pattern 4, your Gleason 4 plus 3

02:50:45.440 equals 7, we generally bundle those together with the 8s and the 9s. You have a lot of pattern 4.

02:50:51.600 You need treatment. And then the discussion becomes whether or not single modality treatment

02:50:58.540 is effective at treating and curing that individual man of their prostate cancer.

02:51:05.060 We're talking about the Gleason 8 on average.

02:51:07.180 Yes. Why? Because the analogy I always use is like a dandelion weed on your front lawn.

02:51:13.580 The higher the Gleason score, the higher the probability that that person can have deep roots

02:51:18.540 in their tumor, extending outside the prostate, potentially into the perirectal fat and beyond.

02:51:24.100 And additionally, you have a higher probability that that dandelion can go to seed and those

02:51:29.300 seeds can float off to the lymph nodes. When you have a higher grade prostate cancer, you

02:51:34.280 need to do a couple different things in your workup. The thing that you need to do, the one

02:51:39.040 key thing is to do a PET PSMA scan. PSMA is a prostate-specific antigen, prostate-specific

02:51:47.380 membrane antigen, particularly, that is enriched in its expression in prostate cancer cells.

02:51:54.180 And it is the most sensitive and specific way to determine the extent of a person who has

02:51:59.620 high-grade prostate cancer's disease.

02:52:02.320 So in other words, it's a PET scan, but instead of using FDG, it uses...

02:52:08.040 PSMA, specific radioligand, because prostate tumors are not FDG-avid.

02:52:12.680 So it's a functional metabolic test as well.

02:52:16.760 You stage somebody's prostate cancer with a PSMA scan, and then from there, you develop

02:52:21.640 a treatment plan. On average, if you have prostate area only, let's just call it prostate only,

02:52:27.940 could be extra-prostatic, but prostate only, or prostate plus lymph nodes, then you have to

02:52:33.620 start thinking about your initial definitive therapy and potentially multimodal therapies

02:52:40.500 to aggressively treat an aggressive lesion. So depending on the patient, their age, the bulk

02:52:47.700 of their tumor, et cetera, I will talk to people about radical prostatectomy as an option for them.

02:52:53.440 There are a select group of people, let's call it 20 to 25 percent of my surgical practice,

02:52:58.640 that presents with very bulky, potentially super bulky aggressive lesions. In those individuals,

02:53:05.440 I'll have an upfront conversation that I don't think that surgery alone will be effective at

02:53:10.860 completely curing you of your prostate cancer, but vis-a-vis breast cancer treatment, colorectal

02:53:16.720 cancer treatment, surgery is an important component of your initial therapy, and we'll do surgery,

02:53:22.400 and we'll follow that up with a radiation-based approach.

02:53:25.380 And that patient that you're describing, they have bulky tumor, but the PET scan doesn't reveal

02:53:31.880 any activity in the bone?

02:53:33.400 Correct.

02:53:34.080 Does prostate cancer metastasize to places outside of the bone besides local invasion?

02:53:39.080 Lymph nodes is the most common place it would metastasize.

02:53:41.560 Within the basin?

02:53:42.700 Yes, it follows a Halsteadian trajectory most of the time.

02:53:47.160 But does it follow para-aortic lymph nodes the way testicular does?

02:53:50.640 Yeah.

02:53:50.920 So it can go to lung?

02:53:51.820 It can be in the thoracic cavity, yes, metastinum, supraclavicular. So yeah, and then it will

02:53:57.600 go to bone.

02:53:58.480 Why bone?

02:53:59.920 The microenvironment of the bone, it's thought to mimic the microenvironment of the prostate.

02:54:05.540 Are there androgen receptors there?

02:54:07.300 No, but the milieu that the other growth factors that prostates may need to grow are there,

02:54:12.780 number one. Number two, as you know, the bone marrow filters all your blood. So if you have

02:54:17.680 circulating tumor cells, they're going to be trapped.

02:54:20.380 But isn't it interesting how few cancers do that besides breast and prostate? Think about

02:54:26.660 colon cancer, pancreatic cancer, I mean, all of these other cancers.

02:54:30.840 Yeah. I mean, the colon one, I think, is that we just pick up advanced colon cancers while

02:54:34.940 they're trapped in their kind of mesenteric blood spread, right? So you're picking them

02:54:39.360 up regionally more.

02:54:40.760 Yeah, you're right. It might just be that the colon is so concentrated towards the liver.

02:54:44.700 Yeah. I mean, the load of circulating tumor cells in colon are filtered by the liver.

02:54:52.180 Yeah. But again, it's not uncommon to see colon go to lung.

02:54:55.160 Yeah. Prostate goes to lung. Prostate goes just everywhere else. But yes, it is true.

02:55:00.240 Lymph node is the most common site of metastasis. And then effectively equivalent or just in a

02:55:04.860 close second is bone.

02:55:05.920 From a staging perspective, do we use typical TNM staging for prostate cancer? And if so,

02:55:12.400 if it's only in the lymph nodes, is it considered...

02:55:15.560 It's considered stage four. For AJCC, that would be stage four at diagnosis if it's in pelvic lymph

02:55:21.500 nodes.

02:55:22.240 Is that considered M0 or M1?

02:55:24.040 We call that regional.

02:55:25.420 Yeah. But it's stage four.

02:55:26.560 Yeah. It's scary to have someone have stage four, but prostate cancer in the pelvic lymph

02:55:31.160 nodes is still curable.

02:55:32.540 How curable?

02:55:33.100 So the devil's in the details. The big differences in prostate cancer overall for the listeners,

02:55:39.080 96, 95, 96% of prostate cancers are diagnosed when they're localized. Okay. Then there are

02:55:45.460 people who have N1 disease and M1 disease, and you can have M1A, M1B. It's just the extent

02:55:51.780 of the metastasis. If you have lymph node only disease, it's rare, but if it's picked up at

02:55:58.760 the time of your initial diagnosis, it's less curable than if you subsequently develop lymph

02:56:04.140 node disease in your follow-up and your survivorship monitoring. In general, I would say that vast

02:56:11.180 majority of people who have lymph node only disease can live 10 years. And are they cured

02:56:17.020 or not? That's debatable. We have this blood test that tells us exactly what's going on,

02:56:21.340 but they can live 10 years.

02:56:23.000 And the treatment is prostatectomy plus radiation?

02:56:25.760 The best treatment, if you look at the data, there's never been a randomized trial that explores

02:56:29.780 which one's better, but the best way to control lymph node disease is probably with radiation.

02:56:35.380 Now, I think about what's the role of surgery in this space. The role of surgery is to debulk

02:56:41.240 the bulky tumor. As we talked about, a lymph node med is probably 40 or 50 million cells at a minimum.

02:56:46.160 And so why not enable the radiation to be more effective by just debulking it? On average,

02:56:52.180 radiation is more effective at controlling that local disease extent than is surgery.

02:56:57.560 The morbidity of radiation is not trivial, not just from the nausea and the sickness that can come

02:57:05.200 from the treatment, but at least in the few cases I've seen of patients many years out,

02:57:10.560 the rectal bleeding that normally gets better, but not always, right?

02:57:14.680 Yeah. The main side effects when you're considering treatment with radiation would be urinary,

02:57:20.880 sexual, and then kind of GI. And GI meaning rectal, rectal irritation, rectal bleeding.

02:57:26.820 The urinary side effects with radiation on average are kind of burning the prostate. So you're going

02:57:32.220 to have these lower urinary tract symptoms that we talked about at the beginning of the podcast.

02:57:36.020 They're always intensified and amplified. They typically persist for the duration of the

02:57:41.560 treatment plus about a two month lag after that. The rectal side effects that you're describing,

02:57:47.560 I think are mostly historical. Why? There's a lot of new technologies that have been used to really

02:57:53.420 minimize that. So you can put in place with the percutaneous approach. Like we talked about for

02:57:58.500 the biopsies, you can percutaneously deposit gel, hydrogel. When it warms up, it thickens. You put it in the

02:58:06.840 plane between the prostate and the rectum, and you elevate the prostate between five and 10 millimeters

02:58:12.760 off the rectal wall. And it gives the radiation oncologist this window to radiate the prostate

02:58:19.020 effectively without damaging the rectum. And it reduces side effects substantially. Now, the other

02:58:26.920 newest and most exciting kind of way to deliver radiation is with MRI guidance. So remember, historically,

02:58:33.840 you are placing fiducial little gold seeds and you'd line up the radiation and you just assume it was

02:58:40.900 going to hit the prostate most of the time. And then we've developed CT guided radiation where you do a

02:58:47.460 quick CT scan. And for that day, you line up the radiation fields with the CT scan, but it's not real

02:58:54.920 time. Now there is MRI guided prostate radiation. So again, we do MRIs to see prostate cancers.

02:59:03.760 Because it's way more resolution, not CT scans. So you can theoretically resolve to the prostate much

02:59:10.440 better. And now there's a single MRI guided linear accelerator that does intrafractional

02:59:16.820 modifications of the dosage based on subtle movements. So if you take a deep breath, or there's a little

02:59:24.120 rectal gas, it will capture it within between the fractions of radiation delivered and alter the

02:59:30.340 trajectory of the beam. There's a trial called the Mirage study. It was done at UCLA. And they showed

02:59:37.060 that there was almost zero rectal side effects from it. The other really, really cool thing about

02:59:42.100 radiation is that when you have an MRI and you have a big RADS lesion, let's say you got a RADS 4,

02:59:48.360 RADS 5, you theoretically can boost that lesion with tremendous precision if you have MRI guided

02:59:56.140 linear accelerator. Because it's so visible on MRI. Yeah. The field of radiation oncology is evolving

03:00:02.040 and they're doing a lot of spectacular things. One, this kind of real-time gating is huge. Two,

03:00:09.860 using and boosting the MRI visible lesions is, I think, huge from a cancer control perspective.

03:00:15.420 And then from a patient morbidity perspective, because the MRI linear accelerators are very expensive.

03:00:20.920 We have one, but they're not widely available. You can do this space OAR. That's the gel that

03:00:26.780 basically separates the prostate from the rectum. And that's been shown to reduce the toxicity of

03:00:32.040 radiation treatment a lot. It's good. You know what? It raises the field and the competition for us to

03:00:38.220 think about ways to do better, less morbid prostatectomies. I guess to close the loop on

03:00:42.860 that, let's talk about systemic therapy. The mainstay of this is androgen deprivation therapy.

03:00:48.380 We've already talked about the morbidity of that. Are there other synthetic agents? Are there any

03:00:54.620 things that are looking promising on the immunotherapy front? We're seeing an enormous

03:00:58.940 surge of that on the side of other epithelial tumors. Let's talk about the first thing, which is

03:01:04.320 when you're doing localized therapy, we do think about utilizing androgen deprivation therapy as a

03:01:10.960 radiation sensitizer. So it is known that when you have a higher grade tumor, let's just say you have

03:01:16.840 a Gleason 8 or 9 like we talked about, that radiation alone is not going to effectively cure

03:01:21.840 that patient of their prostate cancer. You need to deliver, and we know you can deliver radiation

03:01:26.460 sensitization with androgen deprivation. Androgen deprivation induces double-strand DNA breaks.

03:01:32.980 That's the whole purpose of radiation itself is to induce those breaks.

03:01:37.460 So in other words, androgen deprivation makes the cells even more susceptible to the radiation.

03:01:42.140 So we use that routinely. And one of the things that the radonks have to work on and they're doing,

03:01:47.000 there's a series of trials right now exploring this, is either intensifying the androgen deprivation

03:01:53.500 in cases that are very aggressive or de-intensifying androgen deprivation in cases that maybe that the

03:02:00.060 patient would not benefit from it. And the way that they're determining that is with the Decipher test.

03:02:05.320 So we use androgen deprivation therapy typically in two spaces. One, to augment and enhance the results

03:02:14.100 of radiation-based treatments. And two, in individuals who have more advanced prostate cancers.

03:02:20.680 So for individuals who are considering are going to have radiation for their localized or locally

03:02:26.880 aggressive prostate cancers, they will often get that with a course of androgen deprivation.

03:02:32.700 And the course of androgen deprivation typically ranges between six and 24 months, depending on

03:02:39.420 the bulk of the tumor and the aggressiveness or Gleason score of the tumor. That ADT was typically

03:02:45.040 delivered with an LH-RH agonist. So you would give an LH-RH agonist. First, you get a surgeon

03:02:52.940 testosterone, then it shuts the system down. The problem with that is that it is given as a depot that

03:03:00.220 lasts a long time. It's helpful for the patient. But the probability that the patient would ever

03:03:05.220 recover normal testosterone is very low. Why is that? Because of the long-term effects

03:03:12.580 on the hypothalamic pituitary axis. It just gets shut down. And or because, as you know,

03:03:19.280 in the aging male that... It's fragile to begin with.

03:03:21.580 It's fragile to begin with. The good news for men who are getting ADT short course is that there are

03:03:26.860 oral LH-RH antagonists that are out there. And so they're a pill, so their half-life is much shorter.

03:03:34.420 And they have been shown to effectively suppress testosterone to the same levels as an LH-RH

03:03:40.500 agonist. But their half-life is so short that people can have a rapid testosterone recovery.

03:03:46.660 And they do. So for people who are going to get radiation treatment who need a radiation

03:03:51.960 sensitizer with ADT, we will typically use an oral LH-RH antagonist because it's rapid on and rapid

03:03:58.720 off. So good news for those individuals. For individuals who are diagnosed with prostate

03:04:04.400 cancer that progresses to a metastatic state, or individuals who are diagnosed with prostate

03:04:10.160 cancer that's metastatic at the time of diagnosis, those individuals need to go on systemic therapy.

03:04:15.660 And the mainstay of systemic therapy is androgen deprivation, or ADT. That is based off of Nobel

03:04:22.420 Prize-winning work from Charles Huggins out of University of Chicago. That mainstay of therapy

03:04:26.820 has not changed. What has changed is the synthetic molecules that we use in addition to traditional

03:04:34.060 LH-RH agonists or antagonists to further suppress testosterone levels. And the two main classes of those

03:04:41.800 are CYP-17 inhibitors. That's a molecule called abiraterone. So as you alluded to,

03:04:48.640 androgens are made from cholesterol molecules, and you can inhibit a specific enzyme in the

03:04:53.960 androgenic pathway, CYP-17, and you can then prevent production of not just testosterone,

03:05:00.980 but other androgens. Not just in the testicle, but within the adrenal glands and systemically.

03:05:06.560 And it results in a more profound, deeper suppression of testosterone androgen production.

03:05:12.820 That is now recommended as first-line therapy for people with metastatic prostate cancer.

03:05:20.440 What's the median survival for men diagnosed with metastatic cancer to bone? Let's talk about

03:05:27.240 distant metastases with and without ADT. What I'm really getting at is, given the morbidity of ADT,

03:05:35.520 are there men who say, okay, my median survival, if I do nothing, is 12 months versus my median

03:05:43.380 survival is 16 months if I do ADT. It might not be worth an extra four months of life if I have to

03:05:49.260 live sans androgens. The median survival for someone with newly diagnosed prostate cancer that

03:05:54.280 refuses treatment is probably on the order of two to three years. The median survival for somebody who

03:06:02.080 goes on traditional ADT-only, LHRH, agonist, antagonist, is between 48 and 50 months. So you

03:06:09.800 can double it. You can add a year to two years of life. Yes, but it's also the quality of the life

03:06:15.120 of the individual. There are effects that occur in terms of the impact on metabolic syndrome and

03:06:22.380 overall health. But remember, when prostate cancer is metastatic, it starts taking over your bone marrow.

03:06:27.140 You can develop aplastic anemia. I mean, it's brutal. So if you can mitigate that.

03:06:32.440 How do men die? What are the final stages of life?

03:06:35.480 Pathologic fracture, aplastic anemia because of bone marrow replacement. So it's other organ

03:06:41.500 dysfunction because the tumor takes over for it. Reno failure is a classic one too from local tumors.

03:06:47.940 And tumor lysis and things like that.

03:06:49.480 Yeah. Ballpark, you can effectively extend the life of a patient if they're diagnosed with

03:06:54.860 metastatic cancer by about two to three years by going on ADT. The new agents, meaning abiraterone

03:07:01.800 or this other class of agents, which are competitive binders of androgen receptors. So they will bind

03:07:08.300 androgen receptor, tether it in the cytosol and prevent it, the ligand binding domain from binding the

03:07:15.300 DNA in the nucleus, among other mechanisms. Those are things like enzalutamide, apalutamide,

03:07:21.660 and darolutamide. They're related. They're much more evolved cousins to finasteride and dutasteride,

03:07:28.120 but they're very potent. So there's abiraterone. And then there's another class of novel hormonal

03:07:34.380 therapies, the amides, enza, daro, and apa. They will effectively extend the life of a patient

03:07:41.060 in an additional 24 months on average compared to just traditional ADT alone.

03:07:45.860 And they're done in concert?

03:07:47.040 They're done together. Correct. So now if you have someone with newly diagnosed metastatic

03:07:51.680 prostate cancer, median survivals are seven to eight years, which is good. Now it depends a little bit

03:07:58.480 on the situation that they're diagnosed with cancer in. So if you're newly diagnosed de novo metastatic

03:08:05.720 versus you had your prostate cancer treated, and then you develop metastatic, those two men have

03:08:13.220 different outcomes. The men who are newly diagnosed de novo, they have a much shorter life expectancy,

03:08:20.000 three to five years compared to somebody who already had their cancer treated. It progressed to

03:08:26.360 the bone or the lymph nodes. They have a much longer life expectancy on average, probably because of bulk

03:08:33.060 of disease and somewhat lead time bias in terms of the detection. So those are traditional androgen

03:08:39.520 deprivation. Then you have novel hormonal therapies. They're always evolving newer ones. The amides,

03:08:45.740 they have some toxicities. Enzalutamide and apalutamide, they have issues with seizures. They have

03:08:52.760 issues with overall sleepiness and kind of alertness. And so they're real. Their alutamide, which is the

03:08:59.440 newest agent in that family, is much cleaner. There's less cognitive effect of it since it doesn't

03:09:05.980 cross the blood vein barrier very well. No seizure side effects. Abiraterone is pretty well tolerated,

03:09:11.940 but it has an effect on aldosterone production. So you have to monitor people's blood pressures while

03:09:17.840 you have them on those drugs. So there are toxicities with the treatment, but on average, people can have a

03:09:23.380 longer lifespan and a relatively good health span while on these medications.

03:09:28.980 Okay. So let's talk a little bit about surgical therapy. Last time we spoke, we spoke in great length

03:09:34.500 about the evolution of this operation from the way you learned it, which was an open procedure, to the way

03:09:43.680 you did it at the very, very tail end of your residency, which was transitioning to a robot. When was the last time

03:09:49.640 you did an open procedure? 2016. Okay. So it would be almost unheard of today that a patient would have

03:09:59.160 a prostatectomy that has done anything other than through a robot. Correct. What is different today

03:10:06.460 in the surgical practice, your surgical practice, than say four years ago? How has it evolved?

03:10:13.120 What are you doing today to make that operation better? Lots of things. Surgery is always this balance of

03:10:18.920 maximal exposure so that you can see everything with minimal exposure to preserve all the structures

03:10:27.560 around whenever you're removing, whether it's the heart, the colon, the lung, whatever. And so

03:10:32.320 prostate cancer surgeries evolved in a similar way. Historically, the robotic procedure was developed and

03:10:39.860 really mimicked the open surgical procedure, which basically maximally exposed the prostate within the deep

03:10:46.800 pelvis. It's in a very small tube. So for the tennis players out there, the deep pelvis is like the

03:10:53.120 inside of a tennis ball case, the kit where you get the three balls. It's very narrow, very small space,

03:10:58.120 and you enter that space at the top of that case and you're operating at the bottom. That's why it's such

03:11:03.280 a hard procedure to do. Now, we used to expose all the structures around the prostate to see it and

03:11:10.300 delineate it from those structures. The way that my technique has evolved is that now I maximally

03:11:15.960 preserve all those structures around the prostate and basically operate an even smaller hole. What do

03:11:22.120 I mean by that? Well, there's fascia, which for the average listener is effectively like the Kevlar or

03:11:28.600 the Gore-Tex of our entire body. It provides resiliency and strength to the structures. It keeps them in place.

03:11:34.660 And the prostate is surrounded by a tremendous amount of fascia. And when fascia gets really,

03:11:39.740 really thick, we refer to that as a ligament or a tendon. So the prostate has fascia. It has

03:11:45.900 ligaments. They support the prostate in the deep pelvis. And we historically, open and robotically,

03:11:52.760 always would open up and disassemble that fascia, take it apart to expose the prostate, and then we

03:11:58.260 would just sew it back together and hope that people were okay. We would preserve the structures around

03:12:02.180 the prostate, but we'd hope they were okay. Since that time, we now have evolved, not just me, but

03:12:07.500 I think the elite prostate surgeons in the world and the country have developed techniques to do pelvic

03:12:13.520 fascial sparing surgery, leaving all the fascia that surrounds the prostate top, bottom, right, and left

03:12:20.120 alone. And again, the purpose for this is not to enhance the removal of cancer. It's to mitigate

03:12:27.500 the very real side effects of the surgery, namely around erectile function and continence.

03:12:35.400 Yes. So you have to always balance and weigh, are you getting all the cancer out? Because you can

03:12:40.960 maximally preserve all these structures in the fascia and the tissues, but leave a lot of cancer

03:12:44.960 behind, and then what's the point of the procedure? So you're always balancing your outcomes functionally

03:12:50.260 with your outcomes from a cancer control perspective.

03:12:52.900 And a hundred years ago, getting all the cancer out was doable. The problem is the morbidity

03:12:58.060 of the operation was you were guaranteed to be incontinent and impotent.

03:13:01.980 Yes. I would say 60 years ago, that was the case. 100 years ago, we were not picking up early enough

03:13:07.600 anyway. But remember, 100 years ago or 100 plus years ago, the first prostatectomy was a pelvic

03:13:14.320 fascial sparing prostatectomy. It was done in the perineum where all of the fascia that supports the

03:13:19.560 prostate was left in place. It was bloody. You couldn't see what you're doing. So the robot enables

03:13:24.520 you to have no bleeding. It enables you to see what you're doing very, very well.

03:13:28.440 And remind us just where the ports are. Where do you gain access?

03:13:32.440 You gain access to the prostate typically through the abdominal compartment. So you have a central port

03:13:38.660 at the belly button, and then typically a couple ports around at the level of the belly button,

03:13:42.980 more lateral to it, that you insert your instrumentation. Usually the procedure is done

03:13:48.000 transperitoneally, meaning you put the ports into the peritoneum where the intestines live,

03:13:53.880 and then you kind of exit the peritoneum, and you do the procedure extraperitoneally outside of the

03:13:58.520 peritoneum. Outside of the peritoneum in the deep pelvis is where all the fascia is there supporting

03:14:03.460 the prostate and the structures around it. So now when I do the procedure, I do pelvic fascial sparing.

03:14:09.340 I've been doing it for two and a half years now. When I look at my results, I have not impacted at all

03:14:14.940 my cancer control. So some of the early surgeons who did pelvic fascial sparing, they left a lot

03:14:20.640 of cancer behind. You don't want to do that. That's the whole point of the procedure. When I track my

03:14:25.480 data, I am able to have excellent cancer control numbers or data, margin rates, etc., whilst maximally

03:14:33.100 preserving the structures around the prostate. So as we mentioned before, you have your orange. The pulp of

03:14:40.860 the orange is not cancer, but the outer peel is cancer, and just adjacent to that outer peel

03:14:46.100 are nerves for erectile function, nerves for innervation of the urethral sphincter and the

03:14:52.380 urethral sphincter itself. All of those structures are supported by pelvic fascia. We now leave all those

03:14:58.740 structures in place and do the procedure through an even smaller space. It requires a learning curve to

03:15:05.280 adapt to it. But with that approach, you can really effectively eliminate urinary incontinence in almost

03:15:11.520 everybody. And more importantly, the rapidity with which urinary control comes back is outstanding.

03:15:17.960 So what do you tell a patient today?

03:15:19.900 I tell the patients my data. So I tell them that there's about a 4% to 5% chance that if we do your

03:15:25.420 procedure, you'd have a positive margin if the cancer is contained within the prostate, which is what I was

03:15:30.220 doing beforehand. So meaning there's a 95% to 96% chance that this operation will be successful from

03:15:37.780 a cancer perspective, 4% to 5% chance we'd have to go back in to get some of the cancer out?

03:15:42.980 I tell patients that it's a little bit more subtle than that. So a measure of surgical skill is are you

03:15:48.940 taking out the prostate and all the prostate cancer if the cancer is contained within the prostate?

03:15:54.240 Because you can see the prostate, you should take it out. So about 4% to 5% of the time,

03:15:58.140 I make a little nick or I poke a little hole in the side of the prostate and expose some cancer.

03:16:03.340 It doesn't mean that they're going to have a recurrence, but it's a sign of technical skill.

03:16:07.920 In an average surgical series, it's more like 15% or 20%. So we do a good job. Then I tell patients

03:16:15.000 it's 55% chance that when I take your catheter out after the procedure, which is around 10 days,

03:16:21.580 that you'll be dry, no leakage. I tell them that at one month, it's a 66% chance you'll be

03:16:28.120 dry with no leakage. And at three months and your first kind of in-person follow-up, 95% chance

03:16:34.980 you'll be dry, no leakage. Now, when we're doing that, I always tell patients that's no leakage,

03:16:41.940 but you can still wear a pad or liner a day because people will often do that for insurance

03:16:46.780 or for protection. So that's what anterior fascial sparing surgery has done.

03:16:51.600 What about on erectile function?

03:16:53.840 Yeah, it's transformed that space, urinary recovery, substantially. Now, when you do anterior fascial

03:17:00.760 sparing, you can also damage the nerve tissue less when you do it, meaning you're not just fully

03:17:07.220 moving in and dissecting it free. You kind of can leave it in situ. It kind of stays attached to the

03:17:11.980 rectum and the fascia around it. There's still neural trauma. And the biggest hurdle that we have

03:17:17.600 in neurology and in neurologic oncology is really optimizing our neural preservation. So we really

03:17:22.680 are reliant on our neuroscientists to help us find those neuroprotective agents that we can deliver

03:17:28.080 pre-surgery to minimize that trauma. The nerves that we use that are utilized for erection are

03:17:33.800 unmyelinated and they don't really exist in a cable or bundle. They're kind of individual nerve

03:17:39.900 fibers. So they're very sensitive to stretch, pulling, and tugging. So that's what I explain to

03:17:46.920 people. Now, the likelihood or probability that people would recover erectile function is much

03:17:53.620 better when you do anterior fascial or pelvic fascial sparing surgery. But overall, the probability

03:17:59.380 that they recover erectile function is highly dependent on the Gleason score, i.e. the aggressiveness

03:18:05.640 of the tumor and the extent of the tumor. Because if you have a high-grade prostate cancer, there's a

03:18:12.680 60% to 80% chance that that cancer is growing into the nerve tissue on the side that the tumor exists

03:18:18.980 on already. So we don't often think in absolutes like 100% resection of nerve or 0% resection of nerve,

03:18:27.960 but we have to titrate the dissection surgically to incorporate any potential nerve tissue that may have

03:18:34.320 cancer in it. The nice thing and the exciting thing is that we are moving into a space where there are going

03:18:40.680 to be imaging agents in real time. So think about PET-PSMA. They are now linking PET-PSMA to near-infrared

03:18:49.760 base tracers. So you can actually flip a switch and do near-infrared imaging in real time during a

03:18:56.200 prostatectomy to look for residual cancer maybe. So if you maximally nerve spare, you can look at the tumor

03:19:01.760 and look at the nerve and say, hey, is there any tumor left behind? So lots of things that are evolving in

03:19:06.460 surgery that will help advance us in identifying precisely where the tumor is and where it is not.

03:19:13.980 Those trials are kind of evolving and starting soon, which would be really exciting stuff.

03:19:18.760 So if a Gleason 3 plus 4 patient comes into you and it's a high enough 4 that you're going to operate

03:19:26.580 on them. What are you telling him is his on Cialis erectile? Because I assume most of these patients

03:19:34.860 will be on Cialis postoperatively. Age of the patient. What's your sexual function before you

03:19:39.840 start the procedure? So 65-year-old guy who doesn't even require Cialis before surgery.

03:19:46.540 I would tell him it's a 65 to 75% chance they'd recover erections sufficient for intercourse

03:19:52.280 with Cialis on board. Within how long? 24 months. Because that neuropraxia

03:19:59.080 is a 24 to 30-month process. Wow. So for the guys who don't get it back,

03:20:05.240 they're going to be looking at other therapies for erectile function pumps and things of that nature.

03:20:09.480 Well, there's injectable medication. So prostaglandins, they're very effective. They

03:20:13.500 bypass the nerves and or implantable devices. Now, 65-year-old guy who's on Cialis before surgery.

03:20:22.280 What's his recovery on Cialis? It's going to be 10 or 20% less good.

03:20:28.480 Okay. Same guy, but he's a Gleason 4 plus 4. It depends on where the tumor is.

03:20:34.640 So the nerve bundles are in the kind of posterior lateral portions of the prostate. Let's think about

03:20:39.940 like 5 and 7 o'clock, the bulk of them. So if you have an anterior tumor at 1 o'clock,

03:20:45.440 then we can do full nerve sparing. So this is the kind of nuance that again comes into

03:20:50.020 the diagnosis prehand. Yeah. So the prostaglandins have also been a game changer here because it

03:20:55.400 sort of lessens the need for perfect recovery of erectile function postoperatively.

03:21:02.180 Well, we use prostaglandins and injectable medication in that kind of one to two or

03:21:06.500 two-year period of time where the nerve function is recovering.

03:21:09.420 And this is an injection at the base of the penis right at the vascular bundle?

03:21:14.360 At the base of the penis into the cavernosal body.

03:21:16.480 Right into the cavernos. Yeah. Okay.

03:21:18.040 And that will trigger an erection.

03:21:20.500 What prevents that patient from getting priapism?

03:21:23.940 The dosage of the medication. So you start out low and you titrate high.

03:21:28.140 So that reoxygenates the penis, helps maintain penile length. If you're attempting intercourse,

03:21:34.420 it would prevent any kind of potential micro fracture like you had talked about with Mochira with

03:21:39.360 potential scarring and plaque formation. So I strongly advocate for it.

03:21:44.100 For all the patients, it helps with their recovery and helps them with their sexual

03:21:48.080 function, sexual activity in the meantime.

03:21:52.100 Obviously, a lot of people listen to this podcast and some of them at some point in their lives are

03:21:56.260 going to maybe require prostate surgery. Not everybody can come to see you. What are the

03:22:01.840 questions that they should be asking their urologists as they're considering prostatectomy for cancer?

03:22:08.320 A lot of key points we talked about through the whole thing. So when the urologist did their

03:22:13.660 biopsy, did he do an MRI beforehand? Because that means he's just like up to date with modern medicine.

03:22:18.740 When the pathologist read the specimen, did they do things like percent pattern four? That means that

03:22:23.140 the pathologist at that institution is up to date. And then frankly, what is the urologist practice

03:22:28.700 that's offering them a radical prostatectomy? I firmly believe, and there's strong data to suggest

03:22:33.960 that if you are a prostatectomy only practice like mine, that you're dedicated to and focused

03:22:40.320 and thinking about the operation and all the subtleties we've talked about over the last couple

03:22:43.920 hours that are related to the surgical outcome. So if you're a jack of all trade, then I don't

03:22:49.100 recommend that you go to that person for their prostatectomy. So when my patients have kidney

03:22:54.320 stones, I don't treat them. I send them to my partners because they do a better job. All I do is

03:22:58.780 prostatectomy. So for me, it's what's the scope of your practice? Are you prostatectomy only or you do

03:23:05.100 everything? And then on top of that, what are your outcomes? So what's your surgical margin rate

03:23:09.820 and what's your rate of functional recovery? And just understanding what that numbers are.

03:23:16.080 Sometimes I tell people numbers that they're not happy with. I try to set appropriate expectations

03:23:21.340 for them after their procedure. They'll say, well, like, that's not what my physician told me.

03:23:26.880 Some physicians will say 100% chance of erectile recovery. Well, that's not accurate. So that just

03:23:32.340 tells me that they're trying to oversell having the procedure with that particular person.

03:23:37.040 You mentioned that there's maybe only a dozen people that are doing the fascial sparing procedure. Did I

03:23:42.560 hear you correctly? Certainly is a limited number. I mean, it's always evolving in terms of how many

03:23:48.580 people are out there doing it. There is a learning curve. Yesterday when you and I went for a ruck,

03:23:52.840 you mentioned to me, it's added time to your procedure. It's a harder procedure and it takes

03:23:58.680 longer to do. Yeah. There's a new learning curve. So if you can do a prostatectomy,

03:24:04.200 you can't just suddenly flip and do a fascial sparing. How long did it take you to do it without

03:24:09.620 fascial sparing and how long does it take you now? It takes me about 45 minutes longer with fascial

03:24:14.440 sparing. So my average surgical time was maybe 90 to 120 minutes before and I had 45 minutes.

03:24:20.980 You know, it's worth it to do that. We have a bunch of videos on our Northwestern Medicine

03:24:27.100 Urology YouTube channel that show how you can learn the procedure for those surgeons out there.

03:24:33.780 And then there's other approaches to doing anterior fascial sparing than my approach that I show,

03:24:38.000 but there are numerous videos for those as well. All right. One last question, Ted. What are you most

03:24:43.100 excited about in the next five years in the field of prostate cancer? And this could be anything from

03:24:49.280 the diagnostics to the surgical treatment to the post-operative care and management, anything.

03:24:57.260 What are you most excited about? Integration of precision medicine. I've been passionate about

03:25:01.800 and incorporated in my practice for over a decade precision medicine. But like we talked about

03:25:06.920 understanding the molecular subtypes and phenotypes of an individual's tumor is going to be incredibly

03:25:12.620 powerful. And I think it's going to change how we think about and manage these individual patients,

03:25:18.240 not only recommending treatment for the localized disease. Like I think we're going to discover

03:25:22.900 that they're exquisitely radiation sensitive tumors and those that are radio resistant.

03:25:27.160 And we know that there are tumors that are exquisitely sensitive to androgens and those that are

03:25:31.620 inherently androgen resistant. We've never, ever looked or thought about it before, but now we have

03:25:37.180 in our hands the power to do that. And that's going to change everything. In my opinion, it's changing now

03:25:42.020 and we'll see the benefits of those studies in the next five years.

03:25:45.840 Awesome. Well, I think that means we'll probably have to sit down again in five years and talk about

03:25:48.680 sounds good. All right, Ted, thanks so much. I really appreciate it.

03:25:51.220 Thanks for having me, Peter.

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The Peter Attia Drive - October 02, 2023

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

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