Prostate Cancer & Men’s Health Edition | Updates in Advanced Prostate Cancer

This episode is brought to you by Estela Sancology. Estela Sancology is changing the course of cancer treatment. With a world-class team of medical, clinical, and scientific experts, Estela Sancology is driving innovation and collaboration to redefine what's possible for those impacted by hard-to-treat cancers. Learn more at EstelaSancology.com. This is Mayo Clinic Talks, a curated weekly podcast for physicians and health care providers. I'm your host, Darryl Chetka, a general internist at Mayo Clinic and Rochester, Minnesota. Prostate cancer? It's the second most common malignancy in men second only to skin cancer, and due to increased efforts in screening, most prostate cancers are found very early, and these men have an excellent survival rate. Unfortunately, a percentage of men develop an advanced prostate cancer, and the disease becomes much more aggressive with significantly lower survival rates. So who's at risk for advanced prostate cancer? How does the survival rate change with metastatic disease? Finally, what are the various treatment options and how effective are they? We'll discuss these questions with our guest, Dr. Ellen Bryce from the Division of Hematology and Oncology at the Mayo Clinic in Phoenix, Arizona. You're listening to Mayo Clinic Talks. Welcome, Ellen, and thank you for joining me today. Thanks for having me, Darryl. Happy to be here. Well, Ellen, let's start by asking you to describe the grading and staging of prostate cancer, because I think once we understand that, the rest of this podcast will make more sense. So the grading of prostate cancer is what we learn back in medical school. This is a Dr. Gleason's old system where he describes the grade according to the the microscopic appearance on pathology of the cell. So, you know, that's that familiar Gleason 678910 that we all knew back then. Nowadays, the additional detail you'll see in the pathology report is the pathologist will put it into a Gleason grade group, the GG, and that's just an evolution of the same scoring system for semantic purposes for the most part. So, grade group one is Gleason 6. Grade group two is 3 plus 4. Group three is 4 plus 3, because we've always known that 4 plus 3 is worse than 3 plus 4. Group four is Gleason 8 and Group five is is 910. And then the staging, the only thing that's a little bit unusual about staging in prostate cancer is the fact that, you know, this is the only cancer where the physical exam contributes to the staging. And I think that's probably not an important point for the internist to understand per se. I think more simplistically, we start talking about cancer as being advanced. Once we start to hit stage three, where there's locally advanced disease, invasion of the seminal vesicles, extra-prostatic extension, etc. And then stage four is when there's any distant metastatic disease, inclusive of lymph nodes, bones, or viscera. So, anything that has left the prostate and traveled elsewhere qualifies as stage four. Okay. So, who's at risk to develop advanced prostate cancer? In the most simplistic sense, right? Anybody with a prostate? Any man, I mean, this still remains true that advanced prostate cancer is a function of age, you know, more than anything else. And the most effective way we have of preventing it is effective screening. But higher risk populations certainly exist, so people with familial cancer syndromes. So, I think one of the most important things I always want to remind an internal medicine audience is that prostate cancer is a BRCA associated malignancy. So, it's often forgotten. We remember that breast and ovarian cancer are BRCA associated cancers, but we forget that pancreas and prostate cancer are as well. And the reason I know we forget this, right, is we look at notes of women who are asked about their sisters and mothers and men who are asked about their fathers and brothers. But, you know, it's important to remember that there is no such thing as a familial cancer syndrome that is gender specific. All genes that confer a risk of cancer affect both genders. They just cause different cancers in the genders. So, it's really important in taking a family history that we ask about the men and the women and the family alike, regardless the gender of our patient. And that's probably the biggest thing from an internal medicine perspective of who are the highest risk patients. The second piece of that is that there are differences based upon ethnicity and background. So, black men clearly have a higher risk of prostate cancer than white men and then Asian men have a lower risk than white men. So, there is some variation there, but that's actually a much less powerful discriminatory factor than the familial genetic risk. So, I think that's probably the highest risk population that most practice you're gonna see. Okay. Well, when I think back to my practice many, many years ago, I saw a fair number of patients with advanced prostate cancer, but I would say in the past 25 years, I can only think of one or two. So, is it more common for a patient to present initially with advanced prostate cancer or do most develop following some treatment, either cross-detectomy or radiation therapy? Well, certainly most men will develop advanced disease after initial treatment without question, but to your point, that has evolved over time in this country and it's entirely a function of PSA screening. So, the reason you saw those men disappear in your practice is because PSA screening was approved, and as that took hold in the 90s, then the number of early diagnoses went up and the number of late diagnoses dramatically declined. And yet, if you look around the world at different countries in the developed world, in the proportion of advanced versus localized disease and initial diagnosis is really completely a function of the screening practices in that country. Now, in the United States, at one point, we were doing a pretty good job and we were able to say that only 5% of men will have metastatic disease and initial diagnosis. But in the last seven, eight years, first due to the change in the US-prevented services task force recommendation, then secondarily due to COVID, the proportion of men with metastatic disease and initial diagnosis has gone back up. It's approaching 10% now. And of course, that's consequential, right? Because in prostate cancer, localized disease, as you said at the top, has a very high cure rate. But metastatic disease over 80% of men with metastatic disease will die of prostate cancer, not anything else. And men with denoval metastatic disease, that is metastases at the time of initial diagnosis, they're overall survival is only about three and a half years. So the most effective way to cure prostate cancer is to find it early and the fact that we're kind of backsliding in that battle is a problem. So it's a much different disease when this thing becomes advanced? Absolutely. All right. Well, what are the common locations for a spread of prostate cancer? Prostate cancer really likes bones and lymph nodes first and second, right? So about 90% of patients with metastatic disease will have bone metastases, 85 to 90% will have lymph nodes. And then in descending order, 25 to 30% might end up seeing lung metastases, 20 to 25% might see liver, 10 to 15% adrenal and then all other organs are fairly uncommon, single-digit percentages, CNS disease in 1% or less. But now what's happening in cancer overall is as we become more successful at treating metastatic disease, as we keep men alive or any cancer patient alive longer with, you know, more lines of therapy, more successful disease, what ends up happening is we end up seeing more aggressive disease developed in the end because the cancer revolves over time and the longer we keep a patient going, the more aberrant the cancer becomes. So, you know, all the statistics I just mentioned in prostate cancer, just like in every other cancer, those numbers are clearly changing as we keep patients alive longer. Well, as primary care providers, we see a fair number of patients for follow-up with prostate cancer. And what should we be assessing in order to determine if there's evidence of spread of this disease? As imperfect as PSA is, if a man has been curatively treated, then PSA is the most effective tool for detecting potential recurrence. So, if a man has had a prostatectomy, his PSA should be zero, and any detectable PSA represents some residual disease, likely metastatic. Now, that circumstance of a slow rising PSA is not a harbinger of doom, which is, in a really important point, I want to convey, when a man has biochemical recurrence, which is the term we use for a rising PSA without radiographic evidence of disease, the vast majority of those men will still live out the rest of their natural lives and die of something else. So, it's a development of visible metastases on scans. It's really the inflection point between men who won't die of prostate cancer and men who will. But biochemical recurrence is no cause for panic, because the typical man with biochemical recurrence will have it for many years, potentially 20 plus, but a median of eight years before you'd see any metastatic disease. That's the one thing I'd have a primary care doctor do, and typically in surveillance. It's only once every six months. after curative intent treatment at Jekyll PSA. - Okay. So let's say a patient doesn't return for follow-up and the disease becomes more advanced. What might they notice in terms of presenting symptoms? - For a patient who presents with symptoms, bone pains probably most likely because bone is the most common sight of disease. Even though plenty of prostate cancer patients with bone metastases are actually pain-free, if it's a man presenting clinically, then obviously we're selecting for the symptomatic man and that'll be bone pain. The other symptoms are constitutional and therefore vague weight loss, fatigue, et cetera. And those are the kind of symptoms that will often just get attributed to non-malignant causes for quite some time before the patient comes in with a complaint. - Okay. Well, let's change directions a little bit. And let's talk about the various treatment options for advanced prostate cancer. Why don't we start with hormonal therapy? - In prostate cancer verbiage, when we say advanced, we're talking about at least locally advanced and therefore potentially requiring radiation after surgery or we're talking about metastatic disease. Now, for systemic therapy, ADT, energy and deprivation is still the backbone of treatment without question. And even though men don't like ADT, because what we're talking about here is inducing andropause, some male equivalent of metapause with all that goes along with that, it is still the single most effective therapy for systemic treatment of prostate cancer. It's something I should have said when we're thinking about what does an internist need to think about? These men who go on ADT, potentially at early stages of their disease can still live for many years. 10, 20 years is entirely possible depending upon when we're initiating treatment. And so management of a long-term effects of ADT is one of the most important things that certainly prostate cancer doctors have to think about, but the internists will see it well as well. Really it's the same as menopause. Men on ADT need a yearly screening for osteoporosis, just like women going through menopause. Of course, these men, their metabolism slows and with slowing metabolism, then we're talking about redistribution of body weight increasing obesity and then all the secondary effects that go with that, right? So increasing hypertension, risk of hyperliplidemia, risk of diabetes, heart disease, et cetera. And it's managing those systemic consequences of treatment that is one of the most important things in the long-term management of advanced prostate cancer. - Is orchiaectomy still used? I haven't seen that in patients for a quarter while. - Yeah, this is simply a matter of patient choice. Orchiaectomy is entirely appropriate. It works. It is more or less equivalent to, you know, the traditional lupron, analogue arts shots that we're so used to, but very few men choose it. We discuss it in the clinic. Now, you know, what I find is that men who choose orchiaectomy are either those that live at a distance and coming into medical care is quite inconvenient for them. Or, you know, the more elderly patients who just say, "Look, I don't care. "Let's just go ahead and do the surgery." It's absolutely an option. It's perfectly appropriate, but men just don't choose it. - Okay. And how about chemotherapy? And why would you use chemotherapy versus hormonal therapy? - Yep, it's not either or. So in prostate cancer and in the broadest general sense, or advanced disease, our systemic therapy options break down as hormonal therapy of which the injection therapy, ADT is the first line, but we actually have multiple subsequent generations. Chemotherapy of which there are two drugs, dose of tax, or cabagetaxle, that have proven to extend overall survival and we'll get into more detail there. We have one mild immunotherapy, if you will, that's Provenge. We now have injectable radio ligand therapies. That's Pluvicto, that's an isotope that gets injected systemically is attached to a targeting molecule, which will deliver that isotope to the prostate cancer cell. And we also have radium 223, which is a more traditional radiopharmaceutical extrinsium Sumerium that gets concentrated in the bone compartment, because in terms of inorganic chemistry, it mimics calcium, right? So it just gets absorbed into bone in the body and is effective for treating bone metastases. So those are the broadest terms, but in terms of the either or question, it's not either or it's really combination. So ADT is the backbone of their P for prostate cancer patients. And essentially what we do is we layer on all these other options on top of ADT, either in combination or in sequence. So for the man with metastatic prostate cancer, the book answer with few exceptions is that he should be on continuous ADT. It's permanent because the testosterone drives prostate cancer cells and whenever we bring testosterone back, the cancer will start to grow again. And then we layer other therapies on top. One of the things that's happened in the prostate cancer world, and I think everyone's well familiar is that there is a fairly unique antagonism towards chemotherapy for prostate cancer patients. For any other cancer, we don't really spend much time debating whether chemotherapy has a role, but in prostate cancer, that conversation never goes away. And I think it has to do with some traditional bias that existed for generations. The story here is dose attacks will clearly extend survival for prostate cancer. And if we use it early in the first line setting, it'll extend overall survival by more than a year. If we use it in the late line setting, it'll extend overall survival by a couple of months. And one of the things I emphasize to patients is, in the world of cancer, amongst all chemotherapies, dose attacks will minor monotherapy as one of the mildest options we have. If I was treating lung cancer, I would use dose attacks will in combination with a platinum or another agent. If we were treating breast cancer again, we'd use the same dose attacks with the same dose in combination with one or two other chemotherapeutic agents. The fact of the matter is, other cancer patients can get much more aggressive chemotherapy and do okay, but for some reason, there's this belief that prostate cancer patients are uniquely fragile. The man's wife can go through combination chemo for her breast cancer, but the man can't get chemo. And I've never understood that thought process. You know, what we do at oncology, at least, is data driven. We talk to the patient about overall survival. We talk to them about quality of life. The encouraging news, and you might not know this, but I mean, I think this is a key point for the internus. I can show you the data from our randomized control trials of dose attacks on the first line setting, using it right up front and prostate cancer patients in combination with ADT. And those studies as all modern cancer trials now have patient reported outcomes in quality life surveys built in that are done longitudinally over the course of the study. And if I ask patients right up front, or if you ask yourrologists, all right, so what were you told about the side effects of chemotherapeutic? Oh, it's terrible. It destroys your quality of life. We shouldn't do it for prostate patients. But the data is clear. We have level one evidence. We don't have to debate it. And what you see in this randomized trial of ADT alone versus ADT plus chemo, the men with chemo had a slight decline in their quality of life during the four months of chemotherapy. But within two months, the men who got chemo ended up with a higher quality of life than the men on ADT alone and that advantage persisted for more than two years. And so people get surprised by this. How is that possible? How does chemo improve your quality of life? Well, the answer is actually really simple. And it's fairly intuitive if you treat cancer patients, which is the primary driver of pain and suffering and decline in any metastatic cancer patient is uncontrolled disease. And when you give better disease control, you improve quality of life. So when we tell our patients, oh, you know, avoid the drug that gives you an extra year of survival because it's too toxic, we're actually condemning them not only to a shorter life, but to a lower quality life. Because better disease control means better quality. That makes sense. When is targeted radiation therapy used? In localized disease, or if there's high risk features at surgery, we would do radiation to the prostate bed, that's salvage or adjuvant. But if we're talking about metastatic disease with visible metsan on imaging, then the role of radiation is mostly twofold. One is to treat symptomatic disease. So painful bone metastasis, certainly we'd want to treat. Or, you know, lesions that are otherwise problematic, lesions that are causing obstruction or whatnot. Now nowadays, we will also do what we call radiation for oligometastatic disease, which means only a couple of spots have popped up. And in that case, what we're doing is we're spot welding in the hopes that by doing that, we can buy the patients sometime and delay the advancement of their systemic therapy regimen to the next line. Sometimes it works. I mean, I have patients where we do the spot welding and they might get an extra 12 months of disease control. And that's a win. But of course, if I do the spot welding and then two months later we have another metastasis and another and another, that's when we know the pace of this disease is too fast for local radiation to help. OK. You made a reference to immunotherapy a little while ago. Can you expand on that? As we mostly think about immunotherapy nowadays, we're talking about checkpoint inhibitors, you know, ketruda, or that's pembrylism, or nevolumab, or some of these other drugs that are dramatically effective in so many cancers. You know, immunotherapy, which checkpoint inhibitor says, has changed. face of oncology without any question. Unfortunately, none of those drugs have proven very effective in prostate cancer. We have a whole series, you know, several now of negative clinical trials with checkpoint inhibitors. So prostate cancer, unfortunately, is one of those cancers where checkpoint inhibitors just don't have much of a role. The proportion of patients who benefit with prostate cancer is probably only five percent or so. However, we do have one approved drug that's proven your Cipulucil T. And that's a very early type of cellular therapy where the patient's own immune cells are taken out by aphoresis, taken over to the lab and then cultured in such a way to try to activate them against prostate cancer cells. And then those cells are re-infused back to the patient. It's basically like a blood transfusion, but it's their own cells. It's autologous. This therapy has been shown to extend survival, so it's certainly an option, but it has a very mild effect. I mean, it's not a big impact and it's certainly not curated the way you think about some of these modern immunotherapy. So it's a modest benefit, but it's beneficial nonetheless. And at the moment, that's the only immunotherapy with a survival benefit in prostate cancer. Okay. Are there any other options that you see in the future that get you excited? Yeah, so prostate cancer research right now is absolutely gangbusters. So yes, it is a great time to be a prostate cancer researcher. We have new approvals at least once or twice a year. So you know, there's a slide deck I'd like to present where I show that from 1940 to 2010, prostate cancer, we had something like seven drug approvals. But 2010 to today, we have at the 16 drug approvals. I mean, various indications. It's it's incredible. So the pace of change now is completely different than what it used to be. And you know, the difference is we got past this age of treatment, nihilism in prostate cancer where everyone was telling their patients, so don't bother. There's nothing to be done. Everything's too toxic. And what happened was in every other cancer patients were accruing to trials and research was getting done. But in prostate cancer, we couldn't even get the patients in the door. But that's changed now. So the pace of change is fantastic. Park inhibitors have been approved in the last two years. Radio ligand therapy with lutecium 177PSMA has been approved. New imaging agents with gallium 68 and and PYL PSMA targeting agents for pet scans have been approved by specific antibodies to me are the most exciting potential immunotherapeutic option in prostate cancer. So we're still trying to solve that riddle, even though we haven't yet. And on and on. I mean, really, we do entire lectures and podcast series on where are we going with prostate cancer research and next generation drugs? Well, Alan, you've given us some very encouraging news about advanced prostate cancer. Can you give maybe two or three key points that summarize our discussion on the topic? Yeah, I mean, I would say for the internal medicine audience, I'd say a couple of things PSA screening saves lives that data is clear at this point. It's it's not a question of this PSA screening work. The question and so a second point is which of the prostate cancer patients need treatment? So, you know, even though this podcast was about advanced disease, the fact of matter is prostate cancer was the first cancer in which active surveillance was is a recommendation for a proportion of patients and that's the key is I think when we object to screening what we're actually objecting to is over treatment. And so rather than failing to screen, I would encourage, you know, your listeners to really think about how do we make sure that the right patients are treated and some patients who don't need treatment are offered active surveillance instead. It's better to know who's at risk of prostate cancer or who has it and then make the right decision rather than just deciding not to screen in the first place. So that's the first point I'd make. I think the second point is really about management of the long term comorbidities that go along with prostate cancer treatment. So again, the role of cardiac health is very important in men on ADT managing cardiovascular risk factors. You know, I prescribe resistance exercise and cardio exercise for all my men on prostate cancer. It's a fundamental part of our treatment regimen. Again, screening for osteoporosis fundamentally important. Thinking about what are the comorbidities because of course some of these prostate cancer men, like I say, we can get 10 to 15 years of survival, but if they start suffering osteoporotic fractures or major cardiovascular events, you know, obviously we haven't done them good, right? So I think that's probably one of the most important things for the internist to think about. And then, you know, I guess last, always happy to take calls from internists if they've got questions. We are making progress here. So please, you know, just initiate the conversation. If that's what your patient, you know, is asking about what are my options here? Should I think about clinical trials? Do I seek second opinions? I would tell you that in modern oncology care, almost all oncologists I know of are 100% comfortable with patients getting multiple opinions because it's a healthy process for them. But we also really want patients to think about clinical trials because at the end of the day, my goal is an oncologist is to put myself out of business, right? We want a cure cancer. My passion isn't treating cancer. It's trying to find a cure for it. And we're only going to do that by continuing to do the research and do the clinical trials and, you know, hopefully get to a day where no men are dying of this disease. We've been discussing the management of advanced prostate cancer with oncologist Dr. Alan Brice on the Mayo Clinic. Alan, thank you so much for sharing your knowledge with us today. I pledge you thank you, Darrell. You can now listen to over 100 different medical topics developed for primary care providers on Mayo Clinic Talks podcasts. Find them at ce.mail.edu or your favorite podcasting app. If you've enjoyed Mayo Clinic Talks podcasts, please follow us. Stay healthy and see you next week.