A (17:31)

are going to walk around with a

B (17:32)

baseline PSA less than 4, a sustained rise by more than about 0.35 nanogram per milliliter per year over 18 months is generally our red flag. In 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. So let's make this tangible. So let's say I have a 55 year old patient with a PSA of 1.3. So that's slightly above the median for his age. But 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. So 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. Now 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. So now I'm paying attention. That sustained acceleration is the signal I'm looking for. And it's personalized to him. This is actually what precision medicine is. And incredibly, it costs essentially nothing because this test is so cheap, like we're talking dollars, and it shows up in a routine blood test. So this is a great example of precision medicine. And incredibly, it costs essential essentially nothing beyond showing up for a routine blood draw. Again, the blood test itself costs dollars. But even with his velocity flagging a concern, we no longer would just jump to a biopsy here. The next step would now be an mri, which serves as a much higher resolution test, and it's much less invasive than proceeding to a biopsy. So the MRI gives us yet another metric, which is PSA density, which is simply the PSA concentration in the BL divided by the volume of the prostate provided by imaging. And by the way, you could do that with an ultrasound as well. But with the mri, you're getting two for one because you're getting a better imaging study. And of course, you're getting volume. So here's the logic. A healthy prostate grows PSA and volume tend to increase in approximate proportionality. But when you have a malignancy, the tumor can disrupt the normal architecture of the prostate that normally contains PSA to the gland or alter the endothelia running through the prostate. And in this situation, PSA starts escaping into the bloodstream at a rate that outpaces what you'd expect from the size of the gland alone. So if PSA is rising disproportionately to prostate volume, that's a strong indicator that something is wrong, and it gives us that signal before Anybody needs to think about a needle. So when you put your PSA velocity from serial blood test together with PSA density from mri, the discriminating power of PSA screening today is dramatically better than what existed when the USPSTF made its call. Now, if we focus in on MRI for a moment, there's been a really significant development that I think is going to meaningfully change the accessibility equation beyond PSA density. The main value of MRI in this, you know, algorithm is that it can identify suspicious lesions or regions in the prostate without invasive probing. It can credibly rule in or rule out the need for a biopsy. And if a biopsy is warranted, it guides the needle to the areas most likely to hand us a diagnosis. The obstacle historically was that the gold standard prostate MRI, called a multi parametric mri, requires a contrast called gadolinium. And that meant higher costs, the need for a medical professional to administer an IV injection, and significantly more time in the scanner. All of this of course, limited patient throughput and made pre biopsy MRI impractical in many scenarios. But a trial in 2025 called the PRIME trial changed this. The study directly compared the full multi parametric protocol, which is a T2 weighted image, a diffusion weighted image plus dynamic contrast enhanced imaging, against a stripped down contrast free BI parametric version that drops the contrast component altogether. The goal was to establish non inferiority. In other words, the question asked was does this stripped down version perform at least as well as the gold standard? And the results were essentially a dead heat. The biparametric MRI identified clinically significant cancer in 143 out of 490 men who had been flagged by PSA screening. Whereas the full multi parametric MRI, complete with gadolinium with caught 145 out of that same group of 490 study participants, the difference between those detection rates was 0.4 percentage points, which was statistically indistinguishable. And the practical implications here are huge. Obviously, right, without contrast, the scan takes half the time, 15 to 20 minutes instead of 30 to 40. You don't need a medical practitioner that's standing there giving you the contrast and overseeing you. And of course the costs come down, speed goes up, et cetera. Now, even with all of these improvements in non invasive screening, some men are still going to need a biopsy. If the MRI flags something suspicious and you need tissue to know what you're dealing with, you've only got one place to get it. So it's worth talking about the progress that's been made there as well because the biopsy itself has gotten both safer and more accurate. Now, I mentioned earlier that the traditional approach was a transrectal approach and that carries inherent risk of poking bacteria from the rectum into a sterile space. It also has its anatomical limitations. It biases your sampling towards the back of the prostate near the rectal wall, and this can miss the front and base of the gland. The alternative to this is called a transperineal approach. Entering through the skin between the anus and the scrotum. And this completely bypasses rectum, which dramatically reduces infection risk. And it opens up much better access to the anterior and apical portions of the prostate than the transrectal route does, which it tend to miss. So Ted Schaefer, who's been a guest on this podcast many times, is a very close friend of mine personally and is also the urologist that works with many of our patients when they are diagnosed with prostate cancer, was involved in a large multi center phase 3 trial with over 1700 patients that compared cancer detection rates and complication profiles between the two approaches. Head to head, the transperineal biopsy detected more high grade cancers and fewer low grade ones, which tells you it's doing a better job of finding tumors that actually matter, generating fewer false negatives from indolent disease and obviously creating less emotional distress. And on the safety front, this is really the headline in my mind. Not a single patient who underwent the transperineal biopsy in that study developed an infection. Zip. 0. Compare that to the 5 to 7% infection rate widely reported in the transrectal approach. Importantly, the transperineal method doesn't require prophylactic antibiotics, which is a meaningful benefit both for the patient and for the antibiotic stewardship more broadly. As we face an era of antibiotic resistance. Now, adoption isn't universal yet only about 37% of American urologists currently perform transperineal biopsies versus essentially all of them doing transrectal or being able to. So there's a gap between what the evidence supports and what's happening in practice, but the trajectory is encouraging. All right, so I've been building the case for more screening, for more MRI and for better biopsies. But I haven't forgotten the other side of the original argument, which is the over treatment problem. And I really take this seriously because with all of the advances in surgical care, this is not a benign operation. Not every prostate cancer is going to kill you. Our treatments are effective, but they carry side effects that nobody wants to experience if they don't have to. So here's the critical point that I think changes the over treatment calculus. We no longer treat every cancer we find. The decision tree has gotten much more sophisticated. Now, if you remember the podcast that we've covered in this topic in the past, we go through something called a Gleason scoring, but I'm just going to kind of reiterate it here a little bit because maybe not everybody's familiar with that previous content. So when a pathologist examines a biopsy specimen, they look at the cells under the microscope and they decide how abnormal the cells look relative to healthy cells. And they use a grading scale called a Gleason score. Now, you're getting two numbers in that score because they're looking in two places. So you might get a Gleason 3, 3 or 34 or 4 4. And the highest number there is 5. And the higher the number, the greater the malignant potential of the cell. Now, these numbers get compressed into a grade group, which is a scale that is graded one through five. And again, it's similarly based on the abnormality of these cells. So a grade one or two is a relatively low risk tumor. We know the natural history of grade one and grade two, which are the lower Gleason scores, behave very differently. And these are cancers that may never spread. Now, we don't know that for a fact, but we know that if they're going to spread, they're going to do so by progressing into a higher grade Gleason score. And therefore, for these patients, we can continue to surveil them or do other advanced forms of monitoring, which I'll talk about in a second. Conversely, if a patient presents with a higher grade group, like a grade three, which would be a Gleason 4 3, a grade four, which would be a Gleason4 4, or a grade five, which is anything higher. So a 4 5, 54 or any 5.5, these are very aggressive tumors and treatment is immediately warranted. So going back to what do you do with grade one and two? Well, again, these are patients that have prostate cancer, but our belief is that it is not an imminent threat to their life because it is not clear if these cancers will spread. And if they're going to turn into spreading cancers, they're going to do so by progressing. So we would in this case look at other blood markers, like tests called the phi or the 4K score. These are things that we talked about on previous podcasts. We'll link to some of that stuff in the show Notes, if you want to follow that in more detail. But the point is we now turn into an area called active surveillance. And active surveillance is basically something we're doing to ensure that treatment will be timely once it is required, but no sooner. So the scenario that drove so much of the over treatment concern 15 years ago, which was you find any cancer, you treat it immediately and you deal with the consequences, that's largely been retired from the urologist playbook. The tools and clinical judgments that have evolved today to the point where urologists can meaningfully distinguish between dangerous tumors and ones that can be safely watched is what basically gives us this luxury. And that means that the risk benefit calculation for screening has shifted substantially in favor of screening. Okay, so I spent a good amount of time walking through the modern sort of screening toolkit, and I've tried to be fair to the original USPSTF reasoning along the way. I think the over treatment concern was legitimate and I think the burden of trans rectal biopsies was real. And again, I take those objections seriously. But there's something I've sort of held back on until now, and it's a failure in the data that I think is so significant that it essentially undermines the entire foundation of the USPSTF position. Urologists have been pointing this out for years, and I think it's borderline unbelievable that it hasn't led to a formal revision of the guidelines. So I'm talking about that PLCO trial. That's the study that the USPSTF weighted most heavily when it decided that PSA screening wasn't worth doing. Here's what the PLCO study was supposed to show. You take a large group of men, you randomize half to get regular PSA tests, the other half not to get tested. You follow them over a decade and compare prostate cancer deaths between the two groups. The study found essentially no difference, supporting the conclusion that screening doesn't meaningfully reduce mortality. But here's what went wrong. And I genuinely had trouble believing this the first time I encountered it. The control arm. So this is the group that was not supposed to be screened, was getting screened anyway. The investigators may not have been providing the tests, but when they surveyed the participants, somewhere between 40 and 60% of men in the no screening group reported having had a PSA test within the year. And this wasn't a one time contamination event. That pattern held every single year of the study. So by the final survey, over 90% of the men in the control arm had undergone at least one PSA test in some years. More Men in the supposed control arm reported screening than in the intervention arm. So we will put the figure from the 2016 letter to the editor in the New England Journal of Medicine in the show notes so you can see this for yourself because it is quite striking. The bottom line is this was a study comparing PSA screening to PSA screening and then concluding that screening doesn't work when they didn't find a difference. That is the bedrock upon which the USPSTF built a recommendation that has affected tens of millions of men. Now, this data contamination wasn't published widely until 2016, well after the ORIG guideline change. Once it was out there, a group of researchers went back to the plco data in 2017 and did something really clever. They mathematically accounted for the frequency of screening within the contaminated control arm, calculated amine and lead time, essentially how much earlier cancers were caught in men who were screened more regularly, and then imputed a mortality reduction based on earlier diagnoses. When you run the analysis that way, correcting for the contamination, that made the original study essentially uninterpretable. The same PLCO Data show a 27 to 32% reduction in prostate cancer mortality attributable to regular PSA testing. I just want to sit with that for a second. The same data set, the same patients analyzed honestly, and it shows that screening prevents roughly a quarter to a third of prostate cancer deaths. And yet the USPSTF has not updated its guidelines since 2018. It still does not recommend PSA testing for men 55 to 69 and still recommends against it for men over 70. I think it's long past time for the USPSTF to revisit this. The same is true of organizations like the Canadian Task Force on Preventive Healthcare and the American association of Family Physicians. Until they do so, I think we have reason to be confident in taking this into our own hands. So let me try to synthesize everything we've covered, because I realize it's been a lot. We started with the observation that pulling back on PSA screening led to a measurable, ongoing increase in the incidence of incurable prostate cancers. That's not speculation. It's in the data. It's black and white from multiple countries. We 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. But 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. The ability to catch dangerous, that is lethal, cancers early while avoiding the harms of over diagnosis and over treatment has improved by an order of magnitude. And then we looked at the data that supposedly justified the shift away from screening 15 years ago and found that the Cornerstone study was so contaminated as to be essentially meaningless, and that a proper analysis of the same data clearly supports screening very strongly. So where does that leave us? Well, prostate cancer, as I said, number two cancer killer of men, and it's not receiving the urgency it deserves. I'll go further. I think it's unconscionable that we are still losing men to a disease that in many cases could have been caught years before it became lethal. And this is something I want people to really internalize because it goes to the biology of the disease itself. I've talked about this many times on previous podcasts, but I don't think I can talk about it enough. Cancer falls into roughly two categories. There are those that progress in a relatively predictable stepwise fashion, moving through detectable precursor stages before becoming truly dangerous. And then there are those that don't. They can emerge suddenly, metastasize quickly, and evade early detection no matter how aggressively you screen. I think that pancreatic cancer is the classic example of the latter, and sadly, many breast cancers also fall into that category. But prostate cancer, along with colorectal cancer, fit squarely in the first group. Prostate cancer tends to follow a very predictable path from early localized disease to advanced metastatic disease. And that biological reality is precisely what makes a screening detectable tool like the PSA so powerful. And what makes any deaths, let alone the 36,000 a year in this country alone from prostate cancer, so completely tragic. This isn't a cruelty of biology. It's a failure of our implementation. I've made this comparison before, but I think it's worth repeating. Imagine we had a breast cancer detection tool that cost less than a cup of coffee, could be incorporated into a routine blood test, and was capable of flagging cancer years before it spread. In what universe would we not deploy that tool as widely and aggressively as humanly possible? For prostate cancer, that tool does exist. Your primary care doctor can add it to your next blood draw. It might already be there. The barrier isn't technology. It's awareness. It's education. And most of all, it's outdated guidelines. In our practice, we've seen this play out countless times. Well, patients will come to us with PSA data from other providers, sometimes years of it. And when we calculate their velocity, the red flags are right there. We send them for an mri, depending on what it shows, a biopsy, and we've caught several cancers right at that stage, where had we waited another year or two, they likely would have been metastatic, but they were Gleason three fours or four plus threes that were right in that sweet spot for treatment. Before I close, I want to just sort of spend some time on a topic that is related to this, but a little bit oblique to it. And I think it's also becoming increasingly prevalent. And it's generally, I think, something we need to be alarmed about and physicians and patients alike need to be aware of, given the current state. And it's the interaction between a class of drugs called five alpha reductase inhibitors. The most common of these is finasteride, but there's another one called dutasteride and how they impact prostate cancer screening. So the use of finasteride has exploded in recent years, largely driven by men using it to prevent or treat hair loss. In fact, we've talked about this drug many times on other podcast, both in the context of hair loss and testosterone use. We've discussed the potential risks of finasteride and prostate cancer development elsewhere, but I want to have some dedicated sections here where I talk about that. So I want to focus on one specific issue, which is that finasteride, as far as we can tell from the data, does not cause prostate cancer. Okay? But what it absolutely unequivocally does is suppress PSA in a way that can completely mask the presence of cancer if the treating physician doesn't know how to adjust for it. Now, here's the finasteride blocks the conversion of testosterone into dihydrotestosterone or DHT, in the prostate. And that reduction in local DHT also dramatically reduces PSA production. As a practical matter, you can expect PSA to drop by about a third within six months of starting finasteride and to be roughly cut in half by a year. That suppressed baseline persists for as long as the patient stays on the drug. So let me state this as clearly as I can. If a man has been on finasteride for a year or longer, his PSA value needs to be, at a minimum, doubled to be interpreted correctly. And the correction factor we use actually increases with duration of use. In our practice, we multiply by 2.3 after two to seven years on the drug and 2.5 beyond seven years. Now, while the FDA label recommends multiplying by two. We do this based on data from the Prostate Cancer Prevention trial performed in the late 90s and early 2000s, as well as a follow up analysis from 2005 performed by Ruth Etzione and her colleagues. We've included a table from that in the show. Notes for PSA Velocity the practical implication is simpler but equally important. After about 12 months on finasteride you should not expect your PSA to rise at all. The ongoing suppression from the drug should roughly offset the natural age related increase in PSA. In fact, in a large study of 19,000 older men, those on finasteride who were cancer free actually showed an average 2% annual decrease in PSA. So any upward movement in a man on long term finasteride should be treated as a serious warning sign. And here's where I get concerned. Most general practitioners are not aware of this. It appears A retrospective analysis of VA patients undergoing PSA screening found that men on finasteride were diagnosed with metastatic cancer at a rate more than double that of men not taking five alpha reductase inhibitors 6.7% versus 2.9%. The doctors were reading the raw PSA numbers at face value, not realizing they needed to double them or more. The two groups had nearly identical PSA levels at the time of cancer diagnosis, about 6.8 versus 6.4. But once you correct for the finasteride induced suppression, the true comparison is more like 13 and a half versus 6.4. Those are wildly different clinical pictures and the physicians unfortunately missed it. This is in some ways an even more tragic version of the same problem I've been talking about for the past hour, because even in men who were getting screened, the screening was rendered useless because the physician didn't understand how to correct the results. And I think that's especially urgent because many men are getting finasteride prescriptions from online clinics and then not even mentioning it to their primary care doctors because they don't think it matters. So even a physician who does understand the PSA interaction can't account for it if they don't know the patient's taking it. So if you're listening to this and you're taking finasteride, the onus may fall on you. Please be sure that you not only advocate for regular PSA testing, but make sure that your doctors know about every prescription, including and especially those that involve five alpha reductase inhibitors, and ensure that whoever is interpreting your PSA understands both the drug and its suppressive effects. Again, finasteride does not appear to increase your actual risk of developing prostate cancer, but it can absolutely prevent your doctors from catching it on time. So I want to end where I think the evidence points, which is a place of cautious but genuine optimism. Between our understanding of PSA velocity and density. Again, the increasing accessibility of very high quality mri, the advent of transperineal biopsy, and the sophistication of active surveillance protocols for low grade disease such as those Gleason 3.3s. The field has made enormous progress in minimizing the very real risks of over diagnosis and over treatment that motivated the USPSTF's original positioning. And 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. We are in an extraordinarily fortunate position. We have the tools for early detection that are cheap, simple and effective. We have treatments that work. We have the ability right now to catch most prostate cancers before they become fatal. We just need to use what we have to advocate for it as patients and to understand it as clinicians. And I genuinely believe that if we do, prostate cancer deaths can be all but eradicated. So it doesn't have to be the second leading cause of cancer death in men. It could not even be in the top 20. So a summary of how we approach PSA testing in our own practice can be found in a newsletter that we published yesterday on the same topic and we'll also link to it in the show Notes where you can also find all of the studies and references from today's episode as well. So I hope you enjoyed this episode on a topic that I'm very passionate about.

A (45:03)

Thank you for listening to this week's episode of the Drive. Head over to Peteratti md.com shownotes if you want to dig deeper into this episode. You can also Find me on YouTube in the Instagram and Twitter all with the handle Peteratti md. You can also leave us review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment. Users 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. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or Advise, please visit PeterAttiaMD.com about where I keep an up to date and active list of all disclosures.