00:00:00.000Hey, everyone. Welcome to The Drive Podcast. I'm your host, Peter Atiyah. This podcast,
00:00:16.540my website, and my weekly newsletter all focus on the goal of translating the science of longevity
00:00:21.520into something accessible for everyone. Our goal is to provide the best content in health and
00:00:26.720wellness. And we've established a great team of analysts to make this happen. It is extremely
00:00:31.660important to me to provide all of this content without relying on paid ads to do this. Our work
00:00:36.960is made entirely possible by our members. And in return, we offer exclusive member only content
00:00:42.720and benefits above and beyond what is available for free. If you want to take your knowledge of
00:00:47.940this space to the next level, it's our goal to ensure members get back much more than the price
00:00:53.200of the subscription. If you want to learn more about the benefits of our premium membership,
00:00:58.040head over to peteratiamd.com forward slash subscribe.
00:01:04.260Welcome to a special episode of The Drive. In this episode, I'm going to walk through
00:01:09.680a single topic in depth, and this is prostate cancer screening, something that I'm very
00:01:17.560passionate about. And because we consider this a really important PSA, no pun intended, the full
00:01:24.160episode and the detailed show notes for this discussion will be available to everyone,
00:01:29.200regardless of whether or not you're a premium subscriber. In this episode, I discuss why
00:01:34.340advanced and metastatic prostate cancer diagnoses are rising despite the availability of screening
00:01:40.400tools, what PSA actually measures and why it's more useful when interpreted over time
00:01:46.380than it is in a single one-off number, how MRI, PSA density, PSA velocity, and improved
00:01:53.600biopsy techniques can reduce unnecessary procedures while improving the detection
00:01:58.400of aggressive cancers, how active surveillance helps avoid overtreatment in men with low-risk
00:02:03.580cancers, why the evidence used to argue against PSA screening was deeply flawed,
00:02:09.680how drugs like finasteride, which are commonly used to prevent hair loss, can suppress PSA and
00:02:16.600lead to missed warning signs if clinicians and patients are not vigilant, and why I think regular
00:02:22.120PSA testing is so important if one of our objectives in life would be to eliminate prostate
00:02:29.460cancer mortality. So without further delay, I hope you enjoy this special episode of The Drive.
00:02:39.680Well, today I want to dig into something that I feel quite strongly about and something that I
00:02:46.400think we're getting wrong at the population level in a way that is measurably costing lives.
00:02:52.300We're going to talk about prostate cancer screening, specifically PSA testing, and why
00:02:58.240I believe the current guidelines have failed men and obviously what I think a more modern
00:03:04.120approach to screening should look like in 2026 and beyond. And this is really a discussion that
00:03:10.340I think is relevant for anybody listening to this as a potential patient, someone who cares about a
00:03:16.100patient, or whether you're a clinician. I'm going to spend some time towards the end of this
00:03:21.020discussion on something that I also think is dangerously underappreciated, which is the
00:03:26.560interaction between a drug called finasteride. This is a drug that literally millions of men
00:03:32.640are taking for hair loss prevention and how that drug interacts with our ability to interpret PSA
00:03:38.980correctly. Because if you're on finasteride and your doctor doesn't understand the implications
00:03:44.360of that and how that impacts your PSA values, you could be sitting on a ticking time bomb without
00:03:50.260anybody knowing it. Let me set the stage. Prostate cancer is the second leading cause of cancer
00:03:56.760death in men, with only lung cancer claiming more lives. About one in eight men will receive
00:04:03.800a prostate cancer diagnosis at some point in their lives, and this year alone, roughly 36,000
00:04:10.440American men will die from it. So what makes this disease both uniquely hopeful and uniquely
00:04:17.880frustrating is that when you catch it early, the prognosis is outstanding. So we're talking about
00:04:25.060a 15-year survival rate approaching 97% from first diagnosis. And we have detection tools
00:04:33.900that are simple, widely available, and getting more sophisticated every year. And yet here we
00:04:39.160are watching the rates of advanced stage prostate cancer climb. That's right. So the rates at which
00:04:47.000advanced prostate cancers are showing up is higher today than it was 15 years ago. Recent data out
00:04:53.200of both the United States and Canada confirm what many urologists have been warning about for years.
00:04:58.720We're catching more and more of these cancers only after they have already metastasized or spread.
00:05:06.260And that's what we call stage four disease. And once you're at stage four, the picture
00:05:10.100changes dramatically. Five-year survival falls to 38%, and the median time from diagnosis to death
00:05:18.380is about two and a half years. So the question that I think demands an answer is quite
00:05:24.060straightforward. How did we get here? We have the screening tools. We have effective therapies for
00:05:30.120early cancers. Why are outcomes getting worse instead of better? And of course, most critically,
00:05:36.260then what do we need to do about this? Now, to answer any of that, you need to start with the
00:05:40.260basics of what the PSA actually is, because it's the linchpin of this entire conversation. And
00:05:46.620quite frankly, if we had the PSA equivalent for every other cancer, the world could look a heck
00:05:52.720of a lot different than it does today with respect to cancer mortality. So PSA, which stands for
00:05:57.460prostate-specific antigen, has been available as a blood test since the early 90s. It's a protein
00:06:04.120made by the prostate gland. Its biological function is to help keep seminal fluid in a liquid state.
00:06:11.480So a tiny amount of PSA naturally leaks from the prostate into the bloodstream,
00:06:16.840and that's what we measure when we draw a person's blood.
00:06:20.780So here's the kind of important physiologic point.
00:06:23.400As the prostate grows, which happens in virtually all men as they age,
00:06:28.300the amount of PSA in the blood tends to rise proportionally.
00:06:32.660So when the PSA test was first deployed, the logic was simple.
00:06:36.260if your PSA is unusually high, your prostate is unusually large, and that could mean trouble.
00:06:43.340An elevated PSA would prompt an ultrasound, an abnormal ultrasound would trigger a biopsy,
00:06:49.120and cancer on a biopsy would lead to treatment. And the early data on this approach were generally
00:06:55.080reasonable. Two large trials, followed over 14 and 16 years respectively, showed that routine PSA
00:07:03.080screening cut prostate cancer mortality by 44 and 64% respectively. That translates to preventing
00:07:13.120up to 3.1 cases of metastatic, which means fatal, disease for every 1,000 men who went through the
00:07:22.120screening process. And the test itself costs nothing, a standard blood draw fully covered by
00:07:28.120insurance plans. So you would naturally ask, why wouldn't we screen everyone? Well, here's where
00:07:35.060the story takes a turn that I think had a devastating set of consequences. Even though
00:07:40.640the people who made the decision were operating at least somewhat with reasonable logic at the time.
00:07:47.020The problem was that the straight line from elevated PSA to biopsy was generating too many
00:07:54.940false alarms. PSA can be elevated for many reasons that have nothing to do with cancer,
00:08:00.920including benign enlargement, transient inflammation, such as you might experience
00:08:07.040during a bout of prostatitis, recent sexual activity, and frankly, even just natural
00:08:12.300variation. But the biopsies that followed in elevated reading were hardly benign. The standard
00:08:18.780approach involved punching a needle through the rectal wall to sample prostatic tissue.
00:08:27.320So now you're creating a contaminated pathway from a bacteria-rich environment into what should be a
00:08:33.220sterile organ. And even with things like prophylactic antibiotics and preparation,
00:08:38.320infection rates from these biopsies ran between 5% and 7%, which of course, when you multiply that
00:08:43.860across the number of people that were having them, is an enormous amount of morbidity.
00:08:48.340And prostate infections, of course, are not a joke, especially if they reach into the bloodstream.
00:08:53.260They would frequently land men in the emergency room.
00:08:56.460They could lead to hospitalizations and take people away from work.
00:08:59.380So on top of that, there was the overtreatment issue.
00:09:02.620So back in the 90s and early 2000s, finding cancer on a biopsy almost invariably led to treatment.
00:09:10.600And that treatment, surgical, carried real consequences.
00:09:14.220erectile dysfunction, urinary incontinence, bowel problems, especially if radiation was used.
00:09:20.360The psychological weight of a cancer diagnosis alone is enormous. And what we've come to
00:09:25.740understand since then is that a significant fraction of the cancers caught during the early
00:09:31.260PSA era were actually quite indolent. They were never going to progress to the point of threatening
00:09:37.080someone's life. These men were being subjected to the full burden of cancer treatment for a disease
00:09:43.520that, if left alone, would never have harmed them. There's a saying in the urology world that says
00:09:50.920every man will get prostate cancer, but some will die of it. And the idea here is if you live long
00:09:57.760enough, you're always going to find prostate cancer inside some cells of the prostate. That's
00:10:04.220not the jugular question. The jugular question when you identify prostate cancer is how many
00:10:10.120of these cases are cases where, if left untreated, the cancer will spread from this organ to a
00:10:17.820distant organ, namely the bone, which is the most commonplace of spread. So in response to all of
00:10:23.960this, the United States Preventative Service Task Force, or USPSTF, made its move. And in 2008,
00:10:31.060they stopped recommending PSA screening for men over 70. By 2012, they extended that recommendation
00:10:38.160against screening to men of all ages. The data they leaned most heavily on came from a large
00:10:45.740American trial called the Prostate Lung Colorectal and Ovarian Cancer Screening Trial, or PLCO.
00:10:54.260The prostate arm of this study randomized men to either undergo PSA screening or not,
00:10:59.220and it found essentially no difference in prostate cancer mortality between the two groups.
00:11:05.200The implication was that screening saved, at best, 1.3 lives per thousand men tested.
00:11:14.280And so the USPSTF's calculus went something like this.
00:11:18.160If you're only saving one-tenth of one percent of men while causing serious complications,
00:11:24.280all the things we talked about, right, infections, incontinence, erectile dysfunction,
00:11:28.360the stress that's associated with all of these things,
00:11:31.220In a meaningful proportion of the others, the math simply doesn't add up. The harms of over-diagnosis
00:11:38.620and over-treatment exceed the benefits. Now, again, I can see how one could arrive at that
00:11:45.160conclusion. It's a little bit of a utilitarian argument, and there's a logic to it at the
00:11:50.740population level. But that logic only holds if the underlying data are sound, which we'll discuss,
00:11:57.520and it's been 15 years now. If the USPSTF got it right, we should see at most a marginal uptick
00:12:06.980in late-stage disease, maybe a fraction of a percent. So the obvious next question is,
00:12:13.120what has actually happened over the past 15 years? Well, the data are now in and they paint a very
00:12:19.440clear and very troubling picture. When you group together all prostate cancers caught at stages
00:12:26.420one through three, so these are non-metastatic, five-year survival exceeds 99%. But at stage four,
00:12:35.200which is metastatic disease, tumors that have spread beyond the prostate, survival plummets
00:12:39.940to 38% with a median survival of about 30 months from diagnosis. So the timing of when you find
00:12:46.180the cancer is not a minor detail. It's arguably the determining factor in life and death.
00:12:53.540So what does the recent literature show?
00:12:55.740Well, data published within the last six months from both the American and Canadian registries,
00:13:01.980which builds on the earlier work from Ted Schaefer and his colleagues in 2016,
00:13:07.040is that we are finding more and more prostate cancers only after they've become metastatic.
00:13:12.860This is exactly what many urologists predicted would happen when we pulled back on screening.
00:13:18.160But what's even more alarming is that it's not just older men who are affected. The Canadian
00:13:23.960data show a 3.7 year-over-year increase in stage 4 diagnoses among men under 75 between 2010 and
00:13:33.6802017. And this is happening despite a declining total number of cancers detected in that same
00:13:40.040age group. So it's not that more men are getting cancer, it's that we're only finding it once it's
00:13:45.780too late to cure. The American data tell a similar story. Since the 2012 guideline shift,
00:13:51.720stage 2 cancer detection has been declining by about 0.1% per year across all ages.
00:13:59.100Meanwhile, stage 3 has been climbing at 3.3% per year and stage 4 at 6% per year. Those increases
00:14:09.320in late-stage detection far outpace the modest 0.8% annual increase in total cases.
00:14:17.780So the interpretation here is not complicated, and it is not ambiguous. We stopped looking for
00:14:22.980early disease, so we started finding it late. Stage 4 cancer is what drives all prostate cancer
00:14:30.800mortality, or nearly all of it. And the trajectory we're on is the entirely predictable result of a
00:14:37.960policy that told doctors and patients that looking wasn't worth the trouble. I think the Canadian
00:14:43.420researchers summarized this paradox well, and I'm paraphrasing, but the gist was newer treatments
00:14:49.040have extended survival for men with metastatic disease, but overall survival across the
00:14:55.480population has actually worsened compared to when screening was recommended, because we now have so
00:15:01.520many more men presenting with incurable cancer. And it doesn't have to be the story. It just
00:15:08.060shouldn't be this way. So this is where I want to pivot because I think this is actually the
00:15:13.000most important part of the conversation and honestly the most hopeful. The USPSTF built
00:15:17.980its guidance at a time when our tools were far cruder than they are today. The old pipeline,
00:15:24.780as I kind of talked about a few minutes ago, was essentially PSA goes up, you get an ultrasound,
00:15:28.580ultrasound looks somewhat concerning. You got a biopsy. If the biopsy finds any type of cancer,
00:15:32.920you get treated. And there was very little nuance in that algorithm. But the way we deploy PSA in
00:15:39.0402026, and quite frankly, over the last five years, looks poignantly different. The single biggest
00:15:44.520conceptual shift is this. PSA is most value as a longitudinal trend, not a single snapshot.
00:15:51.840Any individual PSA reading is inherently noisy. Day-to-day values can fluctuate by as much as 15%.
00:15:58.580If a man has recently ejaculated, his PSA can spike by as much as 40%, and the person-to-person variability is staggering.
00:16:06.240A healthy man in his 60s might have a median PSA of 1.0 to 1.2, but the 95th percentile for that exact same demographic in men with no prostate cancer extends all the way up to 4.9.
00:16:20.100So in the show notes, we're going to leave a table that gives you all of this information.
00:16:27.400but the point here is that no single PSA value in isolation tells you very much.
00:16:32.440What does tell you something is the trajectory, and this is what we call PSA velocity, mapping
00:16:38.920a patient's baseline over time and tracking the rate of change of that PSA value. The prostate
00:16:47.100naturally enlarges with age, so some gradual PSA increase is expected, but rapid increases are
00:16:54.980cause for suspecting something pathological. Either the prostate is enlarging abnormally,
00:17:00.460a higher proportion of PSA is leaking into the blood relative to the amount of prostate,
00:17:05.380tissue, or both, and disrupted prostate architecture and vascular leakage are the
00:17:10.720hallmarks of malignant growth. So in general, if we look at increases sustained over an 18-month
00:17:18.120window and use different cutoffs depending on the baseline value, so if we took a patient with a
00:17:24.320baseline PSA of less than four nanograms per milliliter, and in our practice, that's the norm.
00:17:29.860Most of our men are going to walk around with a baseline PSA less than four. A sustained rise
00:17:36.140by more than about 0.35 nanogram per milliliter per year over 18 months is generally our red flag.
00:17:45.960In patients with a PSA value that starts above 4, we would let that increase to about a 0.75 nanogram per milliliter per year bump before we would flag that.
00:18:00.160So let's say I have a 55-year-old patient with a PSA of 1.3.
00:18:04.100So that's slightly above the median for his age.
00:18:07.300But I'm not alarmed, especially because, remember, I've got longitudinal data on him, and I realize that this is about where he settles out.
00:18:13.520So that one time he was 1.6, I didn't overreact because two months later or three months later, he was back to 1.3.
00:18:20.880Now, if he comes back a year later at 1.7, and then six months after that comes back at 1.9, that's an increase of 0.6 over an 18-month period of time, working out to a velocity of 0.4 per year.
00:18:38.460So now I'm paying attention. That sustained acceleration is the signal I'm looking for,
00:18:44.060and it's personalized to him. This is actually what precision medicine is, and incredibly it
00:18:49.500costs essentially nothing because this test is so cheap, like we're talking dollars, and it shows up
00:18:56.880in a routine blood test. So this is a great example of precision medicine, and incredibly it costs
00:19:02.960essentially nothing beyond showing up for a routine blood draw. Again, the blood test itself
00:19:08.720costs dollars. But even with his velocity flagging a concern, we no longer would just jump to a
00:19:16.920biopsy here. The next step would now be an MRI, which serves as a much higher resolution test,
00:19:23.580and it's much less invasive than proceeding to a biopsy. So the MRI gives us yet another metric,
00:19:30.940which is PSA density, which is simply the PSA concentration in the blood divided by the volume
00:19:36.260of the prostate provided by imaging. And by the way, you could do that with an ultrasound as well.
00:19:41.740But with the MRI, you're getting two for one because you're getting a better imaging study,
00:19:46.340and of course, you're getting volume. So here's the logic. A healthy prostate grows,
00:19:50.640PSA and volume tend to increase in approximate proportionality. But when you have a malignancy,
00:19:57.360the tumor can disrupt the normal architecture of the prostate that normally contains PSA
00:20:01.800to the gland or alter the endothelia running through the prostate. And in this situation,
00:20:07.780PSA starts escaping into the bloodstream at a rate that outpaces what you'd expect
00:20:12.780from the size of the gland alone. So if PSA is rising disproportionately to prostate volume,
00:20:19.300that's a strong indicator that something is wrong. And it gives us that signal before anybody needs
00:20:25.200to think about a needle. So when you put your PSA velocity from serial blood test together with PSA
00:20:31.180density from MRI, the discriminating power of PSA screening today is dramatically better than what
00:20:38.800existed when the USPSTF made its call. Now, if we focus in on MRI for a moment, there's been a really
00:20:45.540significant development that I think is going to meaningfully change the accessibility equation.
00:20:51.300Beyond PSA density, the main value of MRI in this, you know, algorithm is that it can identify
00:20:57.280suspicious lesions or regions in the prostate without invasive probing. It can credibly rule
00:21:03.900in or rule out the need for a biopsy. And if a biopsy is warranted, it guides the needle to the
00:21:09.460areas most likely to hand us a diagnosis. The obstacle historically was that the gold standard
00:21:16.300prostate MRI called a multi-parametric MRI requires a contrast called gadolinium. And that meant higher
00:21:24.500costs, the need for a medical professional to administer an IV injection, and significantly
00:21:29.000more time in the scanner. All of this, of course, limited patient throughput and made pre-biopsy
00:21:34.500MRI impractical in many scenarios. But a trial in 2025 called the PRIME trial changed this. The study
00:21:41.240directly compared the full multi-parametric protocol, which is a T2-weighted image,
00:21:47.420a diffusion-weighted image, plus dynamic contrast-enhanced imaging, against a stripped-down
00:21:53.720contrast-free biparametric version that drops the contrast component altogether. The goal was to
00:22:00.900establish non-inferiority. In other words, the question asked was, does this stripped-down
00:22:06.400version perform at least as well as the gold standard. And the results were essentially a
00:22:11.320dead heat. The biparametric MRI identified clinically significant cancer in 143 out of 490
00:22:19.680men who had been flagged by PSA screening, whereas the full multiparametric MRI complete with
00:22:25.980gadolinium caught 145 out of that same group of 490 study participants. The difference between
00:22:35.320those detection rates was 0.4 percentage points, which was statistically indistinguishable.
00:22:41.700And the practical implications here are huge, obviously, right? Without contrast,
00:22:45.360the scan takes half the time, 15 to 20 minutes instead of 30 to 40. You don't need
00:22:49.440a medical practitioner that's standing there giving you the contrast and overseeing you.
00:22:55.000And of course, the costs come down, speed goes up, etc. Now, even with all of these improvements
00:23:00.300in non-invasive screening, some men are still going to need a biopsy. If the MRI flags something
00:23:06.820suspicious and you need tissue to know what you're dealing with, you've only got one place to get it.
00:23:11.980So it's worth talking about the progress that's been made there as well, because the biopsy itself
00:23:16.860has gotten both safer and more accurate. Now I mentioned earlier that the traditional approach
00:23:21.980was a transrectal approach, and that carries inherent risk of poking bacteria from the rectum
00:23:29.500into a sterile space. It also has its anatomical limitations. It biases your sampling towards the
00:23:36.620back of the prostate near the rectal wall, and this can miss the front and base of the gland.
00:23:42.780The alternative to this is called a transperineal approach, entering through the skin between the
00:23:48.000anus and the scrotum, and this completely bypasses the rectum, which dramatically reduces infection
00:23:52.980risk, and it opens up much better access to the anterior and apical portions of the prostate
00:23:59.400than the transrectal route does, which you tend to miss. So Ted Schaefer, who's been a guest on
00:24:05.020this podcast many times, is a very close friend of mine personally and is also the urologist that
00:24:10.560works with many of our patients when they are diagnosed with prostate cancer, was involved in
00:24:16.120a large multi-center phase three trial with over 1,700 patients that compared cancer detection
00:24:22.520rates and complication profiles between the two approaches head-to-head. The transperineal biopsy
00:24:29.260detected more high-grade cancers and fewer low-grade ones, which tells you it's doing a
00:24:34.880better job of finding tumors that actually matter, generating fewer false negatives from indolent
00:24:40.840disease and obviously creating less emotional distress. And on the safety front, this is really
00:24:46.620the headline in my mind, not a single patient who underwent the transperineal biopsy in that study
00:24:52.420developed an infection, ZIP0. Compare that to the 5-7% infection rate widely reported in the
00:24:59.760transrectal approach. Importantly, the transperineal method doesn't require prophylactic
00:25:05.120antibiotics, which is a meaningful benefit both for the patient and for the antibiotic stewardship
00:25:10.680more broadly as we face an era of antibiotic resistance. Now, adoption isn't universal yet.
00:25:16.760Only about 37% of American urologists currently perform transperineal biopsies versus a
00:25:22.300essentially all of them, doing transrectal or being able to. So there's a gap between what
00:25:27.880the evidence supports and what's happening in practice, but the trajectory is encouraging.
00:25:34.300All right, so I've been building the case for more screening, for more MRI, and for better biopsies,
00:25:39.160but I haven't forgotten the other side of the original argument, which is the overtreatment
00:25:43.200problem. And I really take this seriously because with all of the advances in surgical care,
00:25:49.800this is not a benign operation. Not every prostate cancer is going to kill you. Our treatments are
00:25:56.280effective, but they carry side effects that nobody wants to experience if they don't have to.
00:26:01.640So here's the critical point that I think changes the overtreatment calculus. We no longer treat
00:26:08.600every cancer we find. The decision tree has gotten much more sophisticated. Now, if you remember the
00:26:16.160podcasts that we've covered in this topic in the past, we go through something called a Gleason
00:26:21.920scoring, but I'm just going to kind of reiterate it here a little bit because maybe not everybody's
00:26:26.200familiar with that previous content. So when a pathologist examines a biopsy specimen, they
00:26:31.980look at the cells under the microscope and they decide how abnormal the cells look relative to
00:26:39.240healthy cells. And they use a grading scale called a Gleason score. Now you're getting two numbers in
00:26:46.540that score because they're looking in two places. So you might get a Gleason 3 plus 3 or 3 plus 4
00:26:53.980or 4 plus 4. And the highest number there is 5. And the higher the number, the greater the malignant
00:27:02.960potential of the cell. Now, these numbers get compressed into a grade group, which is a scale
00:27:12.400that is graded one through five. And again, it's similarly based on the abnormality of these cells.
00:27:19.020So a grade one or two is a relatively low risk tumor. We know the natural history of grade one
00:27:29.680and grade two, which are the lower Gleason scores, behave very differently. And these are cancers
00:27:36.000that may never spread. Now, we don't know that for a fact, but we know that if they're going to
00:27:42.280spread, they're going to do so by progressing into a higher grade Gleason score. And therefore,
00:27:47.620for these patients, we can continue to survey them or do other advanced forms of monitoring,
00:27:54.680which I'll talk about in a second. Conversely, if a patient presents with a higher grade group,
00:28:01.220like a grade 3, which would be a Gleason 4 plus 3, a grade 4, which would be a Gleason 4 plus 4,
00:28:08.360or a grade 5, which is anything higher, so a 4 plus 5, 5 plus 4, or any 5-5, these are very
00:28:15.480aggressive tumors, and treatment is immediately warranted. So going back to what do you do with
00:28:23.800grade one and two. Well, again, these are patients that have prostate cancer, but our belief is that
00:28:31.780it is not an imminent threat to their life because it is not clear if these cancers will spread.
00:28:37.860And if they're going to turn into spreading cancers, they're going to do so by progressing.
00:28:42.260So we would, in this case, look at other blood markers like tests called the PHI or the 4K score.
00:28:49.660These are things that we talked about on previous podcasts. We'll link to some of that stuff in the
00:28:53.720show notes if you want to follow that in more detail. But the point is we now turn into an
00:28:59.620area called active surveillance. And active surveillance is basically something we're doing
00:29:06.500to ensure that treatment will be timely once it is required, but no sooner. So the scenario that
00:29:15.620drove so much of the overtreatment concern 15 years ago, which was you find any cancer, you
00:29:20.620treated immediately and you deal with the consequences, that's largely been retired from
00:29:24.840the urologist playbook. The tools and clinical judgments that have evolved today to the point
00:29:30.540where urologists can meaningfully distinguish between dangerous tumors and ones that can be
00:29:35.400safely watched is what basically gives us this luxury. And that means that the risk-benefit
00:29:40.100calculation for screening has shifted substantially in favor of screening. Okay, so I spent a good
00:29:47.360amount of time walking through the modern sort of screening toolkit, and I've tried to be fair
00:29:54.160to the original USPSTF reasoning along the way. I think the over-treatment concern was legitimate,
00:30:01.620and I think the burden of transrectal biopsies was real. And again, I take those objections
00:30:07.600seriously. But there's something I've sort of held back on until now, and it's a failure in
00:30:12.720the data that I think is so significant that it essentially undermines the entire foundation of
00:30:18.740the USPSTF position. Urologists have been pointing this out for years, and I think it's borderline
00:30:25.220unbelievable that it hasn't led to a formal revision of the guidelines. So I'm talking about
00:30:30.120that PLCO trial. That's the study that the USPSTF weighted most heavily when it decided that PSA
00:30:37.460screening wasn't worth doing. Here's what the PLCO study was supposed to show. You take a large
00:30:43.220group of men, you randomize half to get regular PSA tests, the other half not to get tested,
00:30:47.120you follow them over a decade, and compare prostate cancer deaths between the two groups.
00:30:51.540The study found essentially no difference, supporting the conclusion that screening
00:30:55.420doesn't meaningfully reduce mortality. But here's what went wrong, and I genuinely had trouble
00:31:01.440believing this the first time I encountered it. The control arm, so this is the group that was
00:31:06.020not supposed to be screened, was getting screened anyway. The investigators may not have been
00:31:12.840providing the tests, but when they surveyed the participants, somewhere between 40 and 60 percent
00:31:19.580of men in the no-screening group reported having had a PSA test within the year.
00:31:26.280And this wasn't a one-time contamination event. That pattern held every single year of the study.
00:31:32.320So by the final survey, over 90% of the men in the control arm had undergone at least one PSA test.
00:31:39.360In some years, more men in the supposed control arm reported screening than in the intervention arm.
00:31:47.160So we will put the figure from the 2016 letter to the editor in the New England Journal of Medicine in the show notes
00:31:54.060so you can see this for yourself because it is quite striking.
00:31:57.220The bottom line is, this was a study comparing PSA screening to PSA screening and then concluding
00:32:03.160that screening doesn't work when they didn't find a difference. That is the bedrock upon which the
00:32:09.740USPSTF built a recommendation that has affected tens of millions of men. Now, this data contamination
00:32:17.400wasn't published widely until 2016, well after the original guideline change. Once it was out there,
00:32:26.160a group of researchers went back to the PLCO data in 2017 and did something really clever.
00:32:31.980They mathematically accounted for the frequency of screening within the contaminated control arm,
00:32:38.420calculated a mean and lead time, essentially how much earlier cancers were caught in men who were
00:32:44.240more regularly, and then imputed a mortality reduction based on earlier diagnoses. When you
00:32:51.680run the analysis that way, correcting for the contamination that made the original study
00:32:57.040essentially uninterpretable, the same PLCO data show a 27 to 32 percent reduction in prostate
00:33:04.920cancer mortality attributable to regular PSA testing. I just want to sit with that for a
00:33:12.300second. The same data set, the same patients, analyzed honestly, and it shows that screening
00:33:19.020prevents roughly a quarter to a third of prostate cancer deaths. And yet the USPSTF has not updated
00:33:26.900its guidelines since 2018. It still does not recommend PSA testing for men 55 to 69, and
00:33:35.480still recommends against it for men over 70. I think it's long past time for the USPSTF to
00:33:42.560revisit this. The same is true of organizations like the Canadian Task Force on Preventive
00:33:47.920Healthcare and the American Association of Family Physicians. Until they do so, I think we have
00:33:52.640reason to be confident in taking this into our own hands. So let me try to synthesize everything
00:33:58.700we've covered because I realize it's been a lot. We started with the observation that pulling back
00:34:04.280on PSA screening led to a measurable ongoing increase in the incidence of incurable prostate
00:34:11.040cancers. That's not speculation. It's in the data. It's black and white from multiple countries.
00:34:16.360We then walk through how PSA testing has evolved. A single PSA value taken once every few years was never a perfect screening tool. It's too noisy, too much individual variation. That part of the old critique was fair.
00:34:30.260But PSA velocity, PSA density, contrast-free MRI, and transperineal biopsies, along with active surveillance for low-grade disease taken together, represent a fundamentally different screening paradigm than what existed when the USPSTF issued its recommendations.
00:34:50.080The ability to catch dangerous, i.e. lethal cancers, early while avoiding the harms of
00:34:56.740over-diagnosis and over-treatment has improved by an order of magnitude. And then we looked at
00:35:02.600the data that supposedly justified the shift away from screening 15 years ago and found that the
00:35:08.680cornerstone study was so contaminated as to be essentially meaningless and that a proper analysis
00:35:16.420of the same data clearly supports screening very strongly. So where does that leave us? Well,
00:35:22.040prostate cancer, as I said, number two cancer killer of men, and it's not receiving the urgency
00:35:27.740it deserves. I'll go further. I think it's unconscionable that we are still losing men to
00:35:32.500a disease that in many cases could have been caught years before it became lethal. And this
00:35:38.380is something I want people to really internalize because it goes to the biology of the disease
00:35:43.740itself. I've talked about this many times on previous podcasts, but I don't think I can talk
00:35:48.540about it enough. Cancer falls into roughly two categories. There are those that progress in a
00:35:54.500relatively predictable, stepwise fashion, moving through detectable precursor stages before
00:36:02.660becoming truly dangerous. And then there are those that don't. They can emerge suddenly,
00:36:08.300metastasize quickly and evade early detection no matter how aggressively you screen. I think that
00:36:15.520pancreatic cancer is the classic example of the latter, and sadly, many breast cancers also fall
00:36:21.860into that category. But prostate cancer, along with colorectal cancer, fit squarely in the first
00:36:29.300group. Prostate cancer tends to follow a very predictable path from early localized disease
00:36:36.020to advanced metastatic disease. And that biological reality is precisely what makes a screening
00:36:43.540detectable tool like the PSA so powerful and what makes any deaths, let alone the 36,000 a year in
00:36:52.140this country alone from prostate cancer, so completely tragic. This isn't a cruelty of
00:36:58.460biology. It's a failure of our implementation. I've made this comparison before, but I think
00:37:04.120it's worth repeating. Imagine we had a breast cancer detection tool that cost less than a cup0.84
00:37:09.820of coffee, could be incorporated into a routine blood test, and was capable of flagging cancer0.91
00:37:15.980years before it spread. In what universe would we not deploy that tool as widely and aggressively
00:37:22.100as humanly possible? For prostate cancer, that tool does exist. Your primary care doctor can
00:37:28.820add it to your next blood draw. It might already be there. The barrier isn't technology. It's
00:37:33.260awareness, it's education, and most of all, it's outdated guidelines. In our practice, we've seen
00:37:39.020this play out countless times. Well, patients will come to us with PSA data from other providers,
00:37:43.720sometimes years of it, and when we calculate their velocity, the red flags are right there.
00:37:48.040We send them for an MRI, depending on what it shows, a biopsy, and we've caught several cancers
00:37:54.780right at that stage where had we waited another year or two, they likely would have been metastatic,
00:38:00.900but they were Gleason 3 plus 4s or 4 plus 3s that were right in that sweet spot for treatment.
00:38:06.580Before I close, I want to just sort of spend some time on a topic that is related to this,
00:38:12.140but a little bit oblique to it. And I think it's also becoming increasingly prevalent. And it's
00:38:19.020generally, I think, something we need to be alarmed about and physicians and patients alike
00:38:23.520need to be aware of, given the current state. And it's the interaction between a class of drugs
00:38:29.480called 5-alpha reductase inhibitors. The most common of these is finasteride, but there's
00:38:34.980another one called dutasteride, and how they impact prostate cancer screening. So the use of
00:38:40.600finasteride has exploded in recent years, largely driven by men using it to prevent or treat hair
00:38:47.000loss. In fact, we've talked about this drug many times on other podcasts, both in the context of
00:38:51.240hair loss and testosterone use. We've discussed the potential risks of finasteride and prostate
00:38:57.200cancer development elsewhere, but I want to have some dedicated sections here where I talk about
00:39:02.100that. So I want to focus on one specific issue, which is that finasteride, as far as we can tell
00:39:09.140from the data, does not cause prostate cancer. Okay. But what it absolutely unequivocally does
00:39:16.160is suppress PSA in a way that can completely mask the present of cancer if the treating physician
00:39:23.140doesn't know how to adjust for it. Now here's the mechanism. Finasteride blocks the conversion
00:39:28.180of testosterone into dihydrotestosterone, or DHT, in the prostate. And that reduction in local DHT
00:39:35.700also dramatically reduces PSA production. As a practical matter, you can expect PSA to drop
00:39:43.600by about a third within six months of starting finasteride and to be roughly cut in half by a
00:39:50.880year. That suppressed baseline persists for as long as the patient stays on the drug.
00:39:56.940So let me state this as clearly as I can. If a man has been on finasteride for a year or longer,
00:40:02.840his PSA value needs to be at a minimum doubled to be interpreted correctly. And the correction
00:40:10.800factor we use actually increases with duration of use. In our practice, we multiply by 2.3
00:40:18.460after 2 to 7 years on the drug and 2.5 beyond 7 years. Now, while the FDA label recommends
00:40:26.980multiplying by 2, we do this based on data from the Prostate Cancer Prevention Trial performed in
00:40:32.580the late 90s and early 2000s, as well as a follow-up analysis from 2005 performed by Ruth
00:40:39.840Etzioni and her colleagues. We've included a table from that in the show notes. For PSA velocity,
00:40:47.860the practical implication is simpler but equally important. After about 12 months on finasteride,
00:40:53.880you should not expect your PSA to rise at all. The ongoing suppression from the drug should
00:41:00.120roughly offset the natural age-related increase in PSA. In fact, in a large study of 19,000 older
00:41:06.880men, those on finasteride who were cancer-free actually showed an average 2% annual decrease
00:41:13.440in PSA. So any upward movement in a man on long-term finasteride should be treated as a
00:41:19.780serious warning sign. And here's where I get concerned. Most general practitioners are not
00:41:25.740aware of this, it appears. A retrospective analysis of VA patients undergoing PSA screening
00:41:31.360found that men on finasteride were diagnosed with metastatic cancer at a rate more than double that
00:41:37.680of men not taking 5-alpha reductase inhibitors, 6.7% versus 2.9%. The doctors were reading the
00:41:47.120raw PSA numbers at face value, not realizing they needed to double them or more. The two groups had
00:41:53.080nearly identical PSA levels at the time of cancer diagnosis, about 6.8 versus 6.4, but once you
00:41:59.680correct for the finasteride-induced suppression, the true comparison is more like 13.5 versus 6.4.
00:42:06.140Those are wildly different clinical pictures, and the physicians unfortunately missed it.
00:42:11.780This is in some ways an even more tragic version of the same problem I've been talking about for
00:42:16.600the past hour, because even in men who were getting screened, the screening was rendered
00:42:21.900useless because the physician didn't understand how to correct the results.
00:42:26.700And I think that's especially urgent because many men are getting finasteride prescriptions from
00:42:30.880online clinics and then not even mentioning it to their primary care doctors because they
00:42:35.620don't think it matters. So even a physician who does understand the PSA interaction can't account
00:42:41.580for it if they don't know the patient's taking it. So if you're listening to this and you're
00:42:46.240taking finasteride, the onus may fall on you. Please be sure that you not only advocate for
00:42:52.780regular PSA testing, but make sure that your doctors know about every prescription, including
00:42:58.460and especially those that involve 5-alpha reductase inhibitors, and ensure that whoever
00:43:02.760is interpreting your PSA understands both the drug and its suppressive effects. Again, finasteride
00:43:08.760does not appear to increase your actual risk of developing prostate cancer, but it can absolutely
00:43:14.180prevent your doctors from catching it on time. So I want to end where I think the evidence points,
00:43:20.440which is a place of cautious but genuine optimism. Between our understanding of PSA velocity and
00:43:27.240density, again, the increasing accessibility of very high quality MRI, the advent of transperineal
00:43:34.520biopsy, and the sophistication of active surveillance protocols for low-grade disease,
00:43:40.300such as those Gleason 3 plus 3s. The field has made enormous progress in minimizing the very
00:43:47.460real risks of overdiagnosis and overtreatment that motivated the USPSTF's original positioning.
00:43:54.360And then, of course, against that, we have to weigh the cost of doing nothing, which is a little over 36,000 lives this year in the United States.
00:44:05.120We are in an extraordinarily fortunate position.
00:44:08.140We have the tools for early detection that are cheap, simple, and effective.
00:44:13.860We have the ability right now to catch most prostate cancers before they become fatal.
00:44:18.580we just need to use what we have to advocate for it as patients and to understand it as clinicians.
00:44:25.600And I genuinely believe that if we do, prostate cancer deaths can be all but eradicated. So it
00:44:32.900doesn't have to be the second leading cause of cancer death in men. It could not even be in the
00:44:37.880top 20. So a summary of how we approach PSA testing in our own practice can be found in a
00:44:45.740newsletter that we published yesterday on the same topic. And we'll also link to it in the show notes
00:44:50.620where you can also find all of the studies and references from today's episode as well. So I
00:44:56.800hope you enjoyed this episode on a topic that I'm very passionate about. Thank you for listening to
00:45:04.840this week's episode of The Drive. Head over to peteratiamd.com forward slash show notes if you
00:45:11.800want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter,
00:45:17.400all with the handle Peter AtiyahMD. You can also leave us review on Apple podcasts or whatever
00:45:23.320podcast player you use. This podcast is for general informational purposes only and does
00:45:29.000not constitute the practice of medicine, nursing, or other professional healthcare services,
00:45:33.140including the giving of medical advice. No doctor patient relationship is formed.
00:45:37.920The use of this information and the materials linked to this podcast is at the user's own risk.
00:45:44.340The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment.
00:45:50.180Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions.
00:46:00.300Finally, I take all conflicts of interest very seriously.
00:46:04.400For all of my disclosures and the companies I invest in or advise, please visit peteratiamd.com
00:46:10.900forward slash about where I keep an up-to-date and active list of all disclosures.