Read the Full Video Transcript

Matthew Cooperberg: Well, good morning. I am Matt Cooperberg from the University of California in San Francisco and it's a pleasure to bring you a new installment of the UroToday Center of Excellence Localized Prostate Cancer with a very exciting update this week in the New England Journal of Medicine. We have been treated to a 23-year update from the ERSPC screening trial. And it is my great pleasure to be joined by Monique Roobol who's the lead author on the study. She is professor of decision-making at the University of Erasmus and Rotterdam in the Department of Urology which I think is a wonderful title by the way. Epidemiologist by allocation. And she's going to give us a bit of an update on the trial. And it's a pleasure to have you here. Thank you so much for joining us.

Monique Roobol: Well, thank you for having me. It's a great honor to give some updates on this latest paper, obviously, which is a great achievement for the ERSPC group.

Matthew Cooperberg: It is wonderful. It's truly a tremendous achievement. I suspect most of the UroToday audience is generally familiar with the trial, but it's been a while since we've had an update. So maybe to start, just give a little bit of background on how the trial was conceived and what its major objectives and previous findings have been.

Monique Roobol: Yeah. Okay. Well, the ERSPC trial is a randomized controlled trial on PSA-based prostate cancer screening and it was initiated in 1993. We had within eight countries approximately 163,000 men randomized to a screening and a control arm. In the screening arm, men were tested with the PSA tests, approximately two or four-year interval. The men were aged 55 to 69 with some exceptions from what younger and some older men. In some centers, the biopsy method was if the PSA was three or higher, the biopsy was systematic random biopsy obviously for that time.

We had screening rounds up to 60 years after randomization. The first results were published in 2009, actually in the New England Journal of Medicine where we showed that we had a 20% relative prostate cancer mortality reduction in favor of screening. We had a number needed to invite and a number needed to diagnose of 1,410 and 48, which obviously brought a lot of discussion about harms and benefits.

The ERSPC trial continued their follow-up. They published again in the New England Journal of Medicine in 2012, an update with 12 years of follow-up, showing similar results with lower number needed to invite and number needed to diagnose, but still obviously the concern of over-diagnosis. And we had one publication in between European Urology with 60 years of follow-up, and now we have our final publication of the ERSPC in the New England Journal of Medicine, again, showing a relative reduction of 17%. But our absolute risk reduction is still increasing, which obviously has an effect on the numbers needed to invite and the numbers needed to diagnose. So that's the story, very short.

Matthew Cooperberg: It's exciting and a really important result. Now just terms to clarify, when that first paper came out, it was actually on my birthday in 2009 where the PLCO came out at the same time. The phraseology at the time was number needed to treat and number needed to screen. Tell us a little bit about the invitation process in the ERSPC and this concept of number needed to invite rather than screen and diagnose rather than treat?

Monique Roobol: Yeah, so what we have in Europe is we have eight centers. Obviously, all men were invited at a population-based level. So from the population registry, men were selected in the age group, let's say 55 to 69. We are all invited by letter. Due to legislation rules, at that time in 1993, it was possible in three countries to invite and randomize without consent. And that makes a difference because in other centers like in the Netherlands that was certainly not an option. So you invite first and only the men that consent you can randomize afterwards.

So we have two designs actually within the ERSPC. And that is also exactly now what is prohibiting us to continue to get at an individual data in the whole of ERSPC because we have men now included in our study in centers that did not need consent in 1993 who never gave consent. So that is currently a problem now with the new GDPR law.

Matthew Cooperberg: I see. That's why this will be the final update.

Monique Roobol: Absolutely. But it doesn't mean that we stop. I just want to add that because each separate center within ERSPC is continuing followup and is continuing to work on the mortality data because we also know that at the moment, at the time of this last analysis, somewhat more than half of the men only have died. So the interesting part might still come actually. So we continue this follow-up and obviously we work as a consortium and we will work together, but sharing at an individual level data will become extremely difficult and prohibited in three of the ERSPC centers.

Matthew Cooperberg: Maybe talk a little more about this core age too. So some of the centers started at 50, some 55. This current analysis only includes the 55 patients. Is that correct?

Monique Roobol: 55 up to 70? Yes, correct. Correct.

Matthew Cooperberg: Is there going to be any further update? I know that was GÖTEBORG. Will there be further updates on this younger age population?

Monique Roobol: For sure. The GÖTEBORG trial is alive and will update their results. Also, we in the Netherlands are on the other side of the spectrum. We have screened up to 74 and we will also still update our Rotterdam data. So we will keep on learning about starting at a younger age and continually up to the age of 74 for sure. And we have now within this New England paper, obviously, a section on what the effect is of stopping with screening because we have such a long followup now also after stopping our active screening period that we... well, we could not resist to do an analysis on that part also.

Matthew Cooperberg: And how has that looked, particularly in the control arm, right? The PSA, there's no national screening programs in any of the countries, but of course secular or ad hoc screening has continued. So as time has gone on, are you seeing more and more testing in both arms?

Monique Roobol: Yeah, that's different. Let me say that in Sweden, there is now the so-called OPT program since a few years actually, and it is not a national program, but it is ongoing virtually the whole of Sweden on a regional level. But it had started a few years ago. So it will not affect our initial analysis obviously, but this has actually been a result, obviously, of all the data that has come out on the prostate cancer screening. So they have started really in a program in Sweden. In other countries, this is definitely not the case. And we have opportunistic testing.

In Netherlands that is actually still relatively low. I would not say zero. Definitely not. But if you compare it to other countries, it is still relatively low. You can also see that in the incidence figures from our two arms of the trial. But opportunistic testing is ongoing in Europe and we are trying to address this. And there are currently in many European countries initiatives to start up implementation studies on for a population-based program to really streamline all the opportunistic testing, which in generally bring more harm than that they bring good.

Matthew Cooperberg: So I want to come back to policy in just one second. Before that though, there's a nice editorial from Andrew Vickers pointing out some of the well-known limitations here. The fact that screening is a little bit... Screening start age was a little later than most of the guidelines are now suggesting that of course there was overdiagnosis in the absence of any MRI or secondary liquid testing after PSA. There was overtreatment of low-risk disease. We can add to that there is some contamination in the control arm. There's non-attendance in the limitation arm.

Monique Roobol: Of course.

Matthew Cooperberg: Do you have any sense of what... And I know your group and the CISNET group have done a lot of work over the years. To what extent do you think the relative risk reduction maybe under makes the true benefit of screening versus absolutely no screening?

Monique Roobol: Yes. I think that's obviously true and we have done some additional analysis. Obviously with the QseC type of analysis, we can do that both for non-attendance and contamination. So this estimate is obviously the intention to screen estimate. And if you look in particular in the Dutch data within ERSPC, you will see that our relative risk is still 24% at the moment. We have a lower contamination. You can see that in the incidence figures that are in the supplementary appendix, we had a very, very strict and intense screening protocol up to the age of 74.

So I do think that obviously ERSPC is the result is the mean of the whole group, but you can see differences and that makes ERSPC so very, very interesting for epidemiologists. At least you can see differences in the results in the incidence in the type of cancers that are diagnosed and in the mortality reduction. So you can learn a lot also from the different centers. And obviously it is important to look at a whole what the result is. But I do think that the intention to screen is underestimating the effect. And I do think with longer followup, I'm very curious how it will end actually. Yes, definitely.

Matthew Cooperberg: I mean, when you look at number nine, number needed to diagnose, 12, this is starting to look favorable to most other things we do in preventive oncology, right?

Monique Roobol: Exactly. Exactly.

Matthew Cooperberg: So to that end, with all the studies coming out, the MRI first and BARCODE 1 and all these studies looking at adjuncts to PSA, do you have any sense that any test will actually come before PSA? Will the PSA forever be the first test in mid-life and then use all these tests as secondary screener?

Monique Roobol: Well, forever is a strong wording.

Matthew Cooperberg: For foreseeable future.

Monique Roobol: Yeah. Well, working in population-based screening, I like PSA a lot actually. Because it's cheap, it's objective, it's fully, fully... How do you say that in good English developed, let's say it like that. It is a perfect first screening test. It can be applied without too much harm. People are not afraid to get it. So for me, it is a very nice test. And the perfect thing for this test is actually that we now have learned with all these long follow-up that within the age category we are talking about approximately 50% of men can be sent home more or less, at least for a very long time. And this is so valuable, so very valuable that I think PSA is for me a very good test. And I'm very curious what will come up to beat this rest.

Matthew Cooperberg: To that end, as a professor of decision making, there's all these decision aids and talk about shared decision making and all the guidelines, at least paid lip service to shared decision making. You can pull decision aids in the US which are 17 pages long, and the primary docs are meant to talk about the risks of incontinence after prostatectomy before you draw a PSA test. Obviously, we're not recommending that men get a PSA sent as part of the Chem 70 every year, but what do you think is really important for men to understand before a first PSA is sent?

Monique Roobol: Sent, yeah. I want to make one distinction and that there is shared decision-making and there there's informed decision making. And shared decision-making is something that happens in the clinics because you share and you share thoughts and you talk about it and sometimes it is done over two consultations, more or less to really come to a decision. In population-based screening, it's different. You get an invitation at a moment often that you totally are not thinking about prostate cancer or prostate cancer screening. You just get it with the male and you get an invitation. You think, "Whoa, what's this?" Right?

So then you have to be informed and there's obviously often not a way to really discuss into depth what are you going to do or something. Some people go to the GP or something, but most of the people have to make the decision based on what they get. The information they get by mail or by video or something like that. So there's a distinct difference between the two. And I'm working obviously most now for informed decision-making. How do we get people that are invited for a program, really good informed that they make a good decision, which is extremely challenging.

I can tell you that because the population is so many subgroups that need so many different approaches that we are working on that very hard within the PRAISE-U consortium in Europe. But with shared decision making, I think we learned from all the reviews and all the work that there is that interaction between not yet patient, but patient and physician is the most crucial part.

The trust, that they trust what is being said and that they trust what is being advised and that the physician really listens to the patient, what are their wishes. But this is, at least in Europe, and I guess in the US, it's not different actually. It is the time that you have to discuss this, which is always the limiting factor. And that is something we have to learn with and all the help and all the decision aids, which are very, very interesting. But the numbers are often a bit different in a different decision aids. So we need to choose carefully in which setting we are going to use, which aid actually. That's my view at the moment.

Matthew Cooperberg: Wonderful. And the last question, you mentioned some of the evolving national screening policies. Do you think we're at the point as the US Preventive Services Taskforce in the process of gathering evidence for a new guideline in a lot of the countries in Europe are readdressing this issue. There's discussion in the UK. Are we at the point where the evidence is strong enough to support a national or in some countries at least national screening policy?

Monique Roobol: Yeah. Well, that's always a balance. Obviously, some would say no because we have still ongoing randomized control trials looking at the effect of risk-based screening like we just talked with reflex testing, MRI or biomarkers, and we do not reach the end point yet. The Finnish trial, it's the only one in my view who really waits for the end point process of cancer mortality. The others have intermediate end points like ISOC2 detection or higher or that kind of stuff.

But the other part is we can wait forever. We can wait forever because there will be a new test and another test and yet another test. So I think, yes, the time is there to really look at how it works out in real life. And that's what we are doing at the moment in Europe. We are starting in many different countries in Europe implementation trials. And they do not have a fixed algorithm. And we say, "You have to do this, you have to do that." No, we have a basic algorithm and they can adapt according to the healthcare structure within the country because otherwise it will never work.

And I can tell you already now that the main barrier and I come back to this informed decision-making is participation rate. Because this is... And we are talking here about men, sorry to say it, but men are not so eager to participate in medical screening programs and so on. So our focus is at the moment on really working on how we get men to participate, which is sometimes an even more important question than what reflex test shall we use? Because if they don't come, you don't need a reflex test also.

Matthew Cooperberg: Yeah, exactly. So maybe that take-home message may need to at least be engaged and in conversation with their primary docs and thinking about this issue. Do you think that... I mean, this issue has come up that the men that need the screening the most are not the ones that know to ask for the test.

Monique Roobol: Exactly.

Matthew Cooperberg: Right? Based on race, based on social demographic factors.

Monique Roobol: Exactly.

Matthew Cooperberg: So with the European consortia, is there proactive approachment of men at risk or is this more opportunistic targeting already having a conversation about PSA?

Monique Roobol: Yeah. So what we're doing, not obviously in ERSPC, ERSPC is now ongoing collecting data over time with respect to mortality. But in PRAISE-U, the other European initiative and another EU can screen a large European initiatives. We are really trying to find ways to talk with men at lower socioeconomic status. For instance, immigrants, people with very low health literacy and talking to health workers within the communities to really get to them and try to learn why they won't come. Is it simply because a very simple example is they don't even know what a prostate is, right? So if you start sending them information or prostate cancer screening, they think, "What is this?"

So really starting again at the basis, what is going on? What are the limitations? And how can we address it? Because we learned that the men that do not come are actually those at the highest risk of getting prostate cancer and getting a prostate cancer that might kill them.

Matthew Cooperberg: Anything else you want to-

Monique Roobol: A lot work to do. A lot of work to do.

Matthew Cooperberg: A lot of work work. Nobody is going out of business in prostate cancer epidemiology anytime soon.

Monique Roobol: No. Definitely not. But it's interesting time. I would like to give-

Matthew Cooperberg: Fascinating.

Monique Roobol: Yeah, that's my final message. We are in a very interesting time at the moment and we are actually leaving more or less to randomize controlled trials and discussing constantly has it an effect or does it have an effect? We know that it has an effect certainly on metastatic disease, but now we need to step over that and see how can we implement it, that it really has an effect for those people that need it.

Matthew Cooperberg: Very exciting times. Thank you so much for sharing your time with us.

Monique Roobol: It was a pleasure.

Matthew Cooperberg: And congratulations once again on the paper.

Monique Roobol: Thank you.

Matthew Cooperberg: I think it's wonderful news for all men everywhere.

Monique Roobol: Yes. Thank you so much.

Matthew Cooperberg: Thank you again.

Monique Roobol: Thank you. Okay.