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Leslie Ballas: Hi. Welcome to ASCO GU. I'm Leslie Ballas. I'm a radiation oncologist at Cedars-Sinai in Los Angeles. And I am lucky to be joined today by Dr. Axel Heidenreich, a urologist from the University of Cologne in Germany, who is going to talk with us about the single-arm COTRIMS study looking at retroperitoneal lymphadenopathy in metastatic seminoma. Thank you so much for joining us today.

Axel Heidenreich: Thank you for the invitation.

Leslie Ballas: Please tell me a little bit about this study.

Axel Heidenreich: OK. So the idea of this study was to reduce long-term toxicity in patients who have this low-volume retroperitoneal lymph node disease. We know that the standard treatment, like three cycles of PEB or four cycles of EP or radiation treatment with 30 gray or 36 gray, has a high cure rate of about 95%.

However, we know that patients have long-term toxicity, metabolic disorders, cardiovascular disease, secondary malignancies, and that they have a significantly elevated long-term non-cancer-related mortality, which is increased by about three to five times as compared to the general population.

So we thought, if we can deliver a local treatment with the same long-term cure rate but reducing treatment-associated morbidity and toxicity, it might be helpful for the patient. So we decided that we could use nerve-sparing retroperitoneal lymphadenectomy in highly selected patients—so pure seminoma patients, no adjuvant chemotherapy following radical orchiectomy, no elevation of tumor markers except an LDH serum level less than 1.5 times the upper limit of normal, and lymph nodes which should be either 2A or low-volume 2B. And so we started this type of retroperitoneal lymphadenectomy in those patients.

Leslie Ballas: And what did you find?

Axel Heidenreich: So we did find that we have a very high cure rate. A median follow-up right now is 43 months, so around four years. We did find only 11% of relapses—so 4 out of 34 patients did relapse. All of those patients relapsed out of field, so not in the field of a unilateral modified RPLND. And all those four patients could be cured by salvage chemotherapy, which was three cycles of PEB.

We also did find that the surgery-associated complications are quite low. So you usually define significant complications by the Clavien-Dindo classification—if it's more than a grade 3A, 3B, or 4, then it's a significant complication. We had four patients with this type of 3A Clavien-Dindo classification complication, and this was mostly chylous ascites or a paralytic ileus. All of these side effects could be treated conservatively.

Leslie Ballas: And did you find—or does it matter, actually—how many lymph nodes are dissected? Within the urologic data in other disease sites, we're finding that extended lymph node dissections in bladder cancer don’t matter. Or does it matter in this disease?

Axel Heidenreich: Not really. Because, I mean, there are some data in the literature, especially from MSKCC. They usually tell us the more lymph nodes you dissect, the better is the outcome. But I think this is a bias because they have a very, very profound pathophysiological workup of their lymphadenectomy specimens.

For me, and also in some other series which also have used retroperitoneal lymphadenectomy in seminoma patients, it is more important that you really dissect out the anatomic landmarks or the anatomic primary landing zones of your lymph nodes. And if you dissect it out very carefully, then the number of lymph nodes doesn’t matter. It’s the careful dissection of the primary landing zones of the right or the left testicle.

Leslie Ballas: Tell me, how do you integrate your data with the SEMS data, with the PRIMETEST data? Do you feel like it’s similar outcomes?

Axel Heidenreich: The outcomes in terms of long-term cure rate is similar. PRIMETEST will present their final results at the EAU, at the upcoming EAU in March. They have a median follow-up of about 15 months, so it’s a little bit longer than our follow-up. They have a relapse rate of 30%, which is much higher than our relapse rate.

And also the SEMS trial has still a very short median follow-up of about two years, and they also have a relapse rate in the range of 18% to 20%. Long-term cure rate is similar—100% in all of those patients. Relapse rate is lower in our series, which is most probably due to the fact that we not only stick to the anatomic boundaries of a typical RPLND, as we know from non-seminomatous testicular germ cell tumors, but we also go a little bit lateral to the ureter, we go a little bit more distal to the ureter, so we also dissect out the common iliac artery. We always dissect out the ipsilateral vas deferens and the testicular vein. And we always go behind the large vessels—so behind the aorta or behind the inferior vena cava—which is not the typical template of a non-seminoma. And I think that this makes the difference.

The Indiana group is just going to publish a series of nodal distribution in those seminoma patients who have undergone RPLND, and they identify about 20% of microscopic lymph node metastases in the area lateral to the ureter, common iliac artery, or around the vas deferens. So I guess our relapse rate is so low because we have a little bit more extended field of dissection.

Leslie Ballas: Similarly, I think that the reason PRIMETEST probably has a higher relapse rate is they also included a little bit of their stage of patients. They included some more aggressive patients in it.

Axel Heidenreich: Probably, they had some more aggressive patients because they also allowed patients who had undergone adjuvant carboplatin therapy after radical orchiectomy. The mean size of their dissected lymph nodes or the positive lymph nodes is similar to our size, so it’s in the range of about 2 centimeters. That’s just the transition zone from 2A to 2B. I’m not sure why they have these high relapse rates.

They also looked at the distribution of robotic-assisted surgery versus open surgery. They didn’t find a difference. They had a little bit more stage IIB disease than we had. This might be the reason for the difference. And so you might think about RPLND plus 1 cycle of PEB, for example, if you have lymph nodes with poor prognostic markers like size larger than 3 centimeters, extranodal extension. And you might think about 1 cycle of PEB, which is the usual approach in the SWENOTECA group in Scandinavia.

Leslie Ballas: If you combine your data with SEMS and PRIMETEST, you still have about—I think it’s like under 100 patients or maybe even near 100 patients. Is this ready for prime time?

Axel Heidenreich: I guess so. If you also consider the two retrospective studies from MSKCC and from Indianapolis, we have 234 patients. They all come to the same conclusion. Also in these retrospective studies, in these high-volume centers, they have a relapse rate in the range of about 10%.

So I guess it’s ready for prime time, but it’s ready for prime time only in excellence centers. So it’s not a surgery that should be done everywhere; it’s a surgery which needs to be done in high-volume centers. And that will be the difficulty, because we know from former trials—like back in the early ‘90s or in the early 2000s, where we used RPLND versus one cycle of PEB in stage I non-seminomatous—that RPLND was less effective than chemotherapy, but only due to the fact that too many people did RPLNDs.

So if you look in the United States or also in Europe, how many RPLNDs are done at each institution, you have roughly three to four RPLNDs a year. And with PRIMETEST, with SEMS, and also with our study and the retrospective study, usually these RPLNDs are done in centers who do more than 100 RPLNDs a year by only one or two surgeons. And this makes the difference.

And this will be the difficulty to transfer our data in clinical reality, because I think that too many urologists will then start to do RPLND because they think, oh, it’s an easy procedure. And then you have an increased rate of relapse, and then you will harm the patient.

Leslie Ballas: When the SAKK data came out looking at combination of chemotherapy with a smaller radiation field, I heard a lot of my urology colleagues say, oh, there’s only three-year follow-up. It’s not ready to be used across the board. And yet I do hear urologists very willing to accept now your data, the SEMS data with similar follow-up and increased failure rates.

SAKK had a three-year progression-free survival of 94%. Your data, you mentioned, it’s like 89% with your 11% failure rate. SEMS is in the 80% range. Why is there a difference in accepting this data versus the SAKK data?

Axel Heidenreich: I guess it’s still the old habit that you usually try to use the type of treatment which you could probably deliver by yourself. So in our institution, if we counsel patients in stage IIA and stage IIB, I usually counsel them between either nerve-sparing RPLND or radiation treatment according to the SAKK protocol.

There is a little bit of criticism to the SAKK protocol. It’s a three-year follow-up. We know cure rate… OK, it’s very, very rare that those seminoma patients will relapse after three years. Even in our study and also the other studies, we could identify that about 95% of the relapses occurred within the first two years of follow-up. So it’s very rare that in the SAKK study you will have more relapses at four or five years.

There is still the question of the long-term toxicity, because you still deliver radiation treatment combined with one cycle of carboplatin. But I would guess both of these treatment options are equally effective. And if you counsel your patient, you have to give him the decision—either use surgery or use radiation treatment. Both are equal, I guess, in terms of oncological efficacy.

Leslie Ballas: Well, with a slight increase in relapse, as far as we know.

Axel Heidenreich: Right now, it’s a slight increase in relapse—

Leslie Ballas: But cure rate, I understand.

Axel Heidenreich: Yeah. Yeah.

Leslie Ballas: Thank you. That is—

Axel Heidenreich: Yeah. Mhm.

Leslie Ballas: Yeah. The question becomes, I mean, the long-term Danish data would show that the rate of second malignancies from radiation at 20 years is about 13.5%, and those who went on to surveillance was just under 8%, meaning a difference of 6 to 6.5% at 20 years. Obviously, these are generally young patients, healthy patients, and maybe that risk is too great in certain patients.

I think that—are you counseling your patients to say that after surgery, those patients would be at a similar risk of second malignancies to surveillance patients of 7.8%? Are you still counseling them that it decreases their risk?

Axel Heidenreich: Yeah. That’s what we do. Our intention, as I said in the beginning, with regard to RPLND, is to reduce long-term toxicity and non-cancer-related mortality. And this is what we usually counsel our patients. So if you consider that all of these stage IIA and B patients are long-term survivors, they have 40 or 50 years of life after the treatment. So we usually counsel them with regard to the increased risk of cardiovascular morbidity, of metabolic morbidity, and of secondary malignancies.

And then they can make the decision if they want to go for surgery or if they choose a radiation treatment. The majority of our patients actually then choose surgery. About 80% of those patients choose surgery, and then 20% of the patients choose radiation treatment plus 1 cycle of carboplatin.

But this is most probably due to the fact that we are, at least in Europe, one of these high-volume centers. So we see or we counsel more than 200 testicular cancer patients a year. So most probably, the majority of patients just rely on our recommendation and the consultation process.

Leslie Ballas: Thank you so much for taking the time to talk with us today. Congratulations on completing this important study. We very much appreciate it.

Axel Heidenreich: Thank you very much for the invitation. I enjoyed it. Thank you.