Sigrid Carlsson joins Charles Ryan discussing the epidemiologic outcomes of men in the current era who are facing active surveillance. She reviews the long term data learned from the Memorial Sloan Kettering Cancer Center Experience which mirrors prior reports with low rates of metastasis or cancer-related deaths for patients on active surveillance. They also discuss the migration of pushing the envelope for active surveillance, how MRI is fitting into the active surveillance patient and the management of cancer, the development of new therapies for the aggressive disease, allowing clinicians to focus more on the types of cancers that need the treatment. Biographies:
Sigrid Carlsson, MD, Ph.D., MPH, is the assistant attending epidemiologist at the Memorial Sloan Kettering Cancer Center. Dr. Carlsson’s research is focused on screening and early detection of prostate cancer. She is an investigator in the world’s largest randomized study of screening for prostate cancer, the European Randomized Study of Screening for Prostate Cancer. Dr. Carlsson’s research aims at finding a better balance between the harms and benefits of prostate-specific antigen (PSA) screening, through the use of multiplex testing and risk-stratified strategies that incorporate clinical information, biomarkers, and magnetic resonance imaging.Charles J. Ryan, MD
is the B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology and Transplantation.
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Charles Ryan: Hello, I'm delighted to be joined today by Dr. Sigrid Carlsson, who is an Assistant Attending epidemiologist at Memorial Sloan Kettering Cancer Center in New York. Thank you for joining me. Eager to talk to you today about active surveillance. This is your area and we've had a few great conversations recently about active surveillance. I wonder if you could start by giving us a sense of the outcomes, the epidemiologic outcomes of men in the current era who are facing active surveillance?
Sigrid Carlsson: Yes. Active surveillance, I would say, is a safe management strategy for carefully selected and carefully monitored patients on active surveillance in these days. We have now reported recently our outcomes of active surveillance at Memorial Sloan Kettering, so we have 17 years of follow-up. We have about 3000 patients on active surveillance that we have monitored. The median follow-up is, of course, shorter because most of these men have joined the program in recent years. The long-term outcomes are good, so we see a 1% risk of metastases over 10 years if they have Gleason 3+4 or Grade Group 2. If they have Gleason 6 the risk of metastases: 0.6% at 10 years.
Charles Ryan: Are these patients who have metastases even though that's a very low number, are these patients who started out with active surveillance, had local therapy then recurred or are these patients who develop metastatic disease in the absence of local therapy?
Sigrid Carlsson: It could be either-or. About 50% of men remain untreated on active surveillance after 10 years of follow-up, but, of course, they convert to treatment upon disease progression. Then, if they have a radical prostatectomy or radiotherapy some of them might have recurred and have pCR and then progressed.
Charles Ryan: I'm assuming because you started out by asserting that metastasis was perhaps the worst outcome, that there have been no deaths from prostate cancer in this group?
Sigrid Carlsson: That's correct. We had one death and there was a very unusual course of the disease, so, of course, there is no strategy that's perfectly safe. There's always someone that would slip through the net, but it's very rare because they are carefully monitored and carefully followed with repeated PSAs, digital rectal exams every six months, we do MRI every 18 months and then we do biopsy every two to three years or if anything indicates that you would need a biopsy earlier; so these men feel safe and secure, and we follow them closely.
Charles Ryan: I see. In a patient who starts out on active surveillance, who is ultimately going to be treated, that 50%; when is that treatment occurring? Is it something that's occurring within the first year or two or is it later on? Give me a sense of that timeline.
Sigrid Carlsson: Yeah, so it's a good question. If you look at the curve of treatment, a lot of them happened early, so either there's a reclassification on the first biopsy or the disease progression on the biopsy within the first three to five years, I would say. That's usually when that occurs or it could be over longer-term follow-up.
Charles Ryan: Is there a single type of progression that occurs? Is it an increase in the Gleason score? Is it an increase in the T stage? What is the progression of that?
Sigrid Carlsson: Could be both.
Charles Ryan: Either, really.
Sigrid Carlsson: It's usually is a Grade progression that triggers treatment.
Charles Ryan: It's usually a Grade progression?
Sigrid Carlsson: Yeah.
Charles Ryan: I see.
Sigrid Carlsson: There are some cases when the patient prefers treatment because dealing with the anxiety and uncertainty of living with untreated cancer could be, but we have programs in place for that too so that men can feel more secure so that we would ideally like it to be just the true biologic disease progression that triggers treatment.
Charles Ryan: Are there patients who are lost to follow-up who are on active surveillance who just decide they're not even going to do that? I mean, I'm sure at your center they are followed-
Sigrid Carlsson: Yeah.
Charles Ryan:... but is that a risk that that is seen at your center, has been seen at others?
Sigrid Carlsson: That's nothing that we've looked at specifically, so I can't give you an answer, but, of course, there are some patients who are lost to follow-up, so it's-
Charles Ryan: But, I'm saying, I should say are there patients who start out in active surveillance who ultimately decide to stop doing active surveillance. Maybe they're not lost to follow-up, but they stopped doing the yearly biopsy and-
Sigrid Carlsson: Yeah. We haven't looked exactly what proportion of men follow the protocol as we would like them to-
Charles Ryan: I see.
Sigrid Carlsson:... but, of course, we see that happening. You can understand that men are reluctant to have repeat biopsy and so on and so forth. We try to do everything to improve men's experience on active surveillance. For instance, the biopsy procedure, what can we do to reduce the pain, discomfort and the anxiety? Can we do a simple brief meditation exercise before the biopsy, can we change the way we do the local anesthesia, can we do transperineal instead of transrectal biopsies and so on and so forth so that men do not feel hesitant to be on a program that's uncomfortable long term?
Charles Ryan: While we're on the topic of biopsies, I think you have been doing a lot of work on MRIs, and when the biopsy and the MRI, how they interact with one another. Tell us about your work on MRI.
Sigrid Carlsson: This is more before the diagnosis. We're here now in Barcelona at the EAU and we had this debate the other day with a Dr. Caroline Moore from the UK. It was really interesting debates because it's becoming more and more common these days to do an MRI before the biopsy, so even before men are diagnosed. They come with an elevated PSA and then they want to have an imaging of the prostate before the diagnosis. Of course, again, it's patient experience. You don't want to have a biopsy if you don't have to. We've been looking in into that literature more and see if the MRI's negative, do you have to do the systematic biopsies, do you only do targeted biopsies if the MRI is positive or what's the pathway? That was the debate with Caroline Moore.
There's more and more push to not do the systematic biopsy if the MRI is negative. But, the problem, so that the other side of the argument would be that the negative predictive value is not 100%, so there's definitely a miss rate by not doing the systematic biopsies. In one of these trials, the PROMIS study, the negative predictive value was 74%, so that means that you know there's the miss rate of up to 24% if you don't-
Charles Ryan: 24% of individuals could have negative MRIs and if they underwent a systematic biopsy, they would have some tumor detected?
Sigrid Carlsson: Exactly. That was clinically significant tumors. It's not safe to avoid the biopsies as of today. Also, depends on who does the MRI and who reads the MRI. What's the quality and the expertise of the radiologist, the machine you're using and what systems do we have in place to have sort of a quality assurance criteria? If you go to Caroline's center in the UK, you might have a beautiful, perfect MRI and it can be safe to say that there's nothing here, but at some other center elsewhere in the world that might not be true.
Charles Ryan: One of the great challenges of logic and science is trying to prove when something isn't present, right?
Sigrid Carlsson: Exactly.
Charles Ryan: You can only prove when it's there and that is a real challenge.
Sigrid Carlsson: But, in this case, that's also a challenge because there are false positives, so even though you say there's a PI-RADS 3 to 4, even 5 we cannot even be sure that that's prostate cancer in that case.
Charles Ryan: What are the factors that lead to a false positive on an MRI?
Sigrid Carlsson: Well, there could be multiple reasons. I mean there are some rare cases where you would think it's prostate cancer, but it could be tuberculosis, so granulomatosis in the prostate that mimics prostate cancer. That could be one of those rare events or it could be just the interpretation by the radiologist. There's a learning curve in interpreting the images, and also if you do the targeted biopsies, there's a learning curve of targeting of the area. There are multiple factors for this concept to be successful. It's very interesting and very promising.
I think from a patient perspective, it would be ideal if we can find a pathway of men who have low risk of having clinically significant disease and a negative MRI who don't need a biopsy. That would be terrific if we could identify that, but then there are some challenges, so the question is how can we prove that. Can we add PSA density, for example, can we add biomarkers before the MRI? These are studies that we need to do and figure out what's the next.
Charles Ryan: I look at this as there's two challenges that I think you face, right? One is improving the sensitivity of your technology at Memorial Sloan Kettering Cancer Center, a world-leading place on the development of this. Then, the next question is how can you export this technology, as you alluded to earlier, to other places that don't have the experience in radiology and don't have perhaps the same type of MRI scan, so how exportable it is there. That's going to provide some interesting and challenging work moving forward.
Sigrid Carlsson: I think so too.
Charles Ryan: I want to go back to active surveillance and ask you a question that I've wondered about. Active surveillance really started 17 years ago at your center as you said, but it seems, and in my conversations with other colleagues, that the envelope for active surveillance is being pushed and so we have patients who clearly would not have been offered active surveillance 10 years ago who now are on active surveillance. Do you see that migration in your study?
Sigrid Carlsson: Yeah.
Charles Ryan: I guess tying it to the MRI then, how is the MRI fitting into the active surveillance patient?
Sigrid Carlsson: Yeah, that's a very good question. If you look at active surveillance, the evolution over time, Laurie Klotz started his series in Toronto and he was very inclusive. He included some Gleason score 7, 3+4, sometimes even 4+3. Then, on the other hand, you had Johns Hopkins, which just did very low-risk disease and very restrictive, so you had the full spectrum. Then, it converted back to, okay, maybe we should focus on Gleason score 6, but then again you want to expand your inclusion criteria to a larger population because otherwise, you become too restrictive. Now, we again see this pushing the envelope towards including at least 3+4 or low volume 3+4 so one or two cores.
What we have recently published a paper from Memorial and my colleague Dr. Behfar Ehdaie Day showing that the tumor quantification is important, so the millimeters of pattern 4 in the biopsy is important. Maybe there is a limit there. Perhaps it's less than five millimeters of pattern 4 among the 3+4, that could also be one of the inclusion criteria. You have the 6s and the 3+4, but low volume. That could be one part of broadening the inclusion criteria because we still want to keep it safe, the strategy, so we will want to make sure that we have carefully selected and carefully monitored these patients.
Charles Ryan: Again with the MRIs then, you are able to, the MRI is able to essentially, hopefully, identify where is the pattern 4, what is the central volume of the pattern 4 and then the urologist can make the decision about potentially recommending treatment based on that?
Sigrid Carlsson: Yes, and the pathologist, the biopsy-
Charles Ryan: The pathologist.
Sigrid Carlsson:... information is, I would say, most important, but the MRI certainly helps. There are a lot of factors that you take into consideration, the PSA level, the Gleason score, the tumor stage, and then the MRI imaging and the age of and the race of the patient, also. But, definitely, if you do an MRI at the start of the active surveillance, that's the good way to start because you're going to have the initial risk stratification.
Charles Ryan: With only 1% progressing to metastases, probably an unanswerable question at this point, but do you see risk factors in the biopsy samples on the active surveillance for the development of those metastases or the numbers just too small to really look at the factors associated with it?
Sigrid Carlsson: Yeah, that's a good question. That's nothing that we've really looked at because like I said, those are rare events.
Charles Ryan: Hopefully will remain rare, but I would imagine your data's only going to become enriched over time because as you said, the median follow-up is eight years or so?
Sigrid Carlsson: It's around four or so.
Charles Ryan: Oh, four years.
Sigrid Carlsson: Because most of these patients have joined the cohort in recent years.
Charles Ryan: You've got a lot of years of work ahead of you.
Sigrid Carlsson: Yes, we do. There are other cohorts.
Charles Ryan: I want to congratulate you for getting this far with this data set, and actually all of you who do research on active surveillance are really to be commended because, speaking now as an oncologist, it's quite amazing that we're identifying patients who a generation ago were told they had cancer and had to have immediate treatment, and in fact, they didn't. This, I think, is an important step in and the management of cancer as is the development of new therapies for the aggressive disease. It allows us to focus really on the types of cancers that need the treatment, but this is the type of work that is needed to be done, so congratulations on that. Thank you for joining me today.
Sigrid Carlsson: Thank you.