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Dr. John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast. Conversations about new developments in medicine, cancer care and research. I’m your host Dr. John Leonard and today’s topic will be prostate cancer screening and treatment. I’m very happy today to be joined by Dr. Jim Hu and urologic oncologist and Director of the LeFrak Center for Robotic Surgery at Weill Cornell Medicine and New York Presbyterian Hospital. Dr. Hu is internationally renowned as a surgical innovator and a health services researcher. His areas of clinical and research expertise include prostate and kidney cancer and his research interests have been funded by the Department of Defense, the National Cancer Institute and the Livestrong Foundation. Jim has performed thousands of robot-assisted prostatectomies, laparoscopic, robotic and open procedures. So, he really is an expert in our topic today. So, Jim, thank you for joining us. It’s great to have you here.

Jim Hu, MD (Guest): Thanks John. I’m delighted to be here today.

Dr. Leonard: It seems like the area of prostate cancer is particularly kind of multidisciplinary and has a lot of beyond the technical aspects of it, which are obviously important and challenging, what we are going to talk about today, I think is one example of how the kind of implementation of what you do when and how and for whom remains a big thing and probably is going to remain a big thing for a long time it seems.

Dr. Hu: Yeah, absolutely. I think one of the overarching things of medicine these days is overdiagnosis and overtreatment and I think as a prostate cancer expert you are not – you are typically not just operating removing people’s prostates robotically now; it’s kind of when to do the right thing so to speak.

Dr. Leonard: Right, so we are going to get more specifically into prostate cancer screening in a second, but just at a high level and I know you have a lot of training and experience in health services research. I mean why is this so complicated? It would seem like it would be very easy on the surface, I’m sure many people in our audience are like well why can’t I just go to my doctor, he or she tells me what to do, I do it and then we are done. What is it about this area of medicine. Why is it so controversial and not cut and dry? Is it just the nature of the data that we have or what?

Dr. Hu: Sure, I think – I think it goes back to when we all took the Hippocratic oath First do no harm and we are recognizing that a lot of things not only beyond just PSA and prostate cancer screening that oftentimes, screening can cause mental anxiety. There are false positives that patients start to worry about. Some of these tests for instance a biopsy for the prostate increasingly there’s more drug resistant bacteria so your risk of infection goes up and it’s not very comfortable and in addition, prostate cancer typically grows very slowly and so even though we are diagnosing something, there may be six or seven years before it may spread outside and the sweet spot of course for this problem is older men and so one has to take into account life expectancy and look at the quantity of life as well as the quality of life.

Dr. Leonard: Right. So, before we get into the details of the data at what point and who should be starting to think about should I get screened for prostate cancer and then kind of walk us through the process of how you approach that with an individual, just in a general sense. 

Dr. Hu: Absolutely. So, I think the – in more recent years really back to 2009, there were two landmark studies, randomized trials that were published in the New England Journal of Medicine which of course is one of our highest impact journals; and really what we gleaned from one of the studies, the European study in fact, is that the study design was such that men started screening at the age of 55 and they stopped at the age of 69. And in that study, there was a benefit to prostate cancer screening. We saw a decline in the mortality associated with or death from prostate cancer and so that’s really – because of the way that that study was designed, the entry being 55 years young and so I think that’s where the guidelines or the opinions of experts have somewhat converged and so presently; for instance we used to as the American Urologic Association or a lot of these professional organizations would want annual screening starting at the age of 50, but based on that randomized trial; we are saying to start at the age of 55, do it every three or four years rather than annually, family history, and that hasn’t been chronicled as well in the past. We are just starting to understand that more with genome sequencing and so forth, inheritable prostate cancer and so if there is two or more relatives, primary relatives, your brother, your father and so forth, that have prostate cancer; it’s thought that one would want to start the PSA screening earlier. And also, African American men because of course the European study included very little men that were not of European descent; we know less about but we do know that African American men in the United States typically are diagnosed with more aggressive prostate cancers. They have a higher prostate cancer specific mortality. They are more likely to die from it and so it’s thought that screening could happen earlier for those men as well.

Dr. Leonard: And then are there any other besides that risk factor, others; I know BRACA genetic background is also at least influences prostate cancer. Any maybe just briefly on that as well as anything else that would perhaps get somebody screened earlier or differently.

Dr. Hu: Absolutely. So, in that family history, if you have a – your mother or a sister who has breast cancer, ovarian cancer, has this screening the genomics test done and has BRACA; certainly that influences and as you said, a BRACA2 in particular and BRACA1 as well can influence the greater risk for having prostate cancer as well as a more aggressive prostate cancer. When they have looked at metastatic prostate cancer which has already spread outside; in fact, about 12% of men have one of those BRACA type mutations or a DNA mismatch repair mutation and so I think we are starting to just scratch the surface at looking at genomics. I think in terms of whether that’s actionable or not I think we are starting to make – there was a meeting just last year in Philadelphia where there was expert consensus that again if you had two family members or so forth, you should do it earlier and consider getting the somatic testing or looking at if these changes were something you acquired over one’s lifetime and if that’s positive then to consider looking at whether it’s a germline or a mutation that was inherited.

Dr. Leonard: So, more or less, it sounds like unless you have a predisposition or a risk factor, 55 is more or less the age where most people are going to be thinking about this. So, then obviously the next question is well okay how can I be screened and I know PSA checks, physical exam, other testing. Give us your sense of that for the average risk kind of person.

Dr. Hu: Sure, absolutely. And so, on caveat and I know we have very sophisticated listeners and so when these experts sit around the table; they are not just prostate cancer experts; they are public health experts, there’s internal medicine, infectious disease, pediatrics and so when you look at the US Preventative Services task force; they are looking at things from a 40,000 foot view. Now we do have various studies that look at men who had a blood test in their forties and it was actually longitudinal studies for other reasons like looking at did they develop heart disease. But because they kept such a great natural history of what they eventually developed over time; it was found that if you had a PSA in your forties and it was less than 1; then your lifetime risk of dying from prostate cancer was less than 10%. And so, although we are speaking of it from a level 1 with these randomized trials; there is some evidence that if you want to get a PSA in your mid-forties or during your forties and extremely low; then that can guide how frequently you may want to check your PSA once you get into your fifties. So, I just wanted to mention that caveat because I think that that is a – that’s something that one’s not going to have to pay out of pocket for a PSA.

Now going back to your original question, how do you typically do it, yes, typically there has been a PSA test as well as a prostate exam, the traditional most exciting part of the visit for a lot of men, but by and large I think even the American Association or Academy of Family Practitioners; a lot of people are moving away from that traditional prostate exam because there is very few people that are going to have a nodule without an elevated PSA. And it also gets into the controversy of what normal versus abnormal is. Now we have age-specific cutoffs, there is an absolute cutoff of four being above four was abnormal. There are more sophisticated ways of looking at this, get a prostate size and PSA density or using PSA as the numerator over the volume of the denominator. So, there – PSA kinetics and it’s almost a field of its own because we have really kind of shed some insight into the controversies.

Dr. Leonard: Right. So, a patient comes in, the routine screening PSA is below four, they are kind of good to go for a while and so what – I don’t want to misrepresent it, but is that basically the story and less focus on the physical exam part, I mean still do it, don’t do it; what do you advise people? 

Dr. Hu: Sure. So, there is definitely as you mentioned, there is definitely some subjectivity in whether you feel a nodule or not and we have to keep in mind that some of them may be what we call false positives oftentimes and so, I still do the – as part of prostate cancer screening; I will still do the prostate exam because we do know that there’s some very aggressive or what we like to throw around the word poorly differentiated cancers that aren’t going to produce a high level of PSA and so, in theory, you can still have prostate cancer when your PSA is normal because as we know, normal is 95% of the population. As far as the cutoffs, I tend to use what’s called age-specific PSA cutoffs and so, going back to that example for a man in his forties; that person’s PSA should be less than 2.5. For someone in their fifties, it should be less than 3.5. Someone in their sixties less than 4.5 or seventies less than 6.5. So, there is a jump and the reason for that is that we know that as men get older; there’s the process of benign prostatic hyperplasia, why men have to feel like the urine comes out slower, they don’t empty their bladders completely which is separately distinct; but that’s also a manifestation that the prostate enlarges or gets bigger as we get older. And so, that normal level increases as we get older as a result.

Dr. Leonard: Got it. And then I understand just from having an occasional patient where this has come up that there are some kind of fancy versions of PSA tests out there and maybe – and my sense is this is kind of an added level of either reassurance or a concern based on what these are. But maybe if you could just tell us kind of what their role is as of today.

Dr. Hu: Absolutely. And so, I think this area cropped up if you will because if someone had one abnormal PSA, I think one wants to be a little bit more judicious rather than going straight to prostate biopsy. And so, there has been studies that have shown that PSAs can – if you drew one, in two or three months then it’s going to change, so there is natural variation. The first PSA that came out to try to address this question if your PSA was between four and ten; there was getting the percent free PSA and the higher the percent free PSA, the less likely that an elevation was due to prostate cancer. There’s also now what’s called a PCA3 test and that’s if you have an elevated PSA, the FDA approves it only in the setting of a prior negative biopsy and the PSA is consistently elevated; then the urologist or physician does a prostate massage, has the patient urinate and there’s a protein in the urine PCA3 and if it’s above a cutoff of 30, then that’s considered higher and a biomarker or another reason to repeat the biopsy.

More recently, there’s a test called the 4K that looks at different isoforms of PSA and it’s resulted as a percent chance that a man may have what we term a clinically significant prostate cancer. So, we don’t want to find the ones that are indolent and slow growing and isn’t going to cause harm and so that test is standardized to your risk of having clinically significant. And so, these are all the biomarkers or additional blood tests that one can have and there are other ones similar to 4K like a PHI or Prostate Health Index that try to guide whether or not one needs a biopsy.

More recently, there was – and we are fortunate at Cornell to be part of an international randomized trial that was published in the New England Journal of Medicine called the Precision Study where a man with an elevated – single elevated PSA was randomized to getting an MRI, prostate MRI versus just going straight to a regular transrectal ultrasound guided biopsy. And in that study, we found that if you had an elevated PSA, got an MRI first, you could avoid a biopsy in roughly 30% of men and that is the MRI did not see anything abnormal in the prostate or there was low suspicion, but then if you had a – what they term a PI-RADS 3, 4 or 5 – the MRIs are scored on a 5 level category; then those men went on to biopsy and it was found that 36% of the men that – in the MRI arm who went on to biopsy had detection of a Gleason Grade 7, that’s a clinically significant cancer higher, whereas in the arm where everybody underwent biopsy with a transrectal ultrasound, it was only 26%. So, there was a 12% absolute increase and that’s level one evidence, and I think we are seeing it at least in Europe.

The Europeans have adopted getting an MRI now after an elevated PSA as part of their professional guidelines. I worry about widespread adoption of those guidelines here in the United States because not everywhere is equipped to do a high-quality MRI nor do they necessarily have an experienced radiologist who can make that reading. And so, you can see how that may again, with that public health background; you may be looking at the 40,000-foot view of how our healthcare dollars are spent. And I think over time, the expertise will develop, but it may be a little too early just to reflex to an MRI just with an abnormal PSA.

Dr. Leonard: So, I want to get into it in a second, so it seems like there’s a lot of in the tests you just described, whether it’s more sophisticated blood tests or imaging; it sounds like there’s a lot of dancing around who with a borderline or elevated test should get a biopsy and I want to get into that in a second. But, if you look at 100 standard – and I know I am asking you to generalize and it probably depends on risk and age; so, is 100 men come into a primary care practice, let’s say they are 55ish or 55 to 65 in the screening range; what percent will have like a stone cold everything is great PSA see you in a couple of years versus what percent of men, is it 10%, 20% where the PSA is funny enough that you have to now think about these other machinations, ballpark-wise?

Dr. Hu: Sure, so, I wish I had firm statistics to give you an exact answer. So, we know for instance when a man got PSA screening starting at the age of 50 and everyone did it, the primary care doctor just checked off as your annual blood test get a PSA; and this was just as recently as say seven years ago; if you look at the instance of prostate cancer at that time, it was 230,000 US men a year and so at that time, your lifetime risk of being diagnosed with prostate cancer was one out of six. Now as we are – have moved back the age of PSA screening and it doesn’t happen as much; that lifetime risk of prostate cancer is one out of nine and so, often – going back to your question kind of doing the math backwards and ballparking it; a biopsy is positive about a third of the time and so if you think about let’s say one out of nine US men are diagnosed with prostate cancer; you multiply that – so maybe one out of three men had an abnormal PSA, underwent a biopsy and so you can see that the scope of the problem is pretty common in terms of how much we look for it in the United States, also as we live longer, the Western diet and obesity has been associated with a lot of other – increased prevalence of other cancers, I think that’s why in the United States, it’s still the or the most commonly diagnosed cancer in men, but also the second leading cause of death in men.

Dr. Leonard: So, why not get a biopsy? I mean from the standpoint and just walk us through how you think about it with a patient. So, the PSA is slightly elevated, I’m worried, I don’t want to have prostate cancer, if I do I want to get it dealt with quickly. I mean it seems to me like there are issues around the procedure itself and the pros and cons of the biopsy procedure itself and then obviously which maybe we will get to in a second, the concept of whether you might find a cancer that you are not going to do anything about or you might not do anything about. So, kind of frame that how you think about that with patients because it strikes me that all these tests to say yes or no biopsy are geared toward maybe a better selection of patients for biopsy. So, how do you think about that?

Dr. Hu: Absolutely. I think that so and I think you hit the nail on its head when the United States Preventative Services Task Force made its recommendations originally in 2012 against PSA screening; they assigned it a grade D recommendation saying there is very little benefit, I think they were – there was this study, the US study we didn’t realize at the time the amount of contamination or that in the control arm, a lot of men has PSA testing so it looked like there was no difference in whether or not it affected mortality. But now we know, that it was heavily contaminated, so you are comparing apples to apples rather than apples to oranges.

Going back to your original question, so one of the things that they – was mentioned as a reason not to do PSA screening is that the harms of screening of course outweigh the benefits. And one of those harms is that a lot of prostate cancers are overtreated, meaning that if you had a positive biopsy back then for an indolent or low-grade cancer; it was almost a reflex to treat that with either surgery or radiation. And so, one of the things that has happened now is that we know that of all men diagnosed with prostate cancer which in the US is about 170,000 men annually; that more than half of them now go on to active surveillance meaning that it’s just monitored with PSAs every six months, a repeat biopsy in the future and so I think the knowledge based on some of these longitudinal studies that have happened in the UK; I’m sorry to say more than the US, because of the biases inherent in some of these trials; is that we have learned that a lot of prostate cancers are not harmful.

And so, I think that now the decision to undergo a biopsy if you are diagnosed with Gleason 6 prostate cancer and you alluded to the New York Times earlier; one of the things a few years ago if someone came in and they had indolent prostate cancer; I would pull up in our office this article that Gina Collada wrote and it said it had a man leaning on the back of his red Camaro and it said now most men don’t have definitive therapy and so a lot of Americans, they read the New York Times and if it’s in there; they say okay it’s the right thing to do. And so, it’s just an anecdote that the way that we even think of prostate cancer once you have been diagnosed has changed and therefore I think there’s more men who aren’t necessarily as afraid of that diagnosis because they now think of it in terms of a chronic disease like diabetes of hypertension that you just have to keep track of rather than something that maybe life altering in terms of a radical treatment or treat the whole prostate, remove it and so forth.

And so, I think that there’s that knowledge that has probably led more men to be more accepting of at least knowing and one of the – for instance one of the American Urological Association worked in concert with the National Football League and oftentimes those things with sports associations, because men often of course, listen to or watch these sports; and one of the campaigns was Know Your Stats. Just saying that if you know, the knowledge is better than ignorance and so there’s still unfortunately some segments of the population where people aren’t getting screened or tested. But I think that that – the pendulum has swung back from no screening at all to where it’s an individualized choice where you have a discussion with a man about what are the pros and cons of screening and I think that threshold for not getting tested or going on to a biopsy has become lower.

Now a biopsy takes typically about ten minutes if you are using a more sophisticated technique, that MRI-guided technique that we spoke of sooner. It is uncomfortable though, I mean you have a probe that’s a little thicker in diameter that one’s thumb in the rectum for about ten minutes and despite the fact we numb it up, some men find it to be very uncomfortable, there is going to be blood in the ejaculate for about two months afterwards, blood in the urine for about two weeks. And so, for some men, that’s very alarming for them to see blood in the ejaculate which reminds me of an anecdote. A famous urologist once said the cure for blood in the ejaculate is just to turn off the light. So, but it will eventually resolve. But again, that’s something that’s distressing because we have never seen that in one’s lifetime.

Dr. Leonard: So, there are – the implication here is that there are clearly men where you will say we should pursue this, we should pursue a biopsy beyond individual choice or preferences and clearly men who you are not going to pursue a biopsy or you are going to advise against screening and you alluded to that and it sounds like age-based guidelines are part of it, but who are the men who you would say, you shouldn’t get screened or you can maybe get a PSA check, but maybe not be less likely to pursue a biopsy because you are probably not going to have something that at the end of the day we are going to want to intervene with. And I know there is a lot of gray area here, but kind of just in a rough sense, it would be helpful to hear.

Dr. Hu: Absolutely. So, I think the person – the guidelines are that if you are 70 or older, that you don’t need a prostate biopsy and that goes back to the traditional if your life expectancy is less than ten years, then we shouldn’t really look for prostate cancer. I think the challenge of that is that no matter how good these life calculators are and I know why we do that, the 40,000 foot view of using a 70 years as a threshold; but as you and you are a busy clinician I know and you see some 75 year olds and they look like they are 65 and I think our society is now there’s the term ageism out there and so I think you have to assess there’s chronologic age versus biologic age and in particular, where you practice also has a big influence.

For instance, here, we are in New York City, we are fortunate to have very sophisticated patients and very honestly, I think it’s harder to tell these guys heh this is the guidelines we should stop doing PSA testing because people here are very sophisticated. I think they would know what to do with the knowledge of what that PSA is or if they had indolent prostate cancer and they naturally want to know. I think a lot of people think that they have a good shot at getting to 100. Whereas I think in some health systems across the country; where there is more accountable care organizations where for instance, there may be alert you automatically in your electronic medical record are ordering a PSA on the electronic medical record, you are going to get a window pops up that says do you know that this is not guideline medicine and keeps track maybe of how many PSAs you are ordering. So, some of these health system effects I think dictate that. But to your point, I still have a very thorough discussion with everyone but tell them that the experts recommend not getting a biopsy above the age of 70.

Dr. Leonard: Great, so we are going to wrap up soon because we are running out of time. But I want to ask you two questions and in a second, I will get to just your high points on therapy and new things there. But I want to get your sense of maybe from the standpoint of someone who has got again, your background in looking at these and developing these guidelines; at a big picture level, and this comes up with mammography, it comes up with other areas. What’s your take on the concept of guidelines panels? These are sorts of things that are obviously they get out there, obviously they can be often controversial and have different recommendations. Some people worry about conflicts of interest in these panels. Kind of give me your sense of your take on how you view kind of the pros and cons of these guidelines panels when they come out so that you can put them in context for people who may read the next ones that come out and try to interpret what to do with it?

Dr. Hu: Absolutely and I think that’s obviously a very timely question as we get to the conflicts of interest story. I think that guidelines need to be there because a lot of payors, a lot of health systems, insurance companies, there’s not going to be a randomized trial for everything. And therefore, expert consensus is going to be the best thing that’s out there. For instance, when we look at the NCCN or the National Comprehensive Cancer Network; those are prostate cancer guidelines that aren’t only urologists who may want to operate on everyone. Of course, I say that with a grin on my face. There are also medical oncology representation, there’s the radiation oncologists and so, I think that they are still helpful, but I think it’s important – the ethos or culture of our country is that the individuals have a choice. And that’s still the case, although one can see every year we can see how much healthcare is part of the GDP, and that I think things are ratcheted back but I think guidelines are still important and I think they are well-meaning people that try to do the best thing.

Dr. Leonard: Great. So, just in the last thirty seconds or so, what are the big high points that you would say a patient diagnosed with prostate cancer or concerned about prostate cancer as far as therapy should know about? And I know you are involved in a number of these kind of cutting-edge sorts of treatments. What’s top of mind that people should think about or that you are excited about now in the future?

Dr. Hu: Sure. So, I think first people should take a deep breath and relax. The ten-year survival if someone is diagnosed with prostate cancer is 95%, five-year survival is 99%. So, just know that you have time to make the best choice. Secondly, you want to seek out an experienced person regardless of what they do, whether it’s an active surveillance or do biopsies. You alluded to new technologies now, there is partial gland ablation where you are not treating the entire prostate, that’s a radical departure in how we treat it. It is kind of like the paradigm in breast cancer in the 1970s of starting to do lumpectomies rather than sort of remove the entire breast. And so, key thing for that is that it’s an emerging paradigm. We don’t really have a lot of evidence, in fact, going back to guidelines, they say that there’s not enough evidence to really make a suggestion to do it. So, understand that you should be doing it on a clinical trial setting.

Dr. Leonard: Great. Well I want to thank you. This has been a great discussion. I have learned a lot and I know that our audience, many people out there are thinking about these issues for themselves or for their loved ones and it sounds like it’s going to continue to be challenging but thank you for your perspectives which I think the balance that you have kind of laid out for us I think is important to keep in mind and at the end of the day, like most things, I think you want to see a – get educated as a patient and really speak with somebody who can present the pros and cons of any of these situations to you well and make an individualized decision. So, thanks very much for joining us.

Dr. Hu: Oh, it’s my pleasure John. It’s great to chat with you and the audience out there.

Dr. Leonard: Well I want to thank our audience for joining us today and want to encourage you to download, subscribe, rate and review CancerCast on Apple podcasts, Google Play music or online at www.weillcornell.org. We also encourage you to write to us at //This email address is being protected from spambots. You need JavaScript enabled to view it./">This email address is being protected from spambots. You need JavaScript enabled to view it. with questions, comments or topics you would like us to cover in more depth in the future. That’s it today for CancerCast Conversations About New Developments in Medicine, Cancer Care and Research. I’m Dr. John Leonard. Thanks for tuning in.

Melanie Cole: If you or a loved one is undergoing cancer treatment, rehabilitation medicine can help with recovery and ease painful side effects. Listen to Back to Health, Weill Cornell Medicine’s podcast series dedicated to rehabilitation medicine, to learn more about the ways physiatrists can help.

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