COTRIMS Trial Shows High Cure Rates with RPLND in Stage IIA/B Seminoma - Axel Heidenreich
September 15, 2024
Axel Heidenreich discusses the final results of the COTRIMS trial, evaluating retroperitoneal lymph node dissection (RPLND) for clinical stage IIA and IIB seminomas. The study demonstrates high oncological efficacy with a 100% overall survival and 88% treatment-free survival after a median follow-up of three years. Dr. Heidenreich emphasizes the benefits of nerve-sparing RPLND, including preserved antegrade ejaculation in 90% of patients and low complication rates. He highlights the potential of this approach to reduce the need for systemic chemotherapy and its associated long-term toxicity. The discussion also covers the use of microRNA-371 as a biomarker for predicting metastatic disease. Dr. Heidenreich stresses the importance of centralized care for complex cases and provides guidance on patient selection for specialized center referrals. He concludes that nerve-sparing RPLND should be considered a treatment of choice for low-volume metastatic seminoma in experienced centers.
Biographies:
Axel Heidenreich, MD, PhD, Professor, Department of Urology, University of Cologne, Cologne, Germany
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA
Biographies:
Axel Heidenreich, MD, PhD, Professor, Department of Urology, University of Cologne, Cologne, Germany
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA
Read the Full Video Transcript
Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Axel Heidenreich, who's a urologic oncologist at the University of Cologne in Germany. Axel, thanks very much for joining us today on UroToday.
Axel Heidenreich: No, thank you very much for the invitation.
Zach Klaassen: So we're going to be discussing your exciting ESMO 2024 results, basically the final results of the COTRIMS trial. So maybe walk us through the background to the COTRIMS trial as well as the final results.
Axel Heidenreich: Okay, yeah, it's my pleasure to do so. It's a Cologne trial on the role of retroperitoneal lymphadenectomy in metastatic seminomas, and we have the final results with a median follow-up of more than three years.
So the background of this study was that you all know we have clinical stage IIA and B seminomas in only 10 to 15% of all patients who are diagnosed with metastatic testicular cancer. So it's basically a rare clinical situation. If you just consider the guideline-recommended therapy, it's either radiation treatment with 30 or 36 Gray, depending on the clinical stage, or it is three cycles of BEP or four cycles of EP.
And although this treatment is extremely curative with a long-term cure rate of about 85 to 95%, both treatment options are associated with significant long-term toxicity, and especially in seminoma patients with an excess mortality after 15 to 20 years of follow-up. And that was basically the reason why we thought, as others also did, about surgery as a curative treatment option in patients who had marker-negative pure seminoma in clinical stage IIA and B.
None of those patients, at least included in our trial, received adjuvant chemotherapy with carboplatin following orchiectomy. So we just used a single-modality surgical approach without the delivery of DNA-damaging agents. No adjuvant systemic chemotherapy after RPLND, and then once patients had undergone the surgery, they just underwent follow-up examinations according to the guidelines, and whenever we detected a relapse, the patients should undergo systemic chemotherapy.
So the purpose of our trial was at least to look at feasibility, to look at the oncological outcomes in terms of progression-free and overall survival. We also used the new biomarker microRNA-371 to predict the pathohistology of lymph nodes being identified on the preoperative CT scan or MRI scan. We had a specific focus on the preservation of antegrade ejaculation, and then complications were assessed according to the Clavien-Dindo classification.
And this table gives you just a short overview about the patients who were treated. So a total number of 34 patients. If you just look at the clinical stage at diagnosis, about 50% of the patients had clinical stage I at time of initial diagnosis, about 50% of the patients had de novo metastatic disease. If we look at the clinical stage distribution at time of RPLND, about two-thirds of the patients had clinical stage IIA and one-third of the patients had clinical stage IIB disease.
Now this is our surgical approach. As you see, basically all of those patients underwent an open surgical nerve-sparing approach, and the left picture demonstrates a clinical stage IIA patient. And you can nicely see the sympathetic chain and all the sympathetic nerve fibers and then converging in the hypogastric plexus, and you also can do this type of nerve-sparing approach in a clinical stage IIB testis cancer patient.
We had three patients who underwent robotic RPLND, but I basically didn't like it very much, so we stopped it. As you can see, antegrade ejaculation is preserved in about 90% of the patients, and the minority of patients, 11%, developed Clavien-Dindo grade IIIA complications, which was either a lymphocele, chylous ascites, or paralytic ileus, but none of the patients had to undergo any type of revision surgery.
If we look at the oncological outcome after a median follow-up of three years, overall survival is 100%, and then treatment-free survival is 88%, telling you that about 12% of patients relapsed. All of those four patients who did develop relapse relapsed within the first 12 months of follow-up, and all patients were salvaged by four cycles of BEP without having any other type of relapse thereafter.
So in summary, I would like to conclude that nerve-sparing RPLND for marker-negative clinical stage IIA and B is a feasible treatment option, which is associated with a very low percentage of significant morbidity. It has a very high oncological efficacy with a cure rate of about 89% without the addition of any type of chemotherapy, and therefore it is also very cost-effective.
As I said, the number of patients who have clinical stage IIA and B seminomas is very low. So in my view, this type of surgery is a typical center-based surgery. So only experienced surgeons should perform this type of treatment. Nerve-sparing RPLND for low-volume metastatic seminoma has already been included in the guidelines by the AUA and the SWENOTECA, and I did not show the results due to time constraints, but microRNA is a very, very good biomarker with a high predictive accuracy of about 100% to identify patients who have metastatic disease.
When it comes to the regionalization of testis cancer care, so the centralization of RPLND, we have developed this type of, let's say, algorithm, which gives you an idea which patients might be treated either at any center, or who need some specific advice, at least from experienced centers, and still a patient can be treated at home by the urologist.
So everything in green is a patient who can be treated anywhere. Everything in red is a patient who at least needs some advice from experienced centers. So when it comes to primary inguinal exploration of a testicular mass, especially patients who have synchronous bilateral tumors or tumors in a solitary testicle where you think about organ-sparing surgeries, should either be treated or at least advised in specialized centers.
And when we have a look at this table, we have the seminoma, we have the non-seminoma, we have patients either primary malignant somatic transformation or those in whom MST develops during chemotherapy. And again, all these lines outlined in green are patient characteristics which can be treated at any center. And all those lines in red are those treatment options which should be done at an experienced center because whenever something goes wrong with this type of initial treatment, those patients will have a very significant probability to relapse or to even die from testicular cancer.
So the take-home messages would be nerve-sparing RPLND only is a treatment option for marker-negative clinical stage IIA-B seminomas. As I said, it's oncologically highly effective. It reduces the need for systemic chemotherapy from 100% to only about 15 to 20%. Thereby, it reduces the risk of long-term toxicity to less than 10%. And the only long-term toxicity we observed was with retrograde ejaculation.
So in my view, it should be considered as a treatment of choice, at least in clinical stage IIA and in low-volume clinical stage IIB. As I said, it should be performed in experienced centers only, and especially in patients who have clinical stage IIA and equivocal lymph nodes, microRNA measurement will be helpful to identify those who have metastatic disease and to differentiate them from those who will have only a benign lymphadenopathy. So that's all from my side, and thank you very much for your attention, and I'm open for any discussion.
Zach Klaassen: Dr. Heidenreich, thank you so much for that beautiful presentation, and particularly you touched on the referral to tertiary centers, and I think it's important for our listeners that maybe see one or two testis cancer cases per year, whether in the United States or in Europe or across the world, that this is really just understanding not just the tenets of the operation, but the disease process itself. Those two tables were excellent, really showing the green who can be treated locally and then in red who should be sent to a center.
What I wanted to ask you about specifically was we have now radiotherapy, we have chemotherapy, we have surgery for these clinical IIA and in select IIB seminomas. In your opinion, when you're counseling patients, is this more a discussion about side effects, long-term toxicity? Is this sort of how you're guiding your discussions with the patients?
Axel Heidenreich: Yes. So the most important issue is long-term toxicity, and therefore systemic chemotherapy in this low-volume metastatic disease does not play a significant role anymore in our institution. And what is probably a difference between our institution and the US, for example, is that we as urologists deliver chemotherapy. So we don't have to refer a patient to an oncologist. So the number of patients who receive systemic chemotherapy for low-volume metastatic seminoma has decreased significantly.
When it comes to active treatments or radiation treatment versus surgery, I usually counsel patients either with regard to nerve-sparing RPLND or to this type of new radiation treatment. So combination of carboplatin plus radiation treatment, like a boost to the visible lymph node, which also is very effective and which most probably reduces the long-term toxicity as compared to the old extended-field radiation treatment with 30 or 36 Gray.
Zach Klaassen: In your experience, how many patients in this sort of clinical setup of IIA seminoma are now choosing surgery based on the data that you just presented?
Axel Heidenreich: It might be a bias because we are one of the referral centers and we see about 200 newly diagnosed testis cancer patients a year. So in our institution it's about three-quarters of patients who opt for surgery and one-quarter of the patients who opt for radiation treatment.
What we always do in every patient is to measure the microRNA-371, and we could show that those patients who have a negative microRNA always have negative lymph nodes, those who have positive microRNA always have metastatic disease. So we use this type of biomarker to stratify patients, especially the ones with low lymph node diameters, to identify the ones who might be good candidates for surgery or for any type of active treatment.
Zach Klaassen: Excellent. Really enjoyed the discussion. Congratulations on the COTRIMS trial, and thank you so much for your time and expertise on UroToday.
Axel Heidenreich: Okay, thank you very much for the invitation.
Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Axel Heidenreich, who's a urologic oncologist at the University of Cologne in Germany. Axel, thanks very much for joining us today on UroToday.
Axel Heidenreich: No, thank you very much for the invitation.
Zach Klaassen: So we're going to be discussing your exciting ESMO 2024 results, basically the final results of the COTRIMS trial. So maybe walk us through the background to the COTRIMS trial as well as the final results.
Axel Heidenreich: Okay, yeah, it's my pleasure to do so. It's a Cologne trial on the role of retroperitoneal lymphadenectomy in metastatic seminomas, and we have the final results with a median follow-up of more than three years.
So the background of this study was that you all know we have clinical stage IIA and B seminomas in only 10 to 15% of all patients who are diagnosed with metastatic testicular cancer. So it's basically a rare clinical situation. If you just consider the guideline-recommended therapy, it's either radiation treatment with 30 or 36 Gray, depending on the clinical stage, or it is three cycles of BEP or four cycles of EP.
And although this treatment is extremely curative with a long-term cure rate of about 85 to 95%, both treatment options are associated with significant long-term toxicity, and especially in seminoma patients with an excess mortality after 15 to 20 years of follow-up. And that was basically the reason why we thought, as others also did, about surgery as a curative treatment option in patients who had marker-negative pure seminoma in clinical stage IIA and B.
None of those patients, at least included in our trial, received adjuvant chemotherapy with carboplatin following orchiectomy. So we just used a single-modality surgical approach without the delivery of DNA-damaging agents. No adjuvant systemic chemotherapy after RPLND, and then once patients had undergone the surgery, they just underwent follow-up examinations according to the guidelines, and whenever we detected a relapse, the patients should undergo systemic chemotherapy.
So the purpose of our trial was at least to look at feasibility, to look at the oncological outcomes in terms of progression-free and overall survival. We also used the new biomarker microRNA-371 to predict the pathohistology of lymph nodes being identified on the preoperative CT scan or MRI scan. We had a specific focus on the preservation of antegrade ejaculation, and then complications were assessed according to the Clavien-Dindo classification.
And this table gives you just a short overview about the patients who were treated. So a total number of 34 patients. If you just look at the clinical stage at diagnosis, about 50% of the patients had clinical stage I at time of initial diagnosis, about 50% of the patients had de novo metastatic disease. If we look at the clinical stage distribution at time of RPLND, about two-thirds of the patients had clinical stage IIA and one-third of the patients had clinical stage IIB disease.
Now this is our surgical approach. As you see, basically all of those patients underwent an open surgical nerve-sparing approach, and the left picture demonstrates a clinical stage IIA patient. And you can nicely see the sympathetic chain and all the sympathetic nerve fibers and then converging in the hypogastric plexus, and you also can do this type of nerve-sparing approach in a clinical stage IIB testis cancer patient.
We had three patients who underwent robotic RPLND, but I basically didn't like it very much, so we stopped it. As you can see, antegrade ejaculation is preserved in about 90% of the patients, and the minority of patients, 11%, developed Clavien-Dindo grade IIIA complications, which was either a lymphocele, chylous ascites, or paralytic ileus, but none of the patients had to undergo any type of revision surgery.
If we look at the oncological outcome after a median follow-up of three years, overall survival is 100%, and then treatment-free survival is 88%, telling you that about 12% of patients relapsed. All of those four patients who did develop relapse relapsed within the first 12 months of follow-up, and all patients were salvaged by four cycles of BEP without having any other type of relapse thereafter.
So in summary, I would like to conclude that nerve-sparing RPLND for marker-negative clinical stage IIA and B is a feasible treatment option, which is associated with a very low percentage of significant morbidity. It has a very high oncological efficacy with a cure rate of about 89% without the addition of any type of chemotherapy, and therefore it is also very cost-effective.
As I said, the number of patients who have clinical stage IIA and B seminomas is very low. So in my view, this type of surgery is a typical center-based surgery. So only experienced surgeons should perform this type of treatment. Nerve-sparing RPLND for low-volume metastatic seminoma has already been included in the guidelines by the AUA and the SWENOTECA, and I did not show the results due to time constraints, but microRNA is a very, very good biomarker with a high predictive accuracy of about 100% to identify patients who have metastatic disease.
When it comes to the regionalization of testis cancer care, so the centralization of RPLND, we have developed this type of, let's say, algorithm, which gives you an idea which patients might be treated either at any center, or who need some specific advice, at least from experienced centers, and still a patient can be treated at home by the urologist.
So everything in green is a patient who can be treated anywhere. Everything in red is a patient who at least needs some advice from experienced centers. So when it comes to primary inguinal exploration of a testicular mass, especially patients who have synchronous bilateral tumors or tumors in a solitary testicle where you think about organ-sparing surgeries, should either be treated or at least advised in specialized centers.
And when we have a look at this table, we have the seminoma, we have the non-seminoma, we have patients either primary malignant somatic transformation or those in whom MST develops during chemotherapy. And again, all these lines outlined in green are patient characteristics which can be treated at any center. And all those lines in red are those treatment options which should be done at an experienced center because whenever something goes wrong with this type of initial treatment, those patients will have a very significant probability to relapse or to even die from testicular cancer.
So the take-home messages would be nerve-sparing RPLND only is a treatment option for marker-negative clinical stage IIA-B seminomas. As I said, it's oncologically highly effective. It reduces the need for systemic chemotherapy from 100% to only about 15 to 20%. Thereby, it reduces the risk of long-term toxicity to less than 10%. And the only long-term toxicity we observed was with retrograde ejaculation.
So in my view, it should be considered as a treatment of choice, at least in clinical stage IIA and in low-volume clinical stage IIB. As I said, it should be performed in experienced centers only, and especially in patients who have clinical stage IIA and equivocal lymph nodes, microRNA measurement will be helpful to identify those who have metastatic disease and to differentiate them from those who will have only a benign lymphadenopathy. So that's all from my side, and thank you very much for your attention, and I'm open for any discussion.
Zach Klaassen: Dr. Heidenreich, thank you so much for that beautiful presentation, and particularly you touched on the referral to tertiary centers, and I think it's important for our listeners that maybe see one or two testis cancer cases per year, whether in the United States or in Europe or across the world, that this is really just understanding not just the tenets of the operation, but the disease process itself. Those two tables were excellent, really showing the green who can be treated locally and then in red who should be sent to a center.
What I wanted to ask you about specifically was we have now radiotherapy, we have chemotherapy, we have surgery for these clinical IIA and in select IIB seminomas. In your opinion, when you're counseling patients, is this more a discussion about side effects, long-term toxicity? Is this sort of how you're guiding your discussions with the patients?
Axel Heidenreich: Yes. So the most important issue is long-term toxicity, and therefore systemic chemotherapy in this low-volume metastatic disease does not play a significant role anymore in our institution. And what is probably a difference between our institution and the US, for example, is that we as urologists deliver chemotherapy. So we don't have to refer a patient to an oncologist. So the number of patients who receive systemic chemotherapy for low-volume metastatic seminoma has decreased significantly.
When it comes to active treatments or radiation treatment versus surgery, I usually counsel patients either with regard to nerve-sparing RPLND or to this type of new radiation treatment. So combination of carboplatin plus radiation treatment, like a boost to the visible lymph node, which also is very effective and which most probably reduces the long-term toxicity as compared to the old extended-field radiation treatment with 30 or 36 Gray.
Zach Klaassen: In your experience, how many patients in this sort of clinical setup of IIA seminoma are now choosing surgery based on the data that you just presented?
Axel Heidenreich: It might be a bias because we are one of the referral centers and we see about 200 newly diagnosed testis cancer patients a year. So in our institution it's about three-quarters of patients who opt for surgery and one-quarter of the patients who opt for radiation treatment.
What we always do in every patient is to measure the microRNA-371, and we could show that those patients who have a negative microRNA always have negative lymph nodes, those who have positive microRNA always have metastatic disease. So we use this type of biomarker to stratify patients, especially the ones with low lymph node diameters, to identify the ones who might be good candidates for surgery or for any type of active treatment.
Zach Klaassen: Excellent. Really enjoyed the discussion. Congratulations on the COTRIMS trial, and thank you so much for your time and expertise on UroToday.
Axel Heidenreich: Okay, thank you very much for the invitation.