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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today a good friend and colleague, Dr. Stacy Loeb, who is a Professor of Urology and Population Health at NYU and the Manhattan VA. Thank you so much for being here with me today, Dr. Loeb.

Stacy Loeb: Hey, nice to be here. Thank you for having me.

Alicia Morgans: Always a pleasure, and always happy to have you. I wanted to talk with you a little bit about a really fantastic presentation that you gave at GU ASCO 2022, thinking about active surveillance, but not the same old active surveillance, active surveillance in an intermediate-risk population. Can you tell us a little bit about how this approach is being considered? Is this something that we actually do in the care of patients with prostate cancer?

Stacy Loeb: Yeah, absolutely. This is actually on the rise. So whereas, early on, active surveillance was considered experimental and was very much limited to low-risk or very low-risk patients. As we have had increased experience with the approach and see its safety, now we are really expanding the indications for active surveillance to also include selected patients with intermediate-risk disease. This is the standard of care, all the different guidelines do agree that active surveillance can be offered to selected patients with intermediate-risk disease. And the trends seem like it is increasing. In the US, some of the latest data suggested around 10% of intermediate-risk patients were being managed conservatively. Elsewhere there are some numbers that are even higher, like in Sweden, it's about 19% nationwide. So it's definitely a growing area for sure.

Alicia Morgans: Well, that's really exciting, but one word that I want to make sure we focus on is that word that you said, select. So how do you select patients with intermediate-risk disease? Because we know that this is absolutely a heterogeneous population, already really kind of categorized into favorable and unfavorable risk. So how do you really parse that out even more to identify the right patient?

Stacy Loeb: That's a great question. So yes, as you mentioned, there is a favorable and an unfavorable intermediate-risk. So we are really focused here on favorable intermediate-risk, but even that is a really big group and a heterogeneous group. So you've got in there, really one major stratification is why are you intermediate-risk? And so some people it's because they have a small amount of Gleason 3 + 4 disease. Other people, actually have Gleason 6, but their PSA is above 10. So, for example, you may have these patients who have a very enlarged prostate, and maybe their PSA is 11, but they still just have one core of Gleason 6. But because their PSA is above 10, technically they fall into the intermediate-risk category. And those two groups of patients are different. In fact, studies have shown that the patients with the Gleason 3 + 4 have a higher risk of adverse pathology findings at surgery compared to the patients who are intermediate-risk with Gleason 6, just due to a PSA that's above 10.

So that's one big category, but then even within the patients who have Gleason 3 + 4, those are not all the same, the percentage of pattern 4 matters. There are specific histologic subtypes that can make a difference. For example, if they have cribriform histology, that is associated with more aggressive disease, and some guidelines recommend against active surveillance for those patients.

And then just one final comment is just about the importance of considering the patient's overall risk profile. And nowadays we much more incorporate genetics into these considerations. And so there are a number of patients with intermediate-risk prostate cancer who meet the guidelines for germline genetic evaluation, and it's really important that they receive that because those results would also be very important for this decision. We know that patients who have, for example, pathogenic variance and BRCA2 are at higher risk of progression on active surveillance. So if that person has intermediate-risk disease, they would not be a good candidate for active surveillance.

Alicia Morgans: Well that makes a lot of sense. And I think it's so important, as you mentioned, that we are trying to bring this germline genetic data into that decision-making too, to really be, I think, more informed. And there have been questions over the years of how those patients may be incorporated into active surveillance cohorts. So I'm really glad and appreciate that you've been able to bring that data into your talk at GU ASCO, and of course in this conversation. And I wonder too, there is some genomic profiling that happens in some clinics, and this is not necessarily equally distributed among all urology practices, but some practices are using these different tests that help us understand the molecular risk, perhaps, of patients based on their biopsy sample. And I wonder if you use any of those tests, or have any guidance for those who do on whether that can be useful information in this patient population.

Stacy Loeb: Yes, that's a really great point. And there definitely are various adjunctive tests that can be used to further help with risk stratification. For example, tests like Prolaris, Oncotype, and Decipher. And those can certainly be used to assist with decision-making about active surveillance. I do not think that they are necessary in all cases. If it's a very clear-cut case, for example, a very low-risk disease, then I feel that these additional tests are unnecessary. But since we are discussing here intermediate-risk prostate cancer, this is more of a borderline category. And this is definitely a situation where having an additional data point, like a genomic test, could be potentially useful in decision making.

Alicia Morgans: Well that is good to note too, because it's also like you said, it's different than a very low-risk patient, where that added information may not actually add very much at all. And I wonder as we're thinking about this population, this favorable intermediate-risk population, are there differences in how we might monitor and follow up those patients, as we are thinking about putting them onto an active surveillance protocol?

Stacy Loeb: It's a great question. And I think there should be, but the truth is that we just do not know. And what's interesting is that the guidelines about monitoring during active surveillance are basically the same for low-risk and intermediate-risk disease. And they more or less define the maximum amount of testing that should be done. So the guidelines say, for example, that you shouldn't do biopsies more frequently than once a year, you shouldn't do PSAs more frequently than every six months, but it doesn't really say how frequently they should be done or how that might differ between different patients. From my perspective, I think that everything that we do should be risk-adapted. I don't think that somebody who has one core of Gleason 6 disease with very low risk requires the same intensity of active surveillance as somebody who has favorable intermediate-risk disease. So I think that follow-up becomes very important in this population.

And one concerning thing that I talked about in the lecture is some studies about people who are lost to follow-up during active surveillance. And there is a study, quality control study out of the University of Michigan, showing that really the rate of people who were lost to follow up was the same in the intermediate-risk and the low-risk population. But the stakes are higher here. Although it does appear to be safe for selected intermediate-risk patients, there is an increased risk of metastasis or prostate cancer death with active surveillance for intermediate-risk disease compared to the low risk.  That was shown in a systematic review of studies on active surveillance. Now, the good news is that the rate is still very, very low. Even for patients with intermediate-risk disease, the absolute rate of metastasis and death is still low, but it's higher than for low risk, and therefore, I think we need to be more careful about follow-up testing and making sure that the patients are not lost.

Alicia Morgans: I could not agree more. I mean, the goal here is to use active surveillance. And really communicating, especially, that active piece for patients who have intermediate-risk disease, I think is going to be really, really important. And I also really wanted to emphasize that I appreciate your comments on that risk-stratified approach. That is the reason that we put patients into risk categories so that we can understand what their risk is going to be, and we can adapt what we do to meet that risk. So there's a method behind our madness and a reason for what we do. So I thank you for pointing that out. And I wonder, and patients always ask, if there's anything else that can be done in terms of monitoring patients? Or I guess for patients to do on their own. Is there anything they can do to contribute to reducing their risk or stabilize their disease, even if it's just an early signal that something might be possible?

Stacy Loeb: Oh, for sure. Actually, I think this is really critical. All of these patients on active surveillance are much more likely to die from something else than they are from their prostate cancer. In fact, they are most likely to die of cardiovascular disease. And this is a teachable moment. We really have men's attention. And so I think we have, actually, a responsibility to work with them on improving their overall health.

Luckily, there actually are some randomized trials in this space, for example, The Prostate Cancer Lifestyle Trial, which was led by Dean Ornish out of the University of California, San Francisco. That study looked at men on active surveillance and showed that a vegan diet, physical activity, and relaxation training were associated with a reduced risk of progression on active surveillance. And many other health benefits, like a really dramatic reduction in LDL and other cardiovascular risk factors. So something like that is fantastic.

There is another recent study called the ERASE trial. This was a randomized trial of high-intensity interval training during active surveillance, which also showed benefits. So bottom line, I think that we should be more holistic in our approach. In fact, for most of my patients on active surveillance, I may not necessarily be extending their life through my prostate cancer care, but I can really have a large benefit on their overall longevity by recommending lifestyle modification.

Alicia Morgans: And I want to also say that I think we, as a prostate cancer community, should be grateful to you too, for your continued advocacy in this particular regard. Because as you said, at the end of the day, whether you have prostate cancer or not, you still have a heart. You still have the rest of your body. And a holistic approach is so important. And I also want to say that I love that you truly put your money where your mouth is in this situation. You are doing these things too, and have inspired others, including me, to try to make changes in this way. And I think that's incredibly positive for our entire field, and of course, for our patients. So as we wrap up, I'd love to hear your final message for folks who are thinking about active surveillance and extending this into their practice for patients with intermediate-risk disease.

Stacy Loeb: Absolutely. I think that this is a very important option for patients with intermediate-risk disease, and can further help to reduce the overtreatment of prostate cancer. So for carefully selected patients, for example, the patients who are intermediate-risk due to their PSA alone, or with low volume 3 + 4 disease, this is definitely something that they can consider. I do think that we need to be very diligent about the monitoring protocols for these patients. We're currently going the other direction with low-risk disease and trying to de-intensify active surveillance. This is a different patient population, and so we still need more studies as to what is the best follow-up protocol in this patient population.

And then, of course, this holistic approach and taking the opportunity to recommend that patients increase their physical activity. There are published physical activity guidelines for cancer survivors. There are a lot of survivorship guidelines recommending consuming more plant-based foods, avoiding processed meat. These are all easy things that people can do, and most people want to do something. So that's the good news. Patients, don't want to sit there and do nothing, so part of the word "active" isn't just that we are actively doing tests, it's that they are going to be active in getting "active" and modifying their lifestyle so that they can actually increase their longevity.

Alicia Morgans: Well, that is absolutely the perfect message, that active surveillance is getting active, both for the doctors and the clinical teams, as well as for the patients. And I really, really appreciate your review of this with us today. We always appreciate your time and your expertise, Dr. Loeb.

Stacy Loeb: Thanks so much for having me.