Radiation vs Systemic Therapy for Isolated Pelvic Recurrence After Cystectomy - Andrea Necchi & Comron Hassanzadeh
June 9, 2025
Ashish Kamat moderates a debate between Comron Hassanzadeh and Andrea Necchi about optimal management of isolated pelvic recurrences after radical cystectomy. Dr. Hassanzadeh advocates for radiation therapy, citing 9-13% local recurrence rates from SWOG 1011 and emphasizing that local control may prevent future distant metastases. He highlights modern IMRT's safety profile and recommends 50.4 Gray with potential radiosensitizing chemotherapy for isolated disease. Dr. Necchi supports systemic therapy, noting patient perceptions of EV-pembrolizumab as potentially curative across disease stages and citing response rates in oligometastatic lymph node disease from CheckMate-901 and EV-302 trials. Both experts acknowledge the complexity of treatment sequencing, with Dr. Hassanzadeh admitting he typically uses systemic therapy first followed by local consolidation. The discussion touches on emerging biomarkers like ctDNA for treatment guidance, though both note limited data in advanced disease settings. They emphasize multidisciplinary care and shared decision-making, recognizing that treatment approach should consider patient preferences, histologic subtypes, and individual clinical circumstances in this challenging scenario.
Biographies:
Andrea Necchi, MD, Medical Oncologist, Professor of Oncology, Vita-Salute San Raffaele University, Chief of Genitourinary Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy
Comron Hassanzadeh, MD, MPH, Bone Metastasis Clinical Director and Assistant Professor, Department of Genitourinary Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX
Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX
Biographies:
Andrea Necchi, MD, Medical Oncologist, Professor of Oncology, Vita-Salute San Raffaele University, Chief of Genitourinary Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy
Comron Hassanzadeh, MD, MPH, Bone Metastasis Clinical Director and Assistant Professor, Department of Genitourinary Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX
Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX
Related Content:
EAU 2025: Management of Positive Soft Tissue Margins After Radical Cystectomy: What About Isolated Pelvic Recurrences after Radical Cystectomy? – Radiotherapy versus Systemic Therapy as the Optimal Approach
ASCO 2025: Nivolumab + Ipilimumab versus Gemcitabine + Carboplatin Chemotherapy for Previously Untreated Unresectable or Metastatic Urothelial Carcinoma: Final Results for Cisplatin-Ineligible Patients from the CheckMate 901 Trial
ASCO 2024: Characterization of Complete Responders to Nivolumab + Gemcitabine-Cisplatin vs Gemcitabine-Cisplatin Alone and Patients with Lymph Node–only Metastatic Urothelial Carcinoma from the CheckMate 901 Trial
The EV-302 Study and the Implications for Metastatic Bladder Cancer Care - Cora Sternberg
EAU 2025: Management of Positive Soft Tissue Margins After Radical Cystectomy: What About Isolated Pelvic Recurrences after Radical Cystectomy? – Radiotherapy versus Systemic Therapy as the Optimal Approach
ASCO 2025: Nivolumab + Ipilimumab versus Gemcitabine + Carboplatin Chemotherapy for Previously Untreated Unresectable or Metastatic Urothelial Carcinoma: Final Results for Cisplatin-Ineligible Patients from the CheckMate 901 Trial
ASCO 2024: Characterization of Complete Responders to Nivolumab + Gemcitabine-Cisplatin vs Gemcitabine-Cisplatin Alone and Patients with Lymph Node–only Metastatic Urothelial Carcinoma from the CheckMate 901 Trial
The EV-302 Study and the Implications for Metastatic Bladder Cancer Care - Cora Sternberg
Read the Full Video Transcript
Ashish Kamat: Hello, everybody, and welcome to UroToday's bladder cancer center of excellence. I'm Ashish Kamat, Urologic Oncologist in Houston, Texas. And I'm joined today by an all-star panel, Comron Hassanzadeh, who is right here in Houston, Texas, and Andrea Necchi who is joining us from Milan. Welcome, gentlemen.
Andrea Necchi: Welcome, and thank you for inviting.
Comron Hassanzadeh: Yeah. Thank you for having me.
Ashish Kamat: So the two of you debated this in Madrid just recently at EAU25, a very hot topic, which really is a very practical topic, because nowadays we see patients that undergo radical cystectomy for advanced disease. We see where unfortunately, the surgeon gets a positive margin at the surgery. And oftentimes, patients will have isolated pelvic recurrences after cystectomy.
And the question often comes up, well, what's the best next option? So the two of you are given sides. And I'd love to hear your pros and cons on radiation being the optimal therapy for positive margin pelvic recurrence or systemic therapy. So Comron, stage is yours.
Comron Hassanzadeh: Great, yeah. Thank you, again, Ashish, for that introduction. So I'll be presenting on the radiation is optimal therapy side. So I'm an Assistant Professor in the Department of Genitourinary radiation oncology at MD Anderson. And we're going to be talking about a case of an isolated pelvic recurrence after cystectomy. I have no relevant disclosures for today's talk.
So for local pelvic recurrences, a post-cystectomy, this is an issue. Most patients we think have distant metastases. And that's going to be the predominant mode of recurrence for most bladder cancer patients. However, pelvic recurrences and local recurrences are still very relevant. And we'll get into why radiation might actually be the preferred treatment for many of these patients.
We could look to data from SWOG 1011 on what are those rates in a modern cohort of cystectomy patients, how many patients do have local recurrences? Well, in that study, about 9% to 13% did recur. And in other series, locoregional recurrence rates can be as high as 30% to 40% in other cystectomy series. And additionally, while distant metastases do predominate, many times the first site of recurrence in many bladder cancer patients is local.
Actually, about maybe as high as a third of patients will have a local recurrence, and then later on potentially develop a distant metastasis. And looking at some older data, we know that patients who are locally controlled may actually translate into lower rates of distant metastases. And the thought is maybe that local recurrence could be seeding a future distant met down the line.
And also it's very difficult to salvage local recurrences. So how can we prevent them in the first place? So adjuvant radiation to avoid local recurrences has been studied, we have data from Egypt in the Zaghloul data, which actually did show for patients with some high-risk features, T3b, LVSI+, potentially, positive lymph nodes as being risk factors. We saw about a 10% higher rate of locoregional free survival.
And then we have our more modern data of IMRT or Modern Radiation From the BART data, this is Vedang Murthy group from Tata Memorial looking at IMRT versus observation. And while the primary outcome data has not been published, we actually saw that there was an interesting finding of a very safe profile.
The late grade 2 toxicity was very reasonable. It was not a high-rate of significant toxicity. And that had been what we had found in older data with 3D conformal radiation. So we know that adjuvant radiation is probably safe. And it does reduce some of that rate of locoregional recurrence as well. And in fact the EAU, while it's a weak recommendation, does recommend adjuvant radiation to prevent that local recurrence in the first place.
So another thing to remember is that systemic therapy toxicity is really significant, while maybe that toxicity is warranted. When we look at our data from our adjuvant immunotherapy studies that grade 3 toxicity rate can be as high as 50%, EV-302. We know EV is a great therapy, but it can be very toxic.
We see rates of neuropathy, skin toxicity as high as grade 3 toxicity is up to 50% to 60%. And while these toxicities may be warranted given that bladder cancer is going to have a high-rate of distant metastases, if we're just dealing with a local recurrence, why don't we just do radiation, and then maybe reserve that systemic therapy for something down the line?
So when we're talking about a patient with an isolated pelvic recurrence, we're seeing a patient like this where he has left pelvic sidewall lesion, how do we deal with that? Well, I think in my practice getting a good assessment of any additional disease, first of all, staging the local disease with an MRI, see is a local invasion of surrounding bowel or other structures, getting an FDG PET even potentially beyond our normal CT imaging to really rule out any distant or lymph node metastases before jumping into a local therapy, I think is very important.
After you've done all that and proved or at least convinced yourself that we're dealing with just isolated local disease, I would recommend Intensity-Modulated Radiation or IMRT, that is our modern treatment. Typically, we want to do that in a gentle fashion, so 50.4 Gray and 1.8 Gray per fraction. This is about a maybe a 6 to 7-week course of radiation. So going slow and gentle tends to have a lower toxicity rate.
And then we want to boost that involved disease to a high dose while respecting our bowel dosage-- well, and our bowel toxicity rates. And I would also look to my medical oncology colleagues and see if we could potentially add some radiosensitizing chemotherapy. I think this case was a case of a patient who had not had any neoadjuvant chemotherapy upfront. So potentially, some role for radiosensitizing chemo, maybe that's a weekly cisplatin or low dose gem could potentially even help with radiosensitization further.
So in summary, this patient with an isolated pelvic recurrence and patients where we're really proved that we're dealing with just a local issue would really benefit from a local therapy like radiation therapy. If we can prevent these pelvic recurrences by offering adjuvant therapy or adjuvant radiation in the first place, that is the ideal scenario. But what we've done potentially, is something like immunotherapy and then find later on to develop a pelvic recurrence. IMRT is a very safe and a very effective treatment for many of these patients. So thank you.
Ashish Kamat: Thanks, Comron. And we're going to hear from Andrea as to why he thinks that patients such as these deserve to get more than just local therapy. So Andrea.
Andrea Necchi: Thank you, Ashish. UroToday team. I'm pleased to be here today discussing this topic. So as you have heard from Comron, it's a really a compelling topic for multiple reasons. We have heard from Comron what has actually the option for local therapy. I have basically a neutral position regarding the possibility for treatment. Despite today I'm supporting the role of systemic therapy, because as a matter of fact, what we are observing-- I'm just learning from the patient perspective what is perceived as the best option in these past few months.
Actually, we should recognize the fact that there have been multiple advances, as you know, with regards to systemic therapy in patients with advanced disease. And this major breakthrough in systemic therapy in overcoming the limitation, the well known limitation of platinum chemotherapy.
And in particular, the EV pembro story actually has an impact on the overall therapeutic range of cross the therapeutic lines and across the clinical stages of patients with bladder cancer, meaning that the paradigm that is now perceived by most of the patients that jump to us for a consultation, whichever the clinical stage is, is that EV pembro can cure them, regardless of the clinical stage, with a sufficiently well tolerated treatment, at least in the short or medium term.
And this actually that the disposition that is perceived by the patient based on the information that they get from the clinical trials, from the social media. And so it's very, very difficult to change or to modulate depending on the clinical judgment. You see from the ESMO guidelines that is clearly today an indication to first consider EV pembro story, EV pembro applicability, and then deciding afterwards depending on this.
There is uncertainty with regards to the definition of oligometastatic bladder cancer. We start from the paradigm, clear paradigm, that bladder cancer is a systemic disease since the very beginning of muscle invasion. Having said that, even a patient with a clinical T210N0 could be defined as or could be regarded to as having a systemic therapy.
So based on this, we would privilege the option of systemic therapy first and then considering any consolidation, local therapy, including radical cystectomy, including radiotherapy in patients who have already received radical cystectomy. There is clearly an option first to consider systemic therapy. We do have data today from major Phase III trials of subgroup analysis of two major trials, the CheckMate-901 NIVO and Gem/cis versus Gem/cis, showing an improvement in survival with PFS and OS with NIVO.
NIVO Gem/cis has been approved by FDA, is been approved, by EMA on the other side of the Atlantic. And in particular, in CheckMate-901, if we look at the subpopulation subgroup of the patient presenting with oligometastatic lymph node only disease, lymph node in the pelvis, or lymph node in the retroperitoneum and pelvis, there is clearly an enrichment in responses, meaning clinical responses and part and partial responses.
There is strike as compared to chemotherapy option. So there is clearly an opportunity here. Or the same for, on the right inside, the same for EV-302 with EV pembro. The response rate is rises up to almost 80% in the population of patients with lymph node only disease.
Clearly, the judgment of colleagues and most of the young or senior colleagues is today to consider systemic therapy upfront and then deciding on local therapy based on the response. But my point, my last point, is something that has to do in general with the approach of systemic-- with the management of systemic therapy of the patients throughout the clinical stages.
And for sure, the attrition rate of in particular with immunotherapy that is used up and up front in the non-metastatic non-muscle invasive disease, we do have the data released by Sasanlimab trial. We do have the recently released press release by AstraZeneca with POTOMAC study with the volume being in the same population.
So patients who have already received immune therapy upfront, the very upfront in NMIBC stage would be prevented, in theory, to receive rechallenge immunotherapy in later stages, meaning that, again, we go back to the need to have something more locally delivered, meaning radiotherapy primarily in the patient. So this is the reason why still radical local therapy in the pelvic relapses after previous radical therapy. It will still have a role despite this huge movement with systemic therapy with ADC and immune therapy playing a major role in this patient population.
So in conclusion, my conclusion as having said that, we cannot drive any major conclusion at the moment. There is clearly an opportunity for a hearing from the patient. And then trying to be flexible enough to modulate our judgment and our therapeutic proposal based on their desire first. Trying to address the right message to them is coming from the clinical trials.
And maybe offering alternative approaches like systemic therapy or local therapy, or both of them, depending on the response, depending on patient characteristics, and depending on the timing of relapse and other clinical features that are important to consider for everyday practice despite the type of disease progression or the type of previous treatments. So very, very preliminary conclusion. But it's an exciting time to discuss these particular cases today, because we have so many options to discuss as compared to just a few years ago. Thank you.
Ashish Kamat: Thanks both of you. Very nice presentations. And of course, you were given the site. But we all recognize that bladder cancer, especially, patients such as this, it's a multidisciplinary care. It's not just one or the other. Let me ask you some rapid fire questions and just keep your responses to a bare minimum, just in the interest of time. Would you alter your consideration based on histologic subtypes, Andrea?
Andrea Necchi: The answer is no provided that I have the opportunity to still use the best systemic therapies that we are allowed to use for urothelial cancer. So in Italy, for example, no question. There is no role and no opportunity to get EV pembro for none of the patients. So it's a very much difficult to deal with the variant histology issue if you don't have access or a possibility to modulate therapy according to the histology.
In principle, if you have the possibility to get access to all the types of the newer therapy that are already available, there is no clear disconnection in responses in patients who have predominant or predominant that you see with squamous component or predominant squamous component. The paradigm of modulating therapy depending on the histological subtype is maybe overcome by the advent of immune therapy ADC combination. It's likely to be not considered or hopefully will not be considered as a major obstacle in the next trial and the clinical practice.
Ashish Kamat: Comron, question for you. Obviously, you talked about the BART trial and stuff, and that's more adjuvant. But in a patient that has a actual documented pelvic recurrence, what do you consider the optimal timing of local radiotherapy? Would you first do systemic therapy and then follow up with local? Would you, as you alluded to, start with local and then want the patient to get systemic? What's your optimal timing?
Comron Hassanzadeh: Yeah. So I was tasked with supporting the radiation side. But in reality, in practice, I think you start with systemic therapy first and see a good response. Avoid the patient who's quickly going to develop distant metastases. The local therapy is not going to benefit that patient. So I think we're going to sequence it. In our own practice, we typically would do systemic therapy first, restage the patient, see a good response whether that's a PR or stable disease, and then follow that with local therapy. So that's been our own practice.
Ashish Kamat: Now, both of you have been very involved in personalized therapy for patients, and kudos to both of you for all the efforts. Let me address this question first to Andrea and then Comron to you as well. So Andrea, say you have a patient like that with a isolated pelvic recurrence, and you give the patient systemic therapy. Are you using, for example, ctDNA or anything of that nature to suggest the timing of where you might want to either switch systemic therapy or you say, well, my systemic therapy is working, but it's not working in the pelvic region, let me now refer the patient to my radiation oncologist. Are you using any such markers?
Andrea Necchi: A very compelling question. Thank you. So we know that ctDNA is a very compelling story in MIBC. I mean, the data that we have today are particularly focused on patients with non-metastatic disease, trying to modulate the use of adjuvant immune therapy or maybe neoadjuvant systemic therapy. Or neoadjuvant systemic therapy indication in patients who have ctDNA negative status before treatment.
But we have much less clean data in the advanced stage, in locally advanced local recurrence or metastatic stages. And here for the patient, there is clearly an opportunity to well define the role of ctDNA, because today there are many regions in worldwide where we are not allowed to use or we are not able access toxicity assessment. So no question that there is no role for consideration like this.
But if you have access to ctDNA in patients with local relapse or any kind of relapse or locally advanced or metastatic disease, the question regarding the use of ctDNA modulation or treatment depending on ctDNA becomes much more concerning, because we don't have very much data on this from a clinical trial. So if we assume that the situation in more advanced tumors will be the same like in non-metastatic MIBC, I would say yes.
Patient that for any reason will result to have a ctDNA negative test associated with a local relapse that is clear at the imaging, and there is clearly a role for local therapy. And ctDNA positivity will favor a use of systemic therapy. But it's just a theoretical consideration. There is no data supporting this opportunity as of today. I think we have to accumulate that on this, and maybe clinical trials in this particular setting with oligometastatic recurrence are very much needed.
Ashish Kamat: Yeah. No I absolutely agree. Comron, any nuggets of wisdom there.
Comron Hassanzadeh: Yeah. So I agree with Andrea. There's limited data on using ctDNA and MRD assays in this setting. And we're getting CT scans, and we're getting PET scans as our best imaging biomarkers. But I think MRD assays are not quite ready for prime time yet. There's a lot of compelling studies that are ongoing, look at the MODERN data with the Alliance Group looking at ctDNA and adjuvant immunotherapy and seeing is there clearance. Do patients need maintenance? Can we potentially deescalate some of that therapy?
I don't know how that interplays with local therapy though. I think a lot of us are still trying to grapple with it. In our own practice, we'll get Signatera assays occasionally. But I'm always left scratching my head on how exactly to interpret that information, to determine whether I should be doing local therapy or not. I'm typically relying on imaging biomarkers as my tried and true at this point, but I think the future is going to be getting a ctDNA assay and then really helping to determine should we be offering local therapy or not.
Ashish Kamat: Yeah, great points both of you. And this pelvic recurrence is a really frustrating situation for all of us, especially the patient, because you do a complete resection even with negative margins, take out 40, 50 lymph nodes, everything looks great.
And then year later, unfortunately, some patients will develop the local pelvic recurrence despite everything suggesting that they should not. And that's when the conundrum and the multidisciplinary care that all of us aspire to comes into play. Gentlemen, I want to thank you for taking the time. This is really, really enlightening. Thank you very much.
Andrea Necchi: Thank you. Thank you. I enjoyed it very much.
Comron Hassanzadeh: Thanks so much.
Ashish Kamat: Hello, everybody, and welcome to UroToday's bladder cancer center of excellence. I'm Ashish Kamat, Urologic Oncologist in Houston, Texas. And I'm joined today by an all-star panel, Comron Hassanzadeh, who is right here in Houston, Texas, and Andrea Necchi who is joining us from Milan. Welcome, gentlemen.
Andrea Necchi: Welcome, and thank you for inviting.
Comron Hassanzadeh: Yeah. Thank you for having me.
Ashish Kamat: So the two of you debated this in Madrid just recently at EAU25, a very hot topic, which really is a very practical topic, because nowadays we see patients that undergo radical cystectomy for advanced disease. We see where unfortunately, the surgeon gets a positive margin at the surgery. And oftentimes, patients will have isolated pelvic recurrences after cystectomy.
And the question often comes up, well, what's the best next option? So the two of you are given sides. And I'd love to hear your pros and cons on radiation being the optimal therapy for positive margin pelvic recurrence or systemic therapy. So Comron, stage is yours.
Comron Hassanzadeh: Great, yeah. Thank you, again, Ashish, for that introduction. So I'll be presenting on the radiation is optimal therapy side. So I'm an Assistant Professor in the Department of Genitourinary radiation oncology at MD Anderson. And we're going to be talking about a case of an isolated pelvic recurrence after cystectomy. I have no relevant disclosures for today's talk.
So for local pelvic recurrences, a post-cystectomy, this is an issue. Most patients we think have distant metastases. And that's going to be the predominant mode of recurrence for most bladder cancer patients. However, pelvic recurrences and local recurrences are still very relevant. And we'll get into why radiation might actually be the preferred treatment for many of these patients.
We could look to data from SWOG 1011 on what are those rates in a modern cohort of cystectomy patients, how many patients do have local recurrences? Well, in that study, about 9% to 13% did recur. And in other series, locoregional recurrence rates can be as high as 30% to 40% in other cystectomy series. And additionally, while distant metastases do predominate, many times the first site of recurrence in many bladder cancer patients is local.
Actually, about maybe as high as a third of patients will have a local recurrence, and then later on potentially develop a distant metastasis. And looking at some older data, we know that patients who are locally controlled may actually translate into lower rates of distant metastases. And the thought is maybe that local recurrence could be seeding a future distant met down the line.
And also it's very difficult to salvage local recurrences. So how can we prevent them in the first place? So adjuvant radiation to avoid local recurrences has been studied, we have data from Egypt in the Zaghloul data, which actually did show for patients with some high-risk features, T3b, LVSI+, potentially, positive lymph nodes as being risk factors. We saw about a 10% higher rate of locoregional free survival.
And then we have our more modern data of IMRT or Modern Radiation From the BART data, this is Vedang Murthy group from Tata Memorial looking at IMRT versus observation. And while the primary outcome data has not been published, we actually saw that there was an interesting finding of a very safe profile.
The late grade 2 toxicity was very reasonable. It was not a high-rate of significant toxicity. And that had been what we had found in older data with 3D conformal radiation. So we know that adjuvant radiation is probably safe. And it does reduce some of that rate of locoregional recurrence as well. And in fact the EAU, while it's a weak recommendation, does recommend adjuvant radiation to prevent that local recurrence in the first place.
So another thing to remember is that systemic therapy toxicity is really significant, while maybe that toxicity is warranted. When we look at our data from our adjuvant immunotherapy studies that grade 3 toxicity rate can be as high as 50%, EV-302. We know EV is a great therapy, but it can be very toxic.
We see rates of neuropathy, skin toxicity as high as grade 3 toxicity is up to 50% to 60%. And while these toxicities may be warranted given that bladder cancer is going to have a high-rate of distant metastases, if we're just dealing with a local recurrence, why don't we just do radiation, and then maybe reserve that systemic therapy for something down the line?
So when we're talking about a patient with an isolated pelvic recurrence, we're seeing a patient like this where he has left pelvic sidewall lesion, how do we deal with that? Well, I think in my practice getting a good assessment of any additional disease, first of all, staging the local disease with an MRI, see is a local invasion of surrounding bowel or other structures, getting an FDG PET even potentially beyond our normal CT imaging to really rule out any distant or lymph node metastases before jumping into a local therapy, I think is very important.
After you've done all that and proved or at least convinced yourself that we're dealing with just isolated local disease, I would recommend Intensity-Modulated Radiation or IMRT, that is our modern treatment. Typically, we want to do that in a gentle fashion, so 50.4 Gray and 1.8 Gray per fraction. This is about a maybe a 6 to 7-week course of radiation. So going slow and gentle tends to have a lower toxicity rate.
And then we want to boost that involved disease to a high dose while respecting our bowel dosage-- well, and our bowel toxicity rates. And I would also look to my medical oncology colleagues and see if we could potentially add some radiosensitizing chemotherapy. I think this case was a case of a patient who had not had any neoadjuvant chemotherapy upfront. So potentially, some role for radiosensitizing chemo, maybe that's a weekly cisplatin or low dose gem could potentially even help with radiosensitization further.
So in summary, this patient with an isolated pelvic recurrence and patients where we're really proved that we're dealing with just a local issue would really benefit from a local therapy like radiation therapy. If we can prevent these pelvic recurrences by offering adjuvant therapy or adjuvant radiation in the first place, that is the ideal scenario. But what we've done potentially, is something like immunotherapy and then find later on to develop a pelvic recurrence. IMRT is a very safe and a very effective treatment for many of these patients. So thank you.
Ashish Kamat: Thanks, Comron. And we're going to hear from Andrea as to why he thinks that patients such as these deserve to get more than just local therapy. So Andrea.
Andrea Necchi: Thank you, Ashish. UroToday team. I'm pleased to be here today discussing this topic. So as you have heard from Comron, it's a really a compelling topic for multiple reasons. We have heard from Comron what has actually the option for local therapy. I have basically a neutral position regarding the possibility for treatment. Despite today I'm supporting the role of systemic therapy, because as a matter of fact, what we are observing-- I'm just learning from the patient perspective what is perceived as the best option in these past few months.
Actually, we should recognize the fact that there have been multiple advances, as you know, with regards to systemic therapy in patients with advanced disease. And this major breakthrough in systemic therapy in overcoming the limitation, the well known limitation of platinum chemotherapy.
And in particular, the EV pembro story actually has an impact on the overall therapeutic range of cross the therapeutic lines and across the clinical stages of patients with bladder cancer, meaning that the paradigm that is now perceived by most of the patients that jump to us for a consultation, whichever the clinical stage is, is that EV pembro can cure them, regardless of the clinical stage, with a sufficiently well tolerated treatment, at least in the short or medium term.
And this actually that the disposition that is perceived by the patient based on the information that they get from the clinical trials, from the social media. And so it's very, very difficult to change or to modulate depending on the clinical judgment. You see from the ESMO guidelines that is clearly today an indication to first consider EV pembro story, EV pembro applicability, and then deciding afterwards depending on this.
There is uncertainty with regards to the definition of oligometastatic bladder cancer. We start from the paradigm, clear paradigm, that bladder cancer is a systemic disease since the very beginning of muscle invasion. Having said that, even a patient with a clinical T210N0 could be defined as or could be regarded to as having a systemic therapy.
So based on this, we would privilege the option of systemic therapy first and then considering any consolidation, local therapy, including radical cystectomy, including radiotherapy in patients who have already received radical cystectomy. There is clearly an option first to consider systemic therapy. We do have data today from major Phase III trials of subgroup analysis of two major trials, the CheckMate-901 NIVO and Gem/cis versus Gem/cis, showing an improvement in survival with PFS and OS with NIVO.
NIVO Gem/cis has been approved by FDA, is been approved, by EMA on the other side of the Atlantic. And in particular, in CheckMate-901, if we look at the subpopulation subgroup of the patient presenting with oligometastatic lymph node only disease, lymph node in the pelvis, or lymph node in the retroperitoneum and pelvis, there is clearly an enrichment in responses, meaning clinical responses and part and partial responses.
There is strike as compared to chemotherapy option. So there is clearly an opportunity here. Or the same for, on the right inside, the same for EV-302 with EV pembro. The response rate is rises up to almost 80% in the population of patients with lymph node only disease.
Clearly, the judgment of colleagues and most of the young or senior colleagues is today to consider systemic therapy upfront and then deciding on local therapy based on the response. But my point, my last point, is something that has to do in general with the approach of systemic-- with the management of systemic therapy of the patients throughout the clinical stages.
And for sure, the attrition rate of in particular with immunotherapy that is used up and up front in the non-metastatic non-muscle invasive disease, we do have the data released by Sasanlimab trial. We do have the recently released press release by AstraZeneca with POTOMAC study with the volume being in the same population.
So patients who have already received immune therapy upfront, the very upfront in NMIBC stage would be prevented, in theory, to receive rechallenge immunotherapy in later stages, meaning that, again, we go back to the need to have something more locally delivered, meaning radiotherapy primarily in the patient. So this is the reason why still radical local therapy in the pelvic relapses after previous radical therapy. It will still have a role despite this huge movement with systemic therapy with ADC and immune therapy playing a major role in this patient population.
So in conclusion, my conclusion as having said that, we cannot drive any major conclusion at the moment. There is clearly an opportunity for a hearing from the patient. And then trying to be flexible enough to modulate our judgment and our therapeutic proposal based on their desire first. Trying to address the right message to them is coming from the clinical trials.
And maybe offering alternative approaches like systemic therapy or local therapy, or both of them, depending on the response, depending on patient characteristics, and depending on the timing of relapse and other clinical features that are important to consider for everyday practice despite the type of disease progression or the type of previous treatments. So very, very preliminary conclusion. But it's an exciting time to discuss these particular cases today, because we have so many options to discuss as compared to just a few years ago. Thank you.
Ashish Kamat: Thanks both of you. Very nice presentations. And of course, you were given the site. But we all recognize that bladder cancer, especially, patients such as this, it's a multidisciplinary care. It's not just one or the other. Let me ask you some rapid fire questions and just keep your responses to a bare minimum, just in the interest of time. Would you alter your consideration based on histologic subtypes, Andrea?
Andrea Necchi: The answer is no provided that I have the opportunity to still use the best systemic therapies that we are allowed to use for urothelial cancer. So in Italy, for example, no question. There is no role and no opportunity to get EV pembro for none of the patients. So it's a very much difficult to deal with the variant histology issue if you don't have access or a possibility to modulate therapy according to the histology.
In principle, if you have the possibility to get access to all the types of the newer therapy that are already available, there is no clear disconnection in responses in patients who have predominant or predominant that you see with squamous component or predominant squamous component. The paradigm of modulating therapy depending on the histological subtype is maybe overcome by the advent of immune therapy ADC combination. It's likely to be not considered or hopefully will not be considered as a major obstacle in the next trial and the clinical practice.
Ashish Kamat: Comron, question for you. Obviously, you talked about the BART trial and stuff, and that's more adjuvant. But in a patient that has a actual documented pelvic recurrence, what do you consider the optimal timing of local radiotherapy? Would you first do systemic therapy and then follow up with local? Would you, as you alluded to, start with local and then want the patient to get systemic? What's your optimal timing?
Comron Hassanzadeh: Yeah. So I was tasked with supporting the radiation side. But in reality, in practice, I think you start with systemic therapy first and see a good response. Avoid the patient who's quickly going to develop distant metastases. The local therapy is not going to benefit that patient. So I think we're going to sequence it. In our own practice, we typically would do systemic therapy first, restage the patient, see a good response whether that's a PR or stable disease, and then follow that with local therapy. So that's been our own practice.
Ashish Kamat: Now, both of you have been very involved in personalized therapy for patients, and kudos to both of you for all the efforts. Let me address this question first to Andrea and then Comron to you as well. So Andrea, say you have a patient like that with a isolated pelvic recurrence, and you give the patient systemic therapy. Are you using, for example, ctDNA or anything of that nature to suggest the timing of where you might want to either switch systemic therapy or you say, well, my systemic therapy is working, but it's not working in the pelvic region, let me now refer the patient to my radiation oncologist. Are you using any such markers?
Andrea Necchi: A very compelling question. Thank you. So we know that ctDNA is a very compelling story in MIBC. I mean, the data that we have today are particularly focused on patients with non-metastatic disease, trying to modulate the use of adjuvant immune therapy or maybe neoadjuvant systemic therapy. Or neoadjuvant systemic therapy indication in patients who have ctDNA negative status before treatment.
But we have much less clean data in the advanced stage, in locally advanced local recurrence or metastatic stages. And here for the patient, there is clearly an opportunity to well define the role of ctDNA, because today there are many regions in worldwide where we are not allowed to use or we are not able access toxicity assessment. So no question that there is no role for consideration like this.
But if you have access to ctDNA in patients with local relapse or any kind of relapse or locally advanced or metastatic disease, the question regarding the use of ctDNA modulation or treatment depending on ctDNA becomes much more concerning, because we don't have very much data on this from a clinical trial. So if we assume that the situation in more advanced tumors will be the same like in non-metastatic MIBC, I would say yes.
Patient that for any reason will result to have a ctDNA negative test associated with a local relapse that is clear at the imaging, and there is clearly a role for local therapy. And ctDNA positivity will favor a use of systemic therapy. But it's just a theoretical consideration. There is no data supporting this opportunity as of today. I think we have to accumulate that on this, and maybe clinical trials in this particular setting with oligometastatic recurrence are very much needed.
Ashish Kamat: Yeah. No I absolutely agree. Comron, any nuggets of wisdom there.
Comron Hassanzadeh: Yeah. So I agree with Andrea. There's limited data on using ctDNA and MRD assays in this setting. And we're getting CT scans, and we're getting PET scans as our best imaging biomarkers. But I think MRD assays are not quite ready for prime time yet. There's a lot of compelling studies that are ongoing, look at the MODERN data with the Alliance Group looking at ctDNA and adjuvant immunotherapy and seeing is there clearance. Do patients need maintenance? Can we potentially deescalate some of that therapy?
I don't know how that interplays with local therapy though. I think a lot of us are still trying to grapple with it. In our own practice, we'll get Signatera assays occasionally. But I'm always left scratching my head on how exactly to interpret that information, to determine whether I should be doing local therapy or not. I'm typically relying on imaging biomarkers as my tried and true at this point, but I think the future is going to be getting a ctDNA assay and then really helping to determine should we be offering local therapy or not.
Ashish Kamat: Yeah, great points both of you. And this pelvic recurrence is a really frustrating situation for all of us, especially the patient, because you do a complete resection even with negative margins, take out 40, 50 lymph nodes, everything looks great.
And then year later, unfortunately, some patients will develop the local pelvic recurrence despite everything suggesting that they should not. And that's when the conundrum and the multidisciplinary care that all of us aspire to comes into play. Gentlemen, I want to thank you for taking the time. This is really, really enlightening. Thank you very much.
Andrea Necchi: Thank you. Thank you. I enjoyed it very much.
Comron Hassanzadeh: Thanks so much.