Cofounder, Avenda Health
22-11. Prof. Leonard Marks MD. "Contemporary Management of Prostate Cancer"
"This is not Your Father's Prostate Cancer." Dr. Marks talks about the revolutionary advances in detection of prostate cancer, and the target biopsy program at UCLA and elsewhere.
Prostate Forum of Orange County is a Southern California Prostate Cancer Support Group, with online (Zoom) meetings on the second and fourth Tuesday of most months, beginning at 5:00 p. Pacific Time.
Our website address is: www.prostateforum.org
About Leonard Marks
In a November 2022 presentation to the Prostate Forum of Orange County, Leonard Marks, a UCLA urology professor and cofounder of Avenda Health, discussed what he described as a dramatic transformation in prostate cancer management. Marks stated that MRI-guided biopsy has "changed everything" and argued that biopsies for suspected prostate cancer should be preceded by an MRI, saying, "if you get the biopsy wrong the whole journey will be badly affected." He noted that his team was among the first in the United States to use the FDA-approved Artemis image-fusion device for targeted biopsies. Marks also discussed focal therapy options for localized prostate cancer, including cryotherapy, high-intensity focused ultrasound (HIFU), and focal laser ablation, which he said his startup is working to commercialize for use in a clinic rather than an operating room. He estimated that up to 40 percent of newly diagnosed prostate cancer cases may be candidates for focal therapy. Marks additionally highlighted the PSMA scan (Pylarify) as the most sensitive method for detecting metastases and noted that the PIRADS scoring system is used internationally, with PIRADS five lesions harboring clinically significant cancer about 80 percent of the time.
Transcript (54 segments)
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Host0:10
We are excited and honored to welcome Professor Leonard Marks, MD, of the UCLA Urology Department at the Ronald Reagan UCLA Medical Center. Dr. Marks received his MD and Master of Arts in Physiology from the University of Texas and completed urology residency at UCLA. After a lengthy career in private practice, he returned full-time to UCLA in 2009. He is the inaugural holder of the DeKernan Chair in Urology. Dr. Marks is the principal investigator of three R01 grants from the National Institute of Health; he leads a multidisciplinary research collaborative.
I will mute myself and present Dr. Leonard Marks.
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Leonard Marks1:15
Brian, thank you very much. It was a beautiful introduction. I'm delighted to be here. I appreciate the invitation. Brian, Chuck, Neil Arakugan, people I've known for some time, and I'm delighted to be here. The theme of tonight's talk — and permit me to indulge myself a little, being a history buff — we're going to talk about the evolution of prostate cancer management to where it is today. It is one of the most dramatic transformations in all of medicine. We came from a very primitive state.
One slogan really gets it right, but I like this even better: 'It's not your father's prostate cancer.' I don't mean to denigrate anybody's father or their health care, but this is such a different disease. I will show you why I've adopted this slogan in just one minute. The subtitle is: How MRI-guided biopsy has changed everything for prostate cancer management. If the only lesson you take away tonight is that the biopsy of a man suspected of having prostate cancer should, in this time, be guided by a preliminary MRI. After all, the biopsy is where a prostate cancer diagnosis begins.
The notion to use this as a kickoff for this talk came from some time ago. This is Mr. Ransom E. Olds, a gent working in his father's machine shop at the beginning of the 20th century. He got tired of that and decided to start building cars. There were 200 companies making cars in the year 1900; his was one of them. His happened to become very successful; it became the Oldsmobile, one of the best-selling cars in history. The brand is now gone, but in the 1980s, the Oldsmobile was very sluggish.
They introduced a slogan: 'This is not your father's Oldsmobile.' They introduced a Cutlass Supreme which really reinvigorated sales. The analogy here for prostate cancer is very appropriate because this is a lot new in something very old. So we have a completely transformed disease, and that's what I want to get across to you tonight. It's not your father's prostate cancer. The whole paradigm of approach to this disease has changed. Previously, prostate cancer went like this: if you had a nodule or an elevated PSA, you got an ultrasound-guided biopsy. These came out in the 1980s. Tom Stamey at Stanford taught me how to do this.
We would take 12 or so many biopsies, hoping that if that elevated PSA was caused by prostate cancer, one of those blind biopsies would show it. If any cancer was found on the biopsy, then the patient had prostatectomy or radiation therapy if he was lucky enough to be diagnosed early. That's the way it was over the past two generations, from about the 1980s up until fairly recently. Now, prostate cancer is approached a different way. We still have to start with a nodule or elevated PSA.
Low-risk prostate cancers are preferentially managed with active surveillance. Severe, aggressive prostate cancers are preferentially managed with prostatectomy or radiation therapy, as in previous years. And a large, growing group of men with intermediate-risk prostate cancer for whom focal therapy is an increasingly attractive option.
Just a word, and I know you're familiar with this, but to impress upon you how seriously we take this problem: 270,000 new cases are diagnosed every year in the United States, 35,000 deaths — second only to lung cancer as a cause of death.
Prostate cancer frequently has a long natural history. Over three million men are currently alive in the United States with prostate cancer. So this is what we are trying to prevent. This image shows a man with widespread metastatic disease occupying much of his bony skeleton. What we want to do is get to these cancers when they are small, baby cancers living within the prostate, no metastases, to diagnose them early and characterize them accurately as to their severity, and treat them appropriately with increasing emphasis on treatments that do not disrupt quality of life.
In a T1 image, about all you can see is the Foley catheter in the man's bladder. The next landmark that happened was MRI-guided biopsy, performed by Tony D'Amico in Boston — again, a fairly primitive approach to this problem, but that's when it started. MRIs have become quite sophisticated over the years. The MRI we'd like to see now is a prostate-focused, dedicated multiparametric MRI. Those three parameters are the T2-weighted image, which shows the lesion spatially.
A contrast agent is used, and these correspond very nicely in this ideal situation to a cancer localized, when removed, to that part of the prostate. But what has propelled us more than anything is the ability to bring MRI to the patient's bedside using a device called an image fusion device. This is the one we use; it's called the Artemis — the same as the rocket that just went up yesterday into space. I always think NASA stole the name from us. Actually, Artemis was the name of the Greek goddess of the hunt, and I think that's a very appropriate name for this device.
This goes back to the 2008 AUA meeting when I was sitting in the lecture hall during the Whitmore Lecture. Dr. Pat Walsh — who incidentally trained at UCLA, I've known him for a long time, a little older than me — was a man who taught the world how to take out prostates. When he made this statement, it really got my attention. He said to the young people here: 'If you want to make a contribution to medicine for this decade and maybe for the century, address yourself to the problem of imaging cancer within the prostate gland.' So here was a man who spent his whole life taking out prostates, and now he's telling us, 'Wait a minute, let's see what we can see with imaging prostate cancer within the gland.'
The MRI is furnished to the urologist that way, and then when the fusion is performed within the device, we can see the region of interest from the MRI superimposed on the ultrasound image. So we've brought this sophisticated tool called the MRI to the patient's bedside and employed the very fine accuracy of the MRI with the simplicity and convenience of the ultrasound. Here's how we target it. The process involves a 3D reconstructed model of the prostate shown here, with the biopsy sites recorded so we know where we are.
This is a prostate biopsy in the clinic. This setup is very similar to conventional ultrasound. This is a conventional ultrasound unit; this is our image fusion device. It can be done transrectally or transperineally. We'll talk about the differences in just a second. We were among the first in the United States to have image fusion prostate biopsy at our place. The Artemis device, made by a little company in Northern California, was the first one FDA approved, and we got it shortly after it was approved. The people at the NCI received approval for a different device made by the Philips electronics company called the UroNav.
You can see the brown blob here is the prostate. These green spots are part of a template where we take systematic biopsies throughout the prostate. And this spot right here was the MRI-visible lesion, which has now been brought onto the ultrasound, allowing us to do targeted biopsies of this area. The yield from targeted biopsies is a multiple of the yield from conventional ultrasound-guided blind biopsies.
The most important thing about using MRI guidance, the way it helps us the most, is called the PI-RADS score — prostate imaging reporting and data system. PI-RADS three through five: when we see a PI-RADS grade 3 lesion, there's about a 24% chance that's going to harbor a clinically significant prostate cancer. When we see a PI-RADS grade 4 lesion, larger and darker, there's about a 37% chance of finding a clinically significant cancer. When we see a PI-RADS five lesion, about 80% of these will harbor clinically significant prostate cancer.
The assignment of the PI-RADS score is something that very few radiologists can do. So another message tonight is: if you're going to have an MRI, you should make sure you're getting it from a radiologist who knows what they're doing. When we started this, nobody else was doing MRIs of the prostate. If a patient came to me with an MRI that showed his prostate, almost always we had to repeat it. That's happening less and less frequently nowadays as various radiologists are getting trained. To the shame of the radiology societies, there's no credentialing, no certifying mechanism to declare a radiologist an expert in MRI interpretation. So we have to be careful that we're dealing with people who know what they're doing. We've done a lot of these, and I have great confidence in my radiologists.
High-quality MRI is the key. The PI-RADS grading system is the most important predictor of what we're going to find. If someone has a negative MRI, do we do a biopsy? If their MRI doesn't show a lesion, the answer is it depends. Many prostate cancers — not many, but maybe 20% — are MRI invisible. So we have to take into account not only what the MRI shows but other bits of information. I'll show you the next step beyond MRI guidance in just a minute. PI-RADS is the most important predictor. Targeted and templated biopsies are both important, but when we're considering focal therapy, the margins that surround the area of interest become very critical in determining how to treat the patient.
Let me show you one very rewarding area that has happened with our program. Google has a function where if you put in a list of street addresses, it'll spit out a map with a dot where each street address was located. So here's our Google map from the first two years of our program. You can see most of the dots are down here in California, especially Southern California. There were a few elsewhere, but most from our local people.
By earlier this year, we just redid the map. Over 3,300 unique patients coming from 41 states in the union, 15 foreign countries, six continents. We created a big business for UCLA Medical Center because when these people come for the biopsy and they've been disappointed with what they had locally, they typically stay for the treatment. This is my way of giving back to UCLA, which has been a very excellent place where this all sprung from and very supportive.
Focal therapy has led to reduction in morbidity of treatment by following a pattern that was established years ago by the breast cancer doctors. Previously, mastectomy was the only reasonable treatment for a woman with breast cancer. But a major trial was performed showing that lumpectomy in many cases gave equal results with much less deformity and much less morbidity. So this is where we are right now, looking at the concept of focal therapy. The advantages of focal therapy: it offers the potential for cure with few side effects, it can be done as an outpatient procedure, and it can be repeated if necessary.
Using the breast cancer model, this is somebody you should be aware of: Dr. Bernard Fisher. During the 1970s, when radical mastectomy was a knee-jerk reaction to breast cancer, he devised a clinical trial which, a few years ago, culminated with many years of follow-up in women with breast cancer who had been treated with lumpectomy instead of mastectomy. His colleagues at that time did not exactly greet this idea warmly. 'Lumpectomy is murder,' some of them said. 'This is equal to malpractice,' some of them said.
A woman lost her occupation from breast cancer. She then sued the surgeon on the basis that there was no discussion of any other treatment. The jury gave her $2.25 million in 1999. So what an evolution in the breast cancer world, from 'lumpectomy is murder' to 'you better talk about it or you can get sued.' This is an interesting little vignette that gives me confidence in what we're doing. There are currently three widely accepted methods of focal therapy in the United States. Cryotherapy is the oldest.
Cryotherapy produces a freeze that destroys tissue. It can be localized, and the prostate can be treated focally in this way. Another method, approved by the FDA in 2015, is the use of HIFU — high-intensity focused ultrasound. This is a beam that goes transrectally into the prostate. Where the ultrasound beam comes to a point, heat is generated — boiling heat — and you can go spot by spot through the prostate, ablating cancers in a very precise manner. We are doing both of these on a regular basis.
Focal laser ablation will have the advantage of being able to do this in a clinic outpatient instead of an operating room, but this is for the future; it's not quite here yet. But these other two methods are here now and being utilized at our place on a regular basis in selected patients who sign a consent acknowledging they are in a clinical trial. There's no placebo group; this is an open-label, prospective, observational clinical trial. The data are carefully collected; the rules are established in advance. This is up on clinicaltrials.gov, so we are very formal in our methods of focal therapy. We still regard this as investigational, but it is moving rapidly.
I've mentioned breast cancer, but colon cancer: if a man has colon cancer, they don't take out the whole colon; they take out the affected part. The same with thyroid, the same with kidney. These are models that lead us to believe that this may work very well for prostate as well. The efficacy of whole-gland therapy has been called into question by a number of large international prospective randomized trials of radical prostatectomy versus observation alone. The PIVOT trial you may have heard of: our gold standard is not quite as golden as we thought it would be. It's still appropriate, I might say.
There is the monoclonal index origin of prostate cancer, a concept that says that although it may be multifocal, one of those foci in the prostate is the 'mother' and that will determine the metastatic potential of prostate cancer. If you can wipe out the mother, you've done the patient a whole lot of good. Those other little cancers, which typically are small Gleason 6 cancers, have no effect on metastatic potential. This is the main reason that focal therapy is moving forward very rapidly.
I'm speaking to groups like yours. The morbidity of focal therapy is very, very low. If you poll the patients the same way after radical prostatectomy, not so much. So we are very enthusiastic about the potential for focal therapy. We have done more cryoablations than anything else, partly because cryoablation is well covered by insurance and Medicare; it's the oldest form of energy used. It goes back a few decades. We have studied in these trials over 200 men during the past five years. We judge success by follow-up biopsy, and at six months, about 75% of these men have no cancer when we go back to the treated area; we can't find anything.
Frequently the MRI reverts to normal, but we always rely on follow-up biopsy to prove that what we tried to do was in fact successful. The great thing about this: there has not been any incontinence that has resulted from cryoablation. Erectile dysfunction is a plus-minus situation. We're talking about men in their 60s and 70s; sometimes they'll even be a little older. Father Time is working against us. But whatever erectile dysfunction does happen, it's a fraction of what would happen after surgery or radiation therapy.
The takeaway messages that we advocate, and I think the American Urological Association agrees, are that we want cancers that are small enough to get our arms around for good treatment — usually less than 50 ccs. With cryotherapy we can go up a little bit larger. Patients have to be followed like they are in active surveillance programs; it's not one and done. If someone is not reliable, if they're not committed to follow-up, especially with that follow-up biopsy to confirm the results, then I'm not so interested in pursuing that option with them. So we follow them indefinitely just like in active surveillance. We are still learning about the long-term efficacy of focal therapy. Up to 40% of newly diagnosed prostate cancer cases — let's get rid of that — up to 40% of newly diagnosed prostate cancer cases may be eligible for focal therapy.
We want these to be done in research protocols, not willy-nilly without good control and with data collection and reporting. So, the way things have gone: I'm very proud of this. We started with biopsies done here at UCLA in 2009. We have followed that with interest in focal therapy and are researching this. And the latest horizon, which I think you'll find interesting, is the PSMA scan.
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Host30:11
Could you please mute yourself? We're hearing you on the video here. Please mute yourself.
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Leonard Marks30:27
The PSMA scan stands for prostate-specific membrane antigen. Here's the hotspot, the PSMA uptake in a prostate, indicating a very likelihood of showing cancer there. This became FDA approved with one exception.
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Host31:15
Okay, I think we lost him. Go ahead, doctor. I'm sorry.
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Leonard Marks31:20
This scan combines PET imaging, which determines where the radioisotope is taken up, and CT scan imaging together for anatomic localization. Let me show you some examples. This is a patient with a metastatic lesion from prostate cancer. Here is his ischium, and it looks normal on CT scan, but when he undergoes the PET-CT, you can see this hotspot within the ischium, which is a cancer.
For staging purposes, CAT scans or bone scans were used for a long time. We now order the PSMA scan, which offers the best opportunity, the most sensitivity, for determining where and if there are any prostate cancer metastases. It's FDA approved now. It started out being only available at UCLA where the clinical trial was done, and at UCSF, the sister institution. But now a commercial enterprise has become involved and has produced an excellent PSMA scan which is available in virtually every metropolitan area in the United States, called the Pylarify scan. It's widely available and it's an excellent scan.
Rising step by step by step up to a 49 — you all know that's a very high number. He had three separate MRI studies over those years. All three studies, and one done at UCLA, showed no lesions. Six sets of biopsies totaling 74 different cores of prostate tissue taken by different operators — all negative. So he came to UCLA during the period before PSMA was widely available; it was still in clinical trials. And sure enough, the PSMA scan showed a hotspot in the prostate. We were able to do an MRI-PET-CT fusion with ultrasound, and in our clinic we identified and treated it. This was the first case of this kind in the medical literature a few years ago, and they're now involved in a clinical trial to take this to a higher level. It may be that PSMA targeting is more valuable even than MRI targeting has been so far.
Just to tell you a little bit about what our organization has done over the past few years, I'm very happy to have been involved. When I first started working on this, we got a pathologist, we got a radiologist, we got a biomedical team. But I've got a good job already and we're going to keep at it. We've now done probably more targeted biopsies than any other institution in America — over 5,000 of these involving more than 3,000 separate patients. We're using this in our active surveillance program as well. We've had 132 national presentations, over 100 peer-reviewed publications in the medical literature, some $6 million in NIH funding. A startup company has been launched — I disclose this at the beginning — to try to commercialize focal laser ablation using an in-clinic approach. But most importantly, countless lives have been changed.
There was a nodule palpable in the prostate. He came, he had the biopsy, and it showed where his cancer was, and he got appropriate treatment. These are very grateful patients. They've helped us; we've helped them, and frequently they've helped us philanthropically as well. This has been just a wonderful adventure over the past dozen years. That small research team you saw originally has grown into this. If you look at what these people do, you'll see essentially one of everything in here, so that a multidisciplinary approach has grown and prospered. If you come, you'll see these people.
Thank you for having me tonight. We're very proud to be at UCLA and do this work with our people — number one public university in America.
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Host38:10
Please put the doctor's website in the chat, and you'll be able to save the chat yourself. Once this presentation is over, let's take a look at Francisco Garcia who wants to know: do you think HIFU is a recommended solution for advanced cancer, 70 plus, Gleason 7 and 8?
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Leonard Marks38:35
Gleason 8 scares me. Gleason 8 is a more aggressive cancer than Gleason 7. We reluctantly treat a few patients with Gleason 8 who have said they'd rather die than have surgery or radiation therapy, provided they meet other criteria. The exclusion criteria do not include Gleason 8 specifically. The European data is interesting in this regard. The British use HIFU more often in advanced prostate cancers, and in the half a dozen or so that we've done, the results are about the same as in the ones with intermediate risk cancer. But I'm not enthusiastic about it; I kind of do it under protest.
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Host39:41
Okay. Frank has a question: can focal therapy be done with an intermediate to high-risk Gleason 4+3?
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Leonard Marks39:51
Now we're getting back into that 7 range again. We do 4+3s. I would be cautious about this, but low-volume 4+3 well localized — I have no problem with that. We are treating those patients, and they're doing as well. The 18-month data shows they fail a little bit more often, but it's not terrible, and we can still do something else like surgery or radiation if they do fail. You've got to remember: every treatment has a failure rate. So I'm not embarrassed that focal therapy has a certain failure rate. We recognize it early, in time to change course or to repeat the treatment.
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Host41:11
Another question: we've had a lot of discussion about radiation therapy for localized prostate cancer. Is there a role for focal radiotherapy?
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Leonard Marks41:14
I'm not a radiation therapist, so I'm not the right one to ask that question. But radiation therapy has a number of complications you should be well aware of. In fact, at five years out after surgery or radiation therapy, they have about the same incidence of erectile dysfunction and incontinence, with the added problem of rectal toxicity. So I think it's commendable that the radiation therapists want to localize their treatment more. I think this is something that has not been studied very much, and I look forward to seeing more data. There's something called brachytherapy where they can actually put those wires directly in access to the prostate and don't have to treat the whole prostate. But I don't think there's much published on this, so I look forward to seeing it.
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Host42:26
I'm going to call on George, who has a question for you.
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George42:37
I don't want to take everyone's time because it doesn't seem like the presentation is focused on the level of advanced cancer that I have. But I was just wondering if you can make a couple of comments on what's the cutting edge for people that are staged for advanced cancer?
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Leonard Marks43:10
We want to find this disease before it gets to be an advanced, metastatic situation. But I can tell you lives are being extended every day. I share my office one day a week with an excellent oncologist, and I know that there are a whole variety of treatments. Abiraterone, Zytiga was a huge advance; there are many others as well. I don't think it's necessarily game over, but we sure do want to find this disease early like any cancer. We all wish you the very best.
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Host43:50
Dr. Marks, thank you very much. This was a John Wooden type lecture for us. We just really appreciate this excellent lecture. It was well worth the feature lecture of 2022. So we thank you very much. Outstanding lecture.
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Leonard Marks44:26
Thank you. It's been a pleasure for me and fun to see Ira Haggett and others who I've known for a good while. Good luck with your mission; you have a wonderful mission.
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Host44:37
Well, I promised Ira you would use extra KY the next time he came in, so that's going to cost him extra.
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Leonard Marks44:45
I'll leave that up to you. Good night.