Regional Lymph Node Staging for High-Risk and Locally Advanced Prostate Cancer – What Should be the Standard? “Presentation” - Jochen Walz
November 15, 2024
At the 2024 Advanced Prostate Cancer Consensus Conference (APCCC), Jochen Walz examines lymph node management in prostate cancer, addressing staging methods, PSMA PET's role in avoiding dissection, and ePLND's diagnostic and therapeutic value. He affirms ePLND as the staging gold standard, noting its benefits in reducing metastasis risk.
Biographies:
Jochen Walz, MD, Associate Professor in Urology, Head of the Department of Urology, Institut Paoli-Calmettes Cancer Centre, Marseille, France
Biographies:
Jochen Walz, MD, Associate Professor in Urology, Head of the Department of Urology, Institut Paoli-Calmettes Cancer Centre, Marseille, France
Read the Full Video Transcript
Jochen Walz: Secretary Aurelius, thank you very much for this invitation to this yet another great meeting to be coming up here in the next two days and to talk about lymph nodes, which is still like a very hot topic now for decades, basically, in prostate cancer. These are my disclosures relevant for this presentation.
I would like to concentrate on what I consider being the three burning questions we have with regards to lymph nodes now in the management of prostate cancer. The first one being what is the most reliable method to stage our patient with regards to the lymph nodes. The second one being what is the role of PSMA PET in this situation, especially when it's negative? Can we skip the lymph node dissection in this situation? And the third one, the burning question, is the lymph node dissection a staging procedure or does it have also a therapeutic effect on our patients?
The current standard is the extended pelvic lymph node dissection. And you need to be aware that it is very effective. You do what we call an extended pelvic lymph node dissection, taking out the nodes from the external iliac vessels down to the obturator fossa, further down to the internal iliac vessels and maybe some nodes from the presacral area. You will correctly stage 94% of all our patients with regards to the presence or absence of lymph node metastasis. And that is relative to a super-extended pelvic lymph node dissection you see down there on the left-hand side where you would go up to the inferior mesenteric artery. This is a procedure which basically takes three to four hours and just by concentrating on the area that I was showing you on the right-hand side gives you a very high reliability to stage your patients.
At the same time, you will remove basically 90% of all positive nodes. So from a diagnostic point of view, it is very effective, and the bar is very high to compete with this, and does also add some therapeutic effect to it, if ever you consider this being present for lymph node dissection. And this is the current standard of lymph node staging in prostate cancer patients.
But we have now PSMA that was already mentioned on several occasions this morning, and this is the great ProPSMA study from Australia that clearly showed that PSMA is doing better than conventional imaging with regards to the area under the curve, the sensitivity, and the specificity.
But if we would like to answer the question if we can skip lymph node dissection if PSMA is negative, we need to have a look at the negative predictive value. That is the diagnostic value that tells you if a test is negative, that the outcome that the test is supposed to predict really is not present in a patient. And if you look at what I consider high-quality studies prospectively done, more than 100 patients included and using lymph node dissection as the reference to see if there are lymph metastases or not, you end up by having a negative predictive value somewhere around 80 to 90%.
This looks really good, but be a little bit careful. What is the negative predictive value? It actually is calculated by taking the true negatives divided by the true negatives plus the false negatives. And I would like to do a short assumption with you. Let's take 100 patients that were staged for lymph node metastasis and the test said all of them are negative. And then you have six patients that actually do have N1 disease after the radical prostatectomy and the lymph node dissection. That would make the true negatives 94 plus the false negatives plus six makes a negative predictive value of 0.94.
Looks very, very good, but actually, you would miss all of the events. All the N1 events would be missed. The sensitivity is zero. So you cannot rely on the negative predictive value without having another look at the sensitivity of the same test.
And how good is the sensitivity? Once more, the ProPSMA study. You'll see on the right-hand side the sensitivity for lymph node metastasis somewhere around 80%. But be aware that it's not lymph node dissection being the reference. It's a composite endpoint, imaging, PSA, follow-up, and so on.
But if you look at lymph node dissection as the reference, you see that the sensitivity on the left-hand side drops to 40%, repeatedly 40% in four studies. There's one outlier who would like to call it 50%, but not sure that the sensitivity of 50% is really good enough. And you see on the right-hand side, the negative predictive value. You need to be aware that the negative predictive value strongly depends on the incidence. Actually, the worst negative predictive value that you can get is 100 minus the incidence. And if you would calculate those, you would be very close to what you'll see on the right-hand side. So without performing good sensitivity, you cannot rely on the negative predictive value because it depends so much on the incidence.
It's not only myself telling you. This is a recent meta-analysis, a systematic review done by Armando Stabile who looked at the negative predictive value of PSMA to rule out the need for lymph node dissection. And he observed the same observation. The higher the likelihood of finding lymph node metastasis, the higher the risk strata of the patients, the lower the negative predictive value. And he very correctly concludes that in high-risk prostate cancer patients, a negative PSMA PET cannot replace a staging extended pelvic lymph node dissection.
And if you would like to formally conclude what is the role of PSMA [inaudible 00:05:05], we need to wait for the results of PSMA-Select. Roderick Vandenberg is running this trial in the Netherlands, really trying to triage the patient before surgery using PSMA to decide whether lymph node dissection should be done or not. And I hope we will have these results in the near future.
But how about the therapeutic effect of the pelvic lymph node dissection? We have two prospectively randomized trials available, the first one being the Brazilian Lestingi Trial, 300 patients included, an extended pelvic lymph node dissection versus a limited one. 70 nodes versus three nodes. And you'll see on the right-hand side the primary outcome, biochemical recurrence-free survival. No difference between the two arms. It is a negative study.
And then we have Karim Touijer's trial from the US from MSKCC and he just presented here an update three weeks ago in Paris at the EAU24 and he included 1,400 patients compared to also a limited with an extended pelvic lymph node dissection, only 12 nodes versus 14 nodes. That is one of the main criticisms we have here. But for the primary outcome, once more, you see here there's no difference with regards to the biochemical recurrence-free survival between the two groups. Looks like this is, once more, a negative study.
But with a longer follow-up, actually he was able to look at other harder endpoints such as metastasis-free survival, distant metastasis-free survival, and you'll see clearly a difference favoring the extended pelvic lymph node dissection. It is unclear why we don't see a signal for the biochemical recurrence-free survival, but a strong signal for the harder endpoints, but that's how the data is. And they have quite an amount of events here. Over 150 patients developing metastasis. So that is a strong statistic, if you want so... and it seems that the difference is generated in those patients who are node positive. You have positive lymph nodes. You're undergoing an extended pelvic lymph node dissection. You will reduce the risk of developing distant metastasis by half, and you have a very strong statistical significance below 0.001.
And the study was criticized because of the little difference with regards to the lymph node count between the two groups. But independent of the lymph node count, you'll see that effect favoring extended pelvic lymph node dissection, concluding it's not the amount of nodes that makes a difference, but the area where you take the nodes out.
And this is well known, this is the Lestingi trial. If you do a limited one, you will have the obturator nerve cleared and you will have only, in few cases, the positive nodes in this area. If you go to the internal iliac vessels, you will have 65% of all positive nodes in this area. So you take out the right nodes, you will change the outcome of the patient. You will reduce the risk of developing distant metastasis in these patients. So take care to take out these nodes here and you will change the outcome of the patient.
And then we have new technologies available for our patients nowadays. We have radio-guided surgery. You can link PSMA to technetium, then get a gamma emission during surgery, taking a gamma probe, and we will be able to identify those positive nodes inside of the pelvic field. We can also use fluorescence as you'll see on the right-hand side, having PSMA linked to a fluorescence marker and you will then be able to identify the right nodes, which will increase the therapeutic approach as well as the diagnostic performance of this test.
So in conclusion, to answer the three burning questions that we have, the gold standard, the current standard for reliable staging of the lymph nodes of a prostate cancer patient is still the extended pelvic lymph node dissection and that is also confirmed by the guidelines.
With regards to the PSMA to skip the lymph node dissection and not being able to do so, I don't think that the current data allows that, but it makes a lot of sense to integrate now PSMA into the predictive tools in order to better stratify our patients. And it looks like that ePLND finally does have therapeutic effect on the development of distant metastasis, even though we do not really understand the current mechanism behind this.
And with this, I thank you very much for attention.
Jochen Walz: Secretary Aurelius, thank you very much for this invitation to this yet another great meeting to be coming up here in the next two days and to talk about lymph nodes, which is still like a very hot topic now for decades, basically, in prostate cancer. These are my disclosures relevant for this presentation.
I would like to concentrate on what I consider being the three burning questions we have with regards to lymph nodes now in the management of prostate cancer. The first one being what is the most reliable method to stage our patient with regards to the lymph nodes. The second one being what is the role of PSMA PET in this situation, especially when it's negative? Can we skip the lymph node dissection in this situation? And the third one, the burning question, is the lymph node dissection a staging procedure or does it have also a therapeutic effect on our patients?
The current standard is the extended pelvic lymph node dissection. And you need to be aware that it is very effective. You do what we call an extended pelvic lymph node dissection, taking out the nodes from the external iliac vessels down to the obturator fossa, further down to the internal iliac vessels and maybe some nodes from the presacral area. You will correctly stage 94% of all our patients with regards to the presence or absence of lymph node metastasis. And that is relative to a super-extended pelvic lymph node dissection you see down there on the left-hand side where you would go up to the inferior mesenteric artery. This is a procedure which basically takes three to four hours and just by concentrating on the area that I was showing you on the right-hand side gives you a very high reliability to stage your patients.
At the same time, you will remove basically 90% of all positive nodes. So from a diagnostic point of view, it is very effective, and the bar is very high to compete with this, and does also add some therapeutic effect to it, if ever you consider this being present for lymph node dissection. And this is the current standard of lymph node staging in prostate cancer patients.
But we have now PSMA that was already mentioned on several occasions this morning, and this is the great ProPSMA study from Australia that clearly showed that PSMA is doing better than conventional imaging with regards to the area under the curve, the sensitivity, and the specificity.
But if we would like to answer the question if we can skip lymph node dissection if PSMA is negative, we need to have a look at the negative predictive value. That is the diagnostic value that tells you if a test is negative, that the outcome that the test is supposed to predict really is not present in a patient. And if you look at what I consider high-quality studies prospectively done, more than 100 patients included and using lymph node dissection as the reference to see if there are lymph metastases or not, you end up by having a negative predictive value somewhere around 80 to 90%.
This looks really good, but be a little bit careful. What is the negative predictive value? It actually is calculated by taking the true negatives divided by the true negatives plus the false negatives. And I would like to do a short assumption with you. Let's take 100 patients that were staged for lymph node metastasis and the test said all of them are negative. And then you have six patients that actually do have N1 disease after the radical prostatectomy and the lymph node dissection. That would make the true negatives 94 plus the false negatives plus six makes a negative predictive value of 0.94.
Looks very, very good, but actually, you would miss all of the events. All the N1 events would be missed. The sensitivity is zero. So you cannot rely on the negative predictive value without having another look at the sensitivity of the same test.
And how good is the sensitivity? Once more, the ProPSMA study. You'll see on the right-hand side the sensitivity for lymph node metastasis somewhere around 80%. But be aware that it's not lymph node dissection being the reference. It's a composite endpoint, imaging, PSA, follow-up, and so on.
But if you look at lymph node dissection as the reference, you see that the sensitivity on the left-hand side drops to 40%, repeatedly 40% in four studies. There's one outlier who would like to call it 50%, but not sure that the sensitivity of 50% is really good enough. And you see on the right-hand side, the negative predictive value. You need to be aware that the negative predictive value strongly depends on the incidence. Actually, the worst negative predictive value that you can get is 100 minus the incidence. And if you would calculate those, you would be very close to what you'll see on the right-hand side. So without performing good sensitivity, you cannot rely on the negative predictive value because it depends so much on the incidence.
It's not only myself telling you. This is a recent meta-analysis, a systematic review done by Armando Stabile who looked at the negative predictive value of PSMA to rule out the need for lymph node dissection. And he observed the same observation. The higher the likelihood of finding lymph node metastasis, the higher the risk strata of the patients, the lower the negative predictive value. And he very correctly concludes that in high-risk prostate cancer patients, a negative PSMA PET cannot replace a staging extended pelvic lymph node dissection.
And if you would like to formally conclude what is the role of PSMA [inaudible 00:05:05], we need to wait for the results of PSMA-Select. Roderick Vandenberg is running this trial in the Netherlands, really trying to triage the patient before surgery using PSMA to decide whether lymph node dissection should be done or not. And I hope we will have these results in the near future.
But how about the therapeutic effect of the pelvic lymph node dissection? We have two prospectively randomized trials available, the first one being the Brazilian Lestingi Trial, 300 patients included, an extended pelvic lymph node dissection versus a limited one. 70 nodes versus three nodes. And you'll see on the right-hand side the primary outcome, biochemical recurrence-free survival. No difference between the two arms. It is a negative study.
And then we have Karim Touijer's trial from the US from MSKCC and he just presented here an update three weeks ago in Paris at the EAU24 and he included 1,400 patients compared to also a limited with an extended pelvic lymph node dissection, only 12 nodes versus 14 nodes. That is one of the main criticisms we have here. But for the primary outcome, once more, you see here there's no difference with regards to the biochemical recurrence-free survival between the two groups. Looks like this is, once more, a negative study.
But with a longer follow-up, actually he was able to look at other harder endpoints such as metastasis-free survival, distant metastasis-free survival, and you'll see clearly a difference favoring the extended pelvic lymph node dissection. It is unclear why we don't see a signal for the biochemical recurrence-free survival, but a strong signal for the harder endpoints, but that's how the data is. And they have quite an amount of events here. Over 150 patients developing metastasis. So that is a strong statistic, if you want so... and it seems that the difference is generated in those patients who are node positive. You have positive lymph nodes. You're undergoing an extended pelvic lymph node dissection. You will reduce the risk of developing distant metastasis by half, and you have a very strong statistical significance below 0.001.
And the study was criticized because of the little difference with regards to the lymph node count between the two groups. But independent of the lymph node count, you'll see that effect favoring extended pelvic lymph node dissection, concluding it's not the amount of nodes that makes a difference, but the area where you take the nodes out.
And this is well known, this is the Lestingi trial. If you do a limited one, you will have the obturator nerve cleared and you will have only, in few cases, the positive nodes in this area. If you go to the internal iliac vessels, you will have 65% of all positive nodes in this area. So you take out the right nodes, you will change the outcome of the patient. You will reduce the risk of developing distant metastasis in these patients. So take care to take out these nodes here and you will change the outcome of the patient.
And then we have new technologies available for our patients nowadays. We have radio-guided surgery. You can link PSMA to technetium, then get a gamma emission during surgery, taking a gamma probe, and we will be able to identify those positive nodes inside of the pelvic field. We can also use fluorescence as you'll see on the right-hand side, having PSMA linked to a fluorescence marker and you will then be able to identify the right nodes, which will increase the therapeutic approach as well as the diagnostic performance of this test.
So in conclusion, to answer the three burning questions that we have, the gold standard, the current standard for reliable staging of the lymph nodes of a prostate cancer patient is still the extended pelvic lymph node dissection and that is also confirmed by the guidelines.
With regards to the PSMA to skip the lymph node dissection and not being able to do so, I don't think that the current data allows that, but it makes a lot of sense to integrate now PSMA into the predictive tools in order to better stratify our patients. And it looks like that ePLND finally does have therapeutic effect on the development of distant metastasis, even though we do not really understand the current mechanism behind this.
And with this, I thank you very much for attention.