15-Year Follow-Up of the ProtecT Trial: Discussing Results and Changes in Prostate Cancer Management, The ProtecT Trial - Oliver Sartor

May 9, 2023

Alicia Morgans and Oliver Sartor discuss the New England Journal of Medicine editorial on the fifteen-year follow-up of the ProtecT trial. The ProtecT trial was a UK-based study where 1600 men were randomized to either active monitoring, prostatectomy, or radiotherapy. The trial followed up on these men for 15 years and found that there were no significant differences in mortality between the groups. Dr. Sartor also emphasizes the changes that have occurred in localized prostate cancer since the ProtecT trial began in 1999 including the more sophisticated methods of surveillance, which differ from the methods used in the trial.


A. Oliver Sartor, MD, Professor of Medicine, Urology, and Radiology, Director Radiopharmaceutical Trials, Mayo Clinic, Rochester, MN

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi. I'm so pleased to be here with Professor Oliver Sartor, who's a GU medical oncologist. I'm so excited to talk to Dr. Sartor today about the ProtecT trial and the recent editorial that he wrote regarding that trial in the New England Journal of Medicine. Thank you so much for being here today, Dr. Sartor.

Oliver Sartor: Oh, thanks Alicia.

Alicia Morgans: Wonderful and smooth travels with all of that. But in the meantime, I'd love for you to just set up the ProtecT trial, which was recently published in that New England Journal of Medicine Edition that where your editorial was, but it was also, I think, discussed in lay media around the world and really quite a focus for many of our patients. So what was the ProtecT trial?

Oliver Sartor: The ProtecT trial was a really nice trial out of the UK and men who had an elevated PSA, provided that they did not have a PSA above 20 and had localized prostate cancer, these men were randomized to either observation or radiation plus hormones, short course, or radical prostatectomy.

And there were over 1600 patients enrolled on the trial and they were followed for 15 years, and that's what was in New England Journal, 15 year followup. And by the way, 98% of the patients actually were followed for 15 years. I think that was amazing.

So what do they find? The answer is they did not find much in the way of differences. Mortality was basically the same in 15 years, and the authors concluded that, well, we don't really need to treat a lot of prostate cancer and perhaps just putting people on surveillance would be just fine.

Now, if you don't mind, my editorial had a couple of caveats. Because localized prostate cancer is a very heterogeneous group of patients that you could have a Gleason 10, PSA 19, T2C, or maybe you could have a Gleason 6 with a PSA of 4.1 and end up with a very different type of cancer than the high risk patient.

So you first of all have to understand who was enrolled on the trial, and that's really critical, otherwise you can be misled. So who's enrolled? Number one, the median PSA was about 4.6, not very elevated at all. Number two, 77% of the patients had Gleason 6 disease. They didn't really break out the intermediates, but I can say for grade group three, which is Gleason four plus three or higher, it was only 6% of the patients.

So if you are going to be talking about localized prostate cancer, maybe what you ought to be talking about is Gleason 6 patients as a whole with some low or favorable intermediate risk, but only 6% of the patients having that grade group, four plus three, four plus four and higher.

So I think the results apply to the patients that they studied, but I don't think the results apply to the patients they did not study. So if you've got low risk or potentially low intermediate risk, I think that you're going to do pretty well with surveillance.

Now, if you don't mind, there was one other issue that I brought to bear. I called it localized prostate cancer then and now. The ProtecT trial was started in 1999 and things have changed. First of all, and I'm sure this is true in your practice, if somebody has an elevated PSA, we don't necessarily do a biopsy. We get an MRI, a multiparametric MRI. If the MRI has PI-RAD one or two scores, we typically just observe. If there is a PI-RAD three or higher, then we can do a localized biopsy.

Now it turns out that you biopsy a lot fewer men today than in the past. And furthermore, in the past when you biopsied everybody, you've got a whole bunch of Gleason 6 disease and then you put people in surveillance. I think it's actually better not to even biopsy them in the first place, and that's what we're kind of moving toward.

Another important change in addition to the MRI is transcriptomics, and we can call that genomic classifier if you like. I don't necessarily like to use brand names, but we can look at the transcriptome and then look at the outcomes with very good prognosis for those who managed to have a piece of cancer in their core and then that's able to be analyzed. So we can take intermediate risk and we can get a little better idea through the genomic classifier as to what type of risks they might really have.

And then we also do surveillance differently. They were just following PSA basically, and the PSA went up, then they referred somebody. Well, they actually probably missed some of the people that they should have taken off surveillance, and they probably treated some of the people that were likely just to stay on surveillance and do fine.

So their surveillance was not very sophisticated. I think in our practice, and we do a fair amount of surveillance, that we get MRIs on an annual basis and we biopsy when we feel as though there's a need to biopsy. We keep a lot of people on surveillance for a long time and really have very, very few patients that are requiring aggressive therapy. We often can manage these patients on surveillance for years. They had a pretty significant risk of taking people off surveillance.

So anyway, prostate cancer then, prostate cancer now, not the same. ProtecT study is important, but it applies to patients they studied. It does not apply to the high risk patient, and those high risk patients need to be treated in accordance with the paradigms that you and I understand with radical prostatectomy radiation plus hormones or more.

One of the differences I think is a little bit interesting. I don't know how this is proceeding at Dana Farber now. We are looking at focal therapy for an increasing number of men. If you've got an intermediate risk prostate cancer definable on multiparametric MRI, then we might refer that patient to the surgeon who will do potentially HIFU or cryo or radiofrequency ablation or some form of subtotal treatment. And then by the way, put the patient back on surveillance for the rest of the gland.

So anyway, that's a little bit of what the ProtecT study was and then my perspective from the editorial about what the shortcomings might have been from the actual study. It was a nice study but not perfect. And how to think about localized prostate cancer as we go forward. I don't, I'm sure there are questions you might have or comments you might have, but I'd love to hear those.

Alicia Morgans: So thank you so much for walking us through that. I think that I really appreciate your discussion particularly around those higher risk patients because some patients have come in and said, "Oh, I have high risk prostate cancer," but the ProtecT trial says everybody can go on surveillance. So I'm glad that you've talked about that.

That's the patient population where you and I both now engage in PSMA PET screening to really ensure that we don't actually have locally advanced disease or even metastatic disease, which is clearly not a population that was included in a high level in the ProtecT trial or we would've seen, I think, different results.

So very, very interesting. And our group, similar to yours, I think is thinking more and more about focal therapy. And I really do look forward to the standardization of follow up because it is the rest of the gland that I then worry about, and ensuring that we are adequately monitoring that and picking up anything else and not providing a treatment that will limit our options in the future too, should that patient have a recurrence or even metachronous cancer that then arises somewhere else.

I wonder if you could comment, I know that the quality of life data was also published, and this was, I think simultaneously maybe in New England Journal of Medicine evidence. Do you have any thoughts there?

Oliver Sartor: You know Alicia, it was not particularly surprising. We have understood what the side effects of radiation and surgery are for a long time, and it just sort of confirmed what we already knew.

You have a little longer follow up. There was fecal incontinence in 12% of the radiation treated patients, which I thought was a little bit surprising. But we know that incontinence and sexual dysfunction occur with surgery. We know that there can be some rectal injury that occurs with radiation, and we know that surveillance has a tendency to avoid those for patients who are on surveillance and no treatment.

So it was not particularly educational. And by the way, I think you're aware the previous follow up on ProtecT, which was double published in the New England Journal, about the quality of life data as well as the primary outcomes to oncologic outcomes. We've already seen that. So with a little more follow up, not much changes on the quality of life side.

Alicia Morgans: And that is to be expected. Well, thank you so much for sharing your thoughts on this highly publicized and highly useful article that really I think will help to reassure all of us that we can put patients on surveillance, we can keep them safe. We even have, as you mentioned, our programs now that are probably going to be more precise in terms of limiting biopsies that are unnecessary, and then really ensuring that we're able to be active around treatment for those patients where things are maybe more aggressive than they seem.

Well, as usual, thank you so much for your time and for your expertise.

Oliver Sartor: Thank you very much, Alicia. A pleasure to be here.