Read the Full Video Transcript

Matthew Cooperberg: Hi, I'm Matt Cooperberg. Welcome to another installment of the UroToday Center of Excellence for Localized Prostate Cancer Video Series live at the AUA 2023 in Chicago. It is a pleasure to be joined today by Dr. Sigrid Carlsson, who is Director of Research at MSK for Urology and has been one of the main drivers of updating screening policy for prostate cancer in the US. So, welcome.

Sigrid Carlsson: Thank you. Thanks for having me.

Matthew Cooperberg: You were one of the integral members of the AUA's screening guideline panel, which just released its updated report. I want to get your thoughts on what is new in the guideline and where are we going? You and I were both at a session at the EAU a couple months ago, which announced a number of really interesting innovative trials going on across Europe. So, where are we? What progress have we made and what questions do we still have to answer?

Sigrid Carlsson: Yeah, thank you Matt. It's so interesting. Both you and I have been doing this for over 20 years, and so we've made, I think, major headways. We started with having only the DRE, the digital rectal exam, and then the PSA test came in the late nineties and it was a revolution, blood test and you can find prostate cancer. So, now here we are in this new era of risk-stratified screening, so I think we've really moved into how can we keep the benefits of the PSA testing and reduce the harms by adding a more smart way to screen? So, thinking about risk stratification before biopsy, adding to biomarkers and considering MRI before biopsy, and the whole pathway of also incorporating active surveillance for low risk because that's the major harm with screening that you find cancers.

Matthew Cooperberg: So, what does risk stratification look like?

Sigrid Carlsson: Using the power of the baseline PSA, so considering getting a baseline in early midlife, 45 to 50, and then now considering also perhaps starting earlier or having the conversations about the pros and the cons of screening for men at increased risk between 40 and 45. Then once the PSA is elevated, then considering risk stratification before biopsy. So, risk calculators, biomarkers, MRI, and also just repeating the PSA test is a very simple thing to do before biopsy. So, not just the old paradigm where PSA was four and then we jump straight to biopsy, but now it's more a smart way. So, who to screen, who to biopsy.

Matthew Cooperberg: Of men who get a baseline PSA, what thresholds should we be thinking about to drive that conversation about secondary testing?

Sigrid Carlsson: Yes, that's also a more nuanced approach where you consider the man's age, his life expectancy, general health, and the PSA level. So, you kind of take all that into consideration. You can risk stratify, so the older and the lower the PSA, the longer the interval. It's not a one-size-fits-all, although the two to four year rescreening interval based on the European trial is still what we would recommend, but you can modify that to a man's level of risk.

Matthew Cooperberg: So, if we have early baseline testing, use of secondary tests, and yes, of course not overtreating when we find low-risk disease, there are still questions to be answered. So, let's talk a little bit about some of the trials going on in Europe now trying to get at some of these questions, and we can start wherever you like. There's a number of them to review.

Sigrid Carlsson: Yes, it's exciting. Even though we've done this for two, three decades, we're still trying to figure this out. So, I think we've solved the question whether screening reduces prostate cancer mortality by the European trial, the ERSPC, and then the Göteborg trial, and then PLCO here in the US. If you reanalyze that and take into account all that contamination, the control group, all these three trials show that regular screening reduces prostate cancer mortality by about 30%. So, a PSA test in and of itself is a great test if you use it in a dynamic way. A one-time test, as the CAP trial showed in the UK, is not the way to go. Stratifying with a baseline is a great start, but you can't just do one time and never again, but it has to be kind of a dynamic process.

So, then how can you refine that? So, then there are now ongoing trials in Europe, so the Göteborg-1 trial that I have been a investigator of was then succeeded with the Göteborg-2 trial, which is now combining PSA plus MRI and also looking at lowering the cutoff for further investigation from three to 1.8. So, that's data that's forthcoming in the coming years, and that's an interesting concept about imaging of the prostate, because in breast that's been done for a long time, and so you only put needles in what looks suspicious on the MRI, and so by doing the targeted and perhaps omitting the systematic biopsy in some instances might reduce finding the cancers we don't want to find. So, you don't want to put needles in prostates if you don't have to, and then you can reduce the harm also.

Matthew Cooperberg: So, let's talk about that randomization. It is routine PSA testing with a standard threshold of three versus PSA with a threshold of 1.8 and MRI. So in the control arm, those men will go to biopsy without imaging?

Sigrid Carlsson: They also get an MRI. So yeah, MRI in all three arms, but they get the systematic biopsy. So, you have the comprehensive assessment of the prostate and then you compare those three arms.

Matthew Cooperberg: How was 1.8 chosen?

Sigrid Carlsson: Good question. I've asked Professor Hugosson, who's the PA of the trial the same thing. It's kind of a consensus of the body of knowledge right now. We went from three to 2.5, and then I know there's other recommendations of doing reflex testing when the PSA is 1.5. So, somewhere in this gray zone between 1.5, 1.8, to 3, I think, is some sort of balance, because you don't want to have too low thresholds because then you have to work up so many men and expose a lot of men to ancillary testing and biopsy. We might not even have the resources, but if you keep it too high, we know that you might miss some high-grade cancers, although you might delay the detection because you might find them in the subsequent round, but it seems like we need to lower the threshold a little bit. We're still figuring out what that should be.

Matthew Cooperberg: This depends on the age range as well, right? The Malmö data would show the men in the age range you're talking about the 45 to 50, 1.8 puts you already in the top decile, more or less.

Sigrid Carlsson: Exactly. Good point.

Matthew Cooperberg: So, what is the target age range in Göteborg-2?

Sigrid Carlsson: 50 to 60. It's a starting age and then you continue. That's another question. When should you stop? In the Göteborg-1 trial, it was between 70, but some cancers came after the trial had terminated. So, should you continue up to 75? Again, it becomes fluent with comorbidities and competing mortality versus risk. Men now live long lives.

Matthew Cooperberg: What other trials?

Sigrid Carlsson: Other trials. So, in Sweden there's also the Stockholm III trial. The Stockholm III test is a multiplex test, so it really combines the PSA, the other isoforms of PSA, clinical information, DRE if they've had a prior biopsy, ultrasound, and then genetics. So, it's everything together, and then that gives men an individualized risk prediction of high-grade disease on biopsy. Then you can use that to then go to an MRI and then biopsy. So, that strategy has also been shown, similar to the Göteborg-2 trial, to maintain the detection of high-grade disease and reduce the risk of overdiagnosis and unnecessary biopsy. So, you kind of balance the benefits and harms. In Sweden there's also other ongoing initiatives, what's called organized prostate testing. The Swedish government has allocated money for different centers to explore different algorithms because it really becomes a matter of resources and the flow of men through the system and whether we should implement an organized programming in all of Sweden. So, those are ongoing right now, and so we'll hear back in the next coming years about those initiatives.

Matthew Cooperberg: How much variation is there from region to region?

Sigrid Carlsson: A little bit, but on similar principles, PSA and some sort of risk stratification, whether it's a biomarker or MRI. Similar, but slightly different, and also again, the intervals and the age ranges, and so we'll learn a lot from those strategies.

Matthew Cooperberg: Then there's the PROBASE trial.

Sigrid Carlsson: Yeah, there's the PROBASE, led by Peter Albers in Germany, which is answering, or trying to answer the question whether you should start at 45 versus 50, because that's been really the conundrum. How many cancers would have progressed in the interim? Can you start at 50, or should we start at 45? That's ongoing and they reported some initial results, and obviously the risk of finding prostate cancer in younger men is low, so I think the prevalence was about 0.2%. Then they also incorporated the digital rectal examination and that had also low utility in the younger men, so it seems like the PSA test, just a blood draw is the way to go with a screening test, and then the DRE could be a supplement as part of the early detection strategy.

Matthew Cooperberg: Which one are you most excited about, if we think in terms of where are we going over the next five to 10 years as these trials start to come?

Sigrid Carlsson: I think it's really interesting. I think there are many ways to Rome, and I think they might all relate to Rome. There's also other trials. There's the ReIMAGINE, which is led by Caroline Moore, Professor Moore in the UK, which is a MRI-only feasibility study, which is an interesting concept. Can we remove the PSA test altogether, blood draw, and go straight to imaging? I'm wondering about the number needed to MRI in that trial. I still think it needs to be a step-wise approach. Then the Finnish trial led by Professor Anssi Auvinen is interesting, the ProScreen trial, because that kind of combines everything similar to the Stockholm test, that it starts with a PSA. Just by doing that, you can eliminate a large group of men who won't go further down the chain, but then you'll have a reflex test with a 4Kscore, so the PSA isoforms, and then among those who have an elevated 4K, you go to an MRI. So, you kind of have this funnel effect, and so you have fewer and fewer men being exposed to biopsy. That's also another risk-adapted strategy.

Matthew Cooperberg: That's probably close to, I think, what a lot of us are doing in practice today here. This one is a randomized trial?

Sigrid Carlsson: Yes, large randomized trial.

Matthew Cooperberg: What is the control group in this one?

Sigrid Carlsson: Yeah, it's a similar control group, not invited. It's like a very nice RCT design, so that will answer the question. Similar to the Göteborg trial, it's powered with prostate cancer mortality at 15 years. That's the endpoint. So, we'll have to stay patient and wait for the outcomes, but I think we'll learn a lot from all these ongoing initiatives, and then there's of course also the EU initiative, spearheaded by Dr. Van Poppel and Dr. Monique Roobol in the EU, so the EU has now allocated money for them to look at different initiatives in Europe. Obviously, it depends on the country where you are, and the life expectancy there, and the resources and what are the different needs in those countries, but opportunities to explore population-based programs or implementation strategies for screening for prostate cancer for men in the EU. So, a lot of movement is happening. We kind of moved from trials into population-based screening initiatives. It's an exciting phase that we're in and to see what comes out of it.

Matthew Cooperberg: Coming back to ReIMAGINE for a minute, the same group published the MRI-first pilot trial to show that this is feasible. Do you see us getting to that point where MRI... Let's ignore the cost of MRI in the US for a minute. I think the questions are, first of all, it seems like a baseline PSA is hard to beat. From the Malmö studies that you led, you can wipe out 75% of the population basically in terms of prostate cancer risk with just this baseline blood test. So, do you see us getting to the point where an imaging test is going to be better as a first screen?

Sigrid Carlsson: It's an interesting conceptual idea because if you get around the poor specificity of the PSA test, it's like here's an imaging. In breast, we've done mammography for a while, so conceptually, it's an interesting idea, but practically, is it really feasible? Because we all know prostate cancer is heterogeneous disease, it's multifocal, and so how can you really pinpoint with just MRI? I think you need a reflex, so the PSA test first and then the MRI to really harness the power of both those modalities and also the interpreters. We know, as you've published on this too, about the heterogeneity between readers. So, for this concept of pre-biopsy MRI to work, you really need to have a good machine and someone who's experienced at reading. So, if you were to roll this out, do you even have the resources and the radiologists available for this to work?

I think what you were saying, if you used the PSA test first and then go to MRI, it might be a more efficient strategy in terms of implementation and cost-effectiveness. Like you said, the PSA is a fantastic marker of prostate cancer mortality, baseline PSA or PSA at age 60. If your PSA is less than one, your risk of metastasis in 20 years is 0.2%, and the area on the curve is 90%. It's a fantastic prognostic marker. So, for imaging to beat that, I think it's hard, but I think it's a high bar. I think the MRI can definitely supplement, and it's been a game changer for sure. It helps us do a better biopsy, like you always say.

Matthew Cooperberg: Last question. One thing that struck me during this session, and as I kind of look at this literature is how none of this research is happening in the United States. This is a difficult question to answer, I know, but why is none of this happening here? Why are we unable to do a second round of PLCO or anything more innovative in the US when it comes to screening?

Sigrid Carlsson: Yeah, good question. The PLCO trial was fantastic in the design of the trial, but then of course, men in both arms had a PSA test. So, it's really hard statistically to find a difference between the groups. If you were to roll something similar out now, of course men are informed and they don't want to be in the control group, and so it could be hard to implement. Maybe the history in Europe, and especially in Scandinavia has been large randomized trials, and if the government sends you an envelope, you kind of do what you're being told. Still, there's both benefits and harms too that we're learning from.

Matthew Cooperberg: Any other thoughts on where we're heading?

Sigrid Carlsson: It's exciting. It's an exciting phase we're in. This next chapter of PSA screening, moving from the trials, what we've learned, and keeping the benefits, and reducing the harms and saving the lives of men.

Matthew Cooperberg: Well, thanks for joining us. Thanks for sharing your thoughts and your insights, and thanks for all your work on the Guideline panel.

Sigrid Carlsson: Thank you.