David Albala, MD

 I am trying to get a practical little algorithm developed for the audience. Obviously, almost everybody around the country does PSA [prostate cancer antigen] testing in some form, maybe regular to total PSA or free to total PSA or looks at PSA velocity. Then would you go to the blood test, or would you go to the urine-based test? I am curious on how you put that together and then I will tell you what my algorithm is, and we'll see if we're similar.

 Sure. There may be patients who only get a PSA and a rectal exam. For example, a patient with a PSA more than 20 and an abnormal digital rectal exam.

 We need a biopsy. We have been seeing quite a number of those guys seem more as we have gone through COVID. I do not know if it is just more or the fact that this primary care initiative that we have has just been bringing these guys out of the woodworks.

 Or maybe the after-effects as well of the task force were stuck. Several papers have shown that when prostate screening and PSA testing got a de-rating, we started to see an uptake in metastatic disease then they reduced it to a C rating a couple of years later. I do not think we have caught up completely. You are exactly right. I think that patient that has a PSA of 20 or you find an abnormality on the rectal exam, that is a no-brainer. We are going to biopsy those guys and that's the standard of care. Let us take a guy that comes in, his PSA is abnormal, maybe it's between 4 and 10, you don't feel anything which is many of the patients that we examine. How do you work that patient up and what do you do? Do you do the urine-based test first or do you do the blood test?

 First, as a urologist, I do the rectal exam. That is my first step when I'm seeing a patient because I really want to contextualize the PSA based on the size of the prostate. Rectal exams, we all know, are not perfect, and it is hard to teach a primary care physician to do a rectal exam and many of them are not that interested. But we as urologists and as urology educators, we need to make sure all our residents who we train know how to do a good rectal exam and size of prostate. If I have a gentleman who has a very robust prostate, significant BPH on DRE, and it's a smooth DRE with no nodules, sometimes I may just only do the PSA test and reassure that gentleman and schedule him back in a year. Just important to point out that the basics of what we do as urology is still there. However, if it is a borderline on rectal exam, if the patient has a borderline PSA family history, our next test usually is going to be a prostate health index and those are going to be binned in four groups. Generally, if the patient is low risk on pHi then they're going to be reassured and maybe come back in six to 12 months. If it is a high-risk pHi with a 50% greater probability of prostate cancer most of the time, we will recommend a biopsy without necessarily going to the exosome. However, as you said, sophisticated patients, many patients are reluctant, and they want more data. In those patients who want more data we will get the exosome and then if they have a combination of high-risk pHi and exosome greater than 15.6, we are going to really push for a biopsy. If the patient still does not want a biopsy and insists on an MRI, we will order the MRI counseling the patient that he might have to pay out of pocket. Where the exosome has helped me, the most is in patients who have that intermediate prostate health index – the gray zone. There is a gray zone there too. Then I like to get the exosome. Or the patient who is just reluctant and just has a no show and I am the third urologist telling him he needs a biopsy. Sometimes I am using the exosome test to try to convince him that he has a condition that needs to be taken seriously. I use it to try to increase compliance as much as anything. Also, finally I will say, our practice is employing more physician extenders, APPs. We train them the best we can, but they are not urologists, they have not been in practice 30 years like I have. Sometimes our younger APPs are using these tests because they are not quite as confident with a rectal exam. Is that right or wrong? It is a reality of needing some of those tests in our current workforce.

 I think that is terrific. We up here have adopted obviously using PSA as our primary test, much like what I did when I was at Duke. We did go to a blood test with the 4K score and then we pivoted a little bit to the urine studies. It started with SelectMDx and now, I think, with exosome, having the home kit – a couple of things. One is, for exosomes they must be over the age of 50 to do the test. Most of our patients, when they come into the urology clinic leave a urine specimen so it is hard to get them to urinate again. Then I just say, "We're going to mail this to you," and it works out well. That has been my test. When they get the exosome test, as you say, if they are hesitant about a biopsy, that is where the MRI, to me, fits in place. If the patients are concerned, then we go directly to a biopsy. I think the algorithms can be massaged depending on the area where you are and the tests that are readily available. We don't have pHi up here, so we relied on the K, which is commercially available, and it was a good starter test.

 Dave, I do not have a lot of experience or any experience with the Select urine test. What is the difference or what has been your experience when you look at those two?

 They're very comparable tests. With the Select test, you do need to do a rectal massage, so it is almost like a PCA 3 test. Maybe it is a PCA 3 on steroids, so to speak, because you do have to do a rectal exam in these patients. But when you looked at the areas under the curve and the accuracy of the test it appeared to be a little bit better than some of the blood tests and so that's why we initially pivoted a little bit to the urine test and then when exosome came out, just the ease for the physician made it a little bit easier to do. When a new test comes out, I look at the efficacy, I look at the cost, I look at the side effect profile, I look at the ease of doing the test and then the durability. Those five things, whether it's a new drug, a new procedure, or whatever, I always think of those five things in the back of my head to try to put these tests in perspective. Because when they come out, there is a lot of hype, there's a lot of excitement about these new tests, you want to bring them back down to earth and put them in their place on where they really have a place. That is how I've used things and it's served me pretty well.

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Algorithms for Diagnostic Testing in Prostate Cancer

 COVID, I think, hit our whole country, and really turned the way we practice medicine. We saw an explosion happen in telehealth, and these patients did not want to come into the office, but they still wanted to see their physicians. And the beauty of the Exosome test, which really is just a – It's a urine test that I kind of think of like little tweets. The exosomes are tweets of RNA and DNA and proteins that give us some insight on, what is that risk of cancer, of prostate cancer, and of high-grade prostate cancer 7 and above? And the urine test was quite nice. I think that really kind of changed the playing field a little bit. You did not have to do the massage. You could do a tele visit. If the patient had an elevated PSA you would say, "Well, you're in perhaps a gray zone. Let us do a test that may give us a little more insight." You mail them the kit, you get the results back in seven to ten days and then you can say, "I think you should get a biopsy," or "No, I think we're fine. Let us continue to monitor yourself." And bringing them in. Obviously, you did not need to do a rectal exam. I think that that really was a significant boon for us because it allowed us to still diagnose prostate cancer with patients that had elevated PSA's [prostate-specific antigen].

 I just want to make a comment about telehealth and just your experience. COVID [coronavirus disease of 2019] has been a terrible situation for the world and our country, so I do not want to downplay, it's been overall very bad time for us. But out of badness comes some good things and we really forced our profession to really embrace telehealth and so the advances that we had just at our hospital in the technical ability to make telehealth work was amazing. What I have found is it's pretty easy for me to develop a good therapeutic relationship with a patient. My clinic is primarily in a cancer center. It is intimidating. And I have these guys coming in with an elevated PSA into the cancer center, they are uncomfortable, many of them are out of their element and they are nervous, their blood pressure's up. I found that telehealth for an elevated PSA, at least a first-time visit, they are at home, they are more relaxed. They can open to me more; they are not as freaked out. And, as you said, they do not like the rectal exam anyway so they can do potentially a lab. We have set up lab and leave so patients can even go to a remote location – four sites in our health system – and do not even need an appointment. They just call from their car when they are in the parking lot and the lab just go ahead and do it. But with exosome, the mail-order test has been really, nice and we can get those results back. And compliance. It blew me away when we started this initiative with Duke Primary Care, really embracing working with primary care on getting these younger guys in, how non-compliant patients are. Sometimes the patients who had the highest PSA's or seem to be at the highest risk are the ones that were most likely to no show. Not only for their PSA appointment but no show for their biopsy. I guess you do not get that that much in private practice. You used to work at Duke Cancer Center, and you know you might have a CEO in one exam room and someone who is low socioeconomic status or low health literacy in the next exam room. The point is that tests like exosome and/or pHi, more data increases the patient's compliance. Some of my embrace of these tests was to try to convince some of these guys that they need to come in for the procedure and that they should not no-show. I do not know if you have seen that in Syracuse.

 I agree completely with you. Again, we are talking about more sophisticated patients that know a lot about prostate cancer. I am sure many of them have had relatives or family members that have had it so they are really keen on these tests and they know these tests now, which is really a change. The educational level of patients is significantly higher I think than it was 10 years ago. When I was at Duke Cancer Center, I think my active surveillance rate was around 10%. It is now close to 40%. As clinicians, we are seeing, once we diagnose prostate cancer, if they have a Gleason 6, we may do some genomic testing on these individuals. And if they have an Oncotype or a Polaris or a Decipher score that's low risk we are going to follow those patients. Those patients for the most part do quite well, and that is another significant contribution that we've learned over the years to change the way we practice.

David Albala, MD and Judd W. Moul, MD consider the impact that COVID-19 has had on the clinical experience of patients with prostate cancer and share personal insights regarding telehealth and patient compliance.

COVID-19: Telehealth and Compliance in Prostate Cancer

 I want to focus on the markers we use to determine whether patients should have a biopsy. Over the last couple of minutes, I’ve tried to give an overview of where we are, but I want to drill down a little so we can talk about the blood and urine tests. Why don’t we start with the urine tests, because you gave a great description of the PCA3 [prostate cancer antigen 3] test. Maybe you could tell us about exosomes, what they are, and how is the ExoDx test useful?

 We started using the exosome ExoDx test close to 2 years ago. I wanted a urinary replacement for PCA3 because I needed a secondary blood test. But it was important to have a urine test as well. I’ll be honest, at first I was thinking more practically, that I needed a secondary blood test and a urine test, and not necessarily looking at the sensitivity and specificity. Maybe I should have looked at that first. And when you do an exosome ExoDx test, you made the key point that you don’t need to do the rectal exam. With PCA3, which we had used before, you had to do an attentive digital rectal exam prior to the urine test. It wasn’t a big deal, but it was a bit of a hassle. With the exosome ExoDx test the patients would give a first voided urine through a special device. We initially did it in house, meaning the patients would give the urine sample in the clinic, or in 1 of the exam rooms.

More recently—I know you’re involved in this as well—the mail-order tests became available, which is very similar to the Cologuard. For anybody who may have done colon cancer screening with the Cologuard test, the exosome ExoDx urine test is very similar. You put the order in the website, the company sends the kit by FedEx with instructions, the patient gives the urine sample, puts the specimen in a return FedEx, and sends it back. Then we get the results in about a week. It’s important to point out that, just to compare some of the secondary tests—when we talk about the blood, for example, I have more experience with the PHI test, the Prostate Health Index. That predicts the presence of cancer—or the likelihood of cancer, period—in 4 risk groups: low, low-intermediate, intermediate, and high risk. The way that breaks down is that if the patient falls into the best group, they have a 9% risk of cancer. The next is 16%, the next is 33%, and the last group—the high-risk group—is 50%.

It’s important for the doctors listening today who haven’t used the exosome ExoDx test before to know that the test is not predicting cancer or no cancer. It’s predicting the probability of Gleason 7 or higher. You get a dichotomous answer. The cut point is 15.6, so patients who have an exosome ExoDx test less than 15.6 have a 90% to 92% probability that they don’t have Gleason 7 or higher, whereas if they have a score greater than 15.6, it means they have a probability of having Gleason 7. In my mind, the PHI and the exosome ExoDx are somewhat complementary, meaning that secondary blood test is measuring just cancer—yes or no—in those 4 risk groups, whereas the exosome is a little more nuanced; it’s predicting Gleason 7 or higher. Basically, a guy who has an exosome ExoDx less than 15.6 could have Gleason 6 disease. It’s important for folks who haven’t used those tests to be aware of that.

Two experts in the management of prostate cancer provide key insight into the value of blood and urine liquid biopsy tests when deciding whether to perform a prostate tissue biopsy.

Blood and Urine Liquid Biopsy Tests in Prostate Cancer

 We’ve got the PSA [prostate-specific antigen] test. We do a digital rectal examination. We’re trying to consider patients for biopsies. We do a secondary or tertiary marker, whether urine or blood. How do you feel the role of MRI comes in? Over the last few years, a lot of the work from Samir Taneja and Peter Pinto has focused on MRI. How do MRIs play into this? That’s a really hot topic.

 That’s a great question. I admit that I struggle with this a little, because at Duke Cancer Center, we have a very good radiologist who specializes in prostate MRI, and he’s put a lot of effort into it. So I know if I get an MRI at my institution, it’s a good-quality MRI. The downside is he prefers to use the endorectal coil, so most of the MRIs in my own practice or my institution, the men are not so delighted to have the endorectal coil because that probe is actually a little bigger than the probe that’s used for a biopsy.

The other challenge we’ve faced in North Carolina is that many of the insurance plans in our state will not reimburse for an MRI in the setting of no previous biopsy. So in the primary screening setting, where you’ve never had a biopsy before, a lot of the plans won’t cover it, and it’s expensive. Even the cash price at our institution is about $2500 if the patient chooses to have it outside insurance. The other challenge we’ve faced, and I’m sure you’ve faced this in at Crouse Hospital in Syracuse, New York as well, is that the quality of MRI varies around the community. Sometimes patients will come in from the outside with an MRI, and they want a fusion biopsy based on an outside MRI. That’s problematic because it’s difficult to take an outside MRI. So the patient dutifully brings that into the tertiary care center and says, “Here’s my MRI. I want a fusion biopsy.” Then we tell them, “You have to repeat the MRI at our institution before we do a fusion.” The key message is, it’s an expensive test. I’m still not convinced, despite excellent data from the NCI [National Cancer Institute]. I’m not disagreeing with the data, but in practical terms, in the trenches, is it really necessary or cost-effective to get an MRI in every single patient who presents with an elevated PSA? At least with the urine and blood tests, they’re not as expensive as an MRI, and they’re obviously less invasive. At my institution, an MRI is invasive.

 That’s a great point. We’ve run into the challenges with coverage. We’ve worked around that a little, offering patients the option of paying out of pocket. We’ve negotiated an $800 to $1000 rate for an MRI if patients really want to have it. But you’ve alluded to some great points that have been important in trying to make the decision on how to integrate this.

Thought leaders in the management of prostate cancer build a discussion on the challenges associated with the use of MRI to diagnose prostate cancer including insurance coverage and patient discomfort.

David Albala, MD

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