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Charles Ryan: Hello, welcome. I'm Chuck Ryan from the University of Minnesota, and I am delighted to be joined today by Sia Daneshmand, who is a Professor of Urology, with a Clinical Scholar designation, at the University of Southern California, Keck School of Medicine. Dr. Daneshmand just presented a really important phase 2 study in a disease that is common and requires some additional thought future therapies, and that is stage two seminoma. Thank you for joining us. Yeah, tell us a little bit about the background of how this study came to be and what you found.

Sia Daneshmand: Thank you, Chuck. Thanks for having me. Thank you for highlighting the study. It started when I once did an RPLND on a patient who had stage 2 non-seminoma, and I found seminoma in the retroperitoneum, which happens from time to time, but it got me thinking, now wait a minute? We cured this patient without any further systemic therapy, why don't we do this operation for seminoma? For years and years, we've known seminomas are very radio-sensitive or they are very chemo-sensitive, but we tend to treat the stage 2 seminoma with the same regimen as we do a widely disseminated non-seminoma to the lungs, so if its a good risk disease, that's BEP times three.

So, I started thinking and looked at the literature, the very, very few cases that had been done in the very distant past, actually, where it was effective, 11 cases total in the entire literature. So I started judiciously approaching patients who I saw with limited-stage IIA disease and said, "Look, this is completely outside the box, but it works in non-seminoma,. I think it would work with seminoma." So we had four patients initially who we did, and we published a small case series. All four, fortunately, had no recurrence.

And then I thought, in order to move the needle forward, we really need buy-in from other groups and really make this a multi-institutional study, and that is how it began. Literally, from a grassroots sort of case series to gauging interest among our testis cancer experts around the country. And everyone said, "Yeah, sure." Surgeons are more than willing to do more surgery if the indication is right.

So we started this multi-institutional trial in 2015, and actually accrued, initially, as all trials go, slowly, but towards the end, actually went very quickly as more sites came on and it was easier to talk to the patients that there is a phase 2 trial, and the whole point would be to see if surgery is as efficacious in seminomas as it was in non-seminomatous in that 70%, 80% range, I would say 80% for non-seminoma stage 2 without systemic therapy. We initially had 44 patients scheduled for the trial with this for the statistics to work out, and as we were accruing fairly quickly, we actually amended it and made it 55. So that is what we ended up with, as 55 patients at the end, who accrued on to this phase 2, as you said, SEMS trial surgery in early metastatic seminoma.

One of the other things we did early was, initially, I had it limited to stage IIA, but that 2-centimeter cutoff, as you know, is fairly arbitrary and it doesn't really come from robust literature on where that cutoff is, and in the NCCN guidelines, 3 centimeters is actually the cutoff for radiation versus chemo. So a lot of these lymph nodes would be 2.1, 2.2 centimeters, and I thought, we are really not including a good portion of the population here that may benefit from the surgery. So we moved it to 3, and that is why we called it "early metastatic" rather than "stage IIA" you will see, in some places, 2a to 2b, but really we had to be limited to no more than two lymph nodes seen on the CT scan, and certainly not more than 3 centimeters. As you know, the problem is that the larger the lymph node, the more clinical understaging we have, and we ended up with 2c disease and far more nodes involved.

Charles Ryan: Could you describe why, historically, there was ever a reticence to do RPLNDs in seminoma? I think that is underappreciated.

Sia Daneshmand: I think you are right and you sort of have to get back into the mindset of, back in the '70s, '80s, and '90s, what was happening. And I think, again, seminomas were so radio-sensitive and it was so curable, that it just was swept away as one of those stages that nobody looked at anymore, and we concentrated on the non-seminomas and the metastatic potential of those.

And so I think it was, initially, people were doing stage 1 RPLNDs for mostly non-seminomas, and in the '70s and '80s, radiation was the main state of therapy for stage 1 seminomas. Then you realize, well, you don't need radiation as much, many patients do well with surveillance. And so the rate of radiation went down as the rate of surveillance went up, and then, in the 2000s, carboplatin became a thing where you are using adjuvant carboplatin for stage 1 seminomas, which, again, is overtreatment in most of the patients. So I think it was just one of those stages that no one really looked at and concentrated on until more recently.

Charles Ryan: But wasn't there a concern about more surgical complications with seminoma versus non-seminoma? And is that perpetuated to this day, or is that a myth? Is that an artifact of poor imaging that got better? Or is it an artifact of our thinking about the post-chemotherapy seminomas? I've never really quite understood that.

Sia Daneshmand: You got it. You nailed it. It's right there. The bad rap that seminomas get for surgery is post-chemo seminoma, which sends chills down every urologic oncologist's spine as, "This is going to be a horrendous case." Seminomas are so chemo-sensitive that the intense fibrotic reaction that occurs around the great vessels is what really leads to the difficulty in doing. But a stage 2, virgin, primary RPLND for a seminoma looks no different than for a non-seminoma. It's histology-naive. And so the surgery is the same. We are talking about a very, very straightforward, easy surgery for those who do it often, and nerve-sparing techniques and really excellent outcomes. At our center, the median hospital stay is 1 day for these patients through small incisions, and in many centers, it's very, very few days.

And fortunately, one of the things in a modern prospective surgical trial is you get to see what the complication rates are, length of stay, and things like that, in a more modern setting, that many, perhaps, medical oncologists are not familiar with, because all of us, we know what we know from the literature, from the past, where RPLNDs and post-chemo RPLNDs are big cases and a week in the hospital and so on and so forth. So it's a very different operation. Same templates, same operations.  A different approach, and different postoperative management.

Charles Ryan: Well, thank you for clearing that up. In the SEMS study, you have 24 months of follow-up. You did have some recurrences but talk to us a little bit about the findings and what is your interpretation of them.

Sia Daneshmand: Sure. So, as you said, the 2-year recurrence-free survival was 84%. That means 10 patients out of 55 had a recurrence during a median of 2 years, which we thought was a reasonable follow-up for most testis cancer studies. Of course, the secondary objective is 5-year recurrence-free survival, and I'm sure we are going to see a few more here and there. The main point is that all patients are salvageable with chemo as they are in all stage 1 disease and stage 2 non-seminomas. These are all good-risk patients, so we expect that. So obviously the overall survival was 100%.

And that's the main point here, that you are trying to prevent the toxicities of treatment for the majority of patients. Now be it 70%, 80%, 90%, those are the patients who are cured without any long-term side effects of radiation or chemotherapy. I always tell the patient, "Look, if you relapse, you need chemo, you need chemo to save your life. But if we can do something that can prevent a lifelong of potential long-term toxicities, then that is worthwhile."

So 10 of 55 recurred. Since the presentation, I've had one more, so it's 11 that was right around that 2-year mark. So 11 to 55, and again, most patients were treated with chemotherapy except for 2 patients who were treated with additional surgery. And so far, all of those have been disease-free, and we continue to follow those patients.

As far as a lot of people are interested in where these relapses are, and unfortunately to this day, I can't quite tell you because I haven't received all the data.  We are trying to get all the details of where the relapses were exactly.

Charles Ryan: Likely outside of the template, though.

Sia Daneshmand: Likely outside. Yeah, yeah. And those, believe it or not, it is a small trial, but still, you have to get all the pathology reports and CT reports and all that stuff and figure out exactly where they were. So that is what we are working on. But, we set out, our primary objective was to meet a 70% goal for recurrence-free survival at 2 years, and this was in 84, and even within one recurrence, it will still be within the range of about 80%.

Charles Ryan: Although it's a smaller study, it mimics what was seen with non-seminomas and RPLNDs back in the 1980s, I believe.

Sia Daneshmand: Exactly. Yeah.

Charles Ryan:
So it's almost like you are saying stage 2 seminoma should be lumped in, from a surgical perspective, with the non-seminomas. You're saying the surgery is really no different when you are in there. The complication rate, you're not saying is really any different, and salvageable in the 20% to 30% who may relapse with either chemotherapy or other approaches.

Sia Daneshmand: One point I want to highlight is that seminomas tend to be more indolent than non-seminomas. So non-seminomas, we always worry that if we do an RPLND and the patient relapses in the chest, and then we miss that micro-metastatic disease. Typically, that is not the case in seminomas. You don't do an RPLND to have a recurrence in the chest. In fact, we stopped doing chest x-rays on patients in stage 1 seminoma, knowing that the retroperitoneum is the primary landing zone for all the relapses. And tumor markers are of little to no benefit as well.

So, the other point is, when you see a patient who's got a CT scan showing a 2.2-centimeter lymph node in a seminoma in the landing zone, you think you have metastatic disease, it's hard to biopsy this node, and you are going to treat accordingly. Well, one of the things that came out of this trial is, as we knew in non-seminomas, that a good 20% or more of these patients actually have stage 1 disease. And so this becomes a staging procedure for these patients and they don't need any adjuvant further, even intensive follow-up. They were stage 1, to begin with, and this lymph node ranged from absolutely nothing to inflammatory. We had one patient who had lymphoma, for instance, despite being young. So these things happen as well. The largest lymph node we had that was negative, was 3 centimeters.

Charles Ryan: Really?

Sia Daneshmand: Yeah, 3 centimeters. That was PET-positive because PET was an early corollary of the study, and it turned out completely negative. And I was like, "Come on, your pathologist is missing something. This is impossible." And they said, "No, I'm telling you." This was at a very big center, and it was negative. So that is the other thing we learned, relearned, I should say, about RPLND in stage 2 setting, that a fair number of these are actually not what you think.

This brings me to my last point, which is the next phase of these studies is, and you know what I'm going to say, it's microRNA, and I think microRNA is going to be tremendously helpful in distinguishing whether or not we are going to act on this 1.5-centimeter lymph node in the landing zone. If it's negative, maybe we should just hold off and do a repeat imaging in 6 to 8 weeks. So we are kind of working on those on that trial concept now.

Charles Ryan: That's an excellent idea. And on the other end of the spectrum, do you have a sense as to what would be the risk factors for recurrence after an RPLND for seminoma? Is it going to be similar to what we see in non-seminomas?

Sia Daneshmand: Yeah. Good question and I don't have that sense yet. I think I need more data. One of my colleagues in Germany, Peter Albers, is running a similar trial called PRIMETEST, and he is going to have about 50 patients on his trial. So hopefully we will get a sense, is it size? Is it an extra-nodal extension like we see in non-seminomas? Is it the number of lymph nodes? I think, probably, a little factor of each, but so far, it's been fairly random. I can tell you that there are a good number of 2c's that got upstaged from a 2b to a 2c, and those patients have had no relapse. And then we've had some relapses in 2a's that are a single lymph node.

So, perhaps a small trial to answer those specifics, but hopefully once we combine our data, maybe we will get a signal as to what it is. My general sense is it's going to be the burden of disease. So larger lymph node, more lymph nodes involved probably puts you at higher risk.

Charles Ryan: And then final question, two questions, actually. One is, should PET scanning be used in the initial staging of a seminoma? Did it matter in this case? Or is CT scan sufficient?

Sia Daneshmand: Great question. The short answer is, no. I think PET has a largely diminishing role in the diagnosis management of any testis cancer. The only places where it is marginally helpful, as you know, is in a post-chemotherapy seminoma setting where a negative PET scan in a patient with a 3, 4-centimeter retroperitoneal residual mass is one factor to prevent you from doing a post-chemo RPLND in a very difficult setting. So that is really its negative predictive value in that setting.

This was an early corollary in one of our studies, but for insurance reasons and things like that, it was difficult to get it in all the patients, but our false-positive rates were still present and our false-negative rate was there too. So just gestalt, looking at the data, I don't think, going forward, this is going to be helpful. And again, I really look forward to the microRNA studies that will help delineate this better.

Charles Ryan: Yeah. Very interesting, very interesting. Final question. Your comment on surgical case volume in your participants in the study. For surgeons who are doing, urologists who are doing RPLNDS, what type of volume are you seeing out there for people who really feel comfortable doing this at all, much less in the seminoma setting?

Sia Daneshmand: Yeah. Good question. For the trial, we had surgeon eligibility criteria, as you see in some of the surgical trials, to make sure that some standards are met. So for our trial, it was 8 patients per year or 24 in 3 years of RPLND, and we were pretty open about RPLND for anything, including upper tract disease and for ureterectomy, for instance. But again, as you know, the volumes of RPLNDs done by average urologists is extremely low. It's 0 to 1 median, and the vast majority of RPLNDs in the country are done by a handful of surgeons around the country.

We've identified about 25 centers that were considered to be high-volume as we are planning on our next phase of the microRNA studies. And so, if you are doing less than 10 RPLNDs total at a center, then that is probably not adequate enough to be able to answer these questions or get the necessary expertise.

Now I say this, but obviously, there are some very talented surgeons who trained at high-volume centers and they are starting out their practice. I was one of those surgeons. What I mean is, is people always talk about these operations being done by high-volume centers, well, there are some of our fellows who I think are perfectly capable of doing these and they are just starting out their practice. It all depends on where they trained and what their interest levels are. But in general, it should be at a high-volume center, as you know, with just testis cancer management as well from a chemotherapy standpoint, the medical oncology standpoint, as with all diseases, basically.

Charles Ryan: Yeah. Great. Well really learned a lot from this study, learned a lot from this conversation, and congratulations on getting it done.

Sia Daneshmand: Thank you.

Charles Ryan: It adds a lot more knowledge on this disease and where to go with these patients, and I look forward to talking to you in future years on future developments.

Sia Daneshmand: Sounds good. Thank you, Chuck.

Charles Ryan: Thank you for joining us.

Sia Daneshmand: Thanks very much.