Kamal Pohar: Good afternoon. We're here at the AUA 2022. I'm Dr. Kamal Pohar, I'm from Ohio State University. I have the privilege of being with Dr. Brant Inman from Duke University today and Dr. Yair Lotan from UT Southwestern. Good afternoon to both of you.

Brant Inman: Good afternoon.

Yair Lotan: Good afternoon.

Kamal Pohar: So our topic of discussion today will be, is there a role for radical cystectomy for clinical N1 or N2 bladder cancer? So Dr. Inman, you've taken the position that there's a role for radical cystectomy. Do you want to expound on that further? What do you think the value is of doing a cystectomy?

Brant Inman: Sure. My position is that cystectomy with lymph adenectomy has a role after systemic therapy for patients who have clinically node-positive disease. I think that the use of systemic therapy is usually the best first place to start because the response to therapy, shrinkage of nodes, disappearance of nodes, is a good indicator that the patient has a chance of doing very well with the combination of that treatment, plus removal of those lymph nodes in the bladder. And I think it represents the most active form of treatment possible to give the patient the best outcome that they can get.

Kamal Pohar: Dr. Lotan, do you want to comment on that? We start the discussion by systemic chemotherapy and I'll use the term, or induction chemotherapy, new adjuvant chemotherapy, however you want to coin that, that's an important multimodal aspect of treating the disease with node-positive disease. Do you want to comment on radical cystectomy, a single modality therapy for pelvic node-positive disease? What are the outcomes to set the baseline of what the influence of induction chemotherapies? Where do we start the conversation of cystectomy alone?

Yair Lotan: I think there are a couple of challenges. First of all, I think there's heterogeneity in node positivity. When we do cystectomy on patients who are clinical T2 disease, we find even with normal CT scans, we find up to 25% of patients have micrometastatic disease that was not anticipated. In that setting, we can cure up to 30 to 40% of patients, but that is a little different than patients who are clinically node positive, where many studies excluded patients who are clinically node positive. And so it's hard to extrapolate the results for a patient who had clinically node-negative, but pathologically node-positive disease outcomes specifically in saying, "Oh, it's going to be 30 to 40% because in the setting of clinically node negative, pathologically node-positive, we can get those results."

I think if you have clinically node-positive disease, your outcomes are likely going to be worse with cystectomy and lymph node dissection alone. I think the fact that more than 70% of patients likely have systemic disease beyond the lymph nodes, suggest that you really need to start with induction chemotherapy. That gives you two possibilities. First of all, you're going to help treat that disease. Second of all, you might find patients who subsequently within a couple of months, have lung metastases, liver metastases, who will never benefit from local therapy. So it's a bit of a trial for those patients to see, not only do they have responsiveness to chemotherapy, but also are they likely to have systemic disease?

Kamal Pohar: I want to circle back on that. I think that's a good point. And maybe I should have opened this session up by bringing to fruition that the AJCC staging system, the most recent revision changed. Node positive disease was considered stage four disease in the prior classification. Now it's been brought down to stage three disease, suggesting there's some degree of curability. Doctor, do you want to comment on that very important point that we're very much based on clinical nodal staging based on cross-sectional imaging, and there are criteria that are defined by our radiology colleagues based on the short access of measuring a lymph node, what we might define as a positive node. So clearly there's some degree of lack of precision and predictive value, sensitivity, specificity, both in the diagnosis setting and the treatment response setting to chemotherapy, of being able to qualify those nodes as being truly positive. Do you want to comment on the degree of error in both of those settings for us?

Brant Inman: Yeah. Well, I think Yair set an important point actually, which was that it goes both ways. In the patient who has imaging that is negative, has no enlarged lymph nodes, and you might use eight millimeters of short access or 10 millimeters of short access. But in that patient population, in whom we would say they don't have positive lymph nodes, something like a quarter of them probably do. And likewise, in the patients who have enlarged lymph nodes using those criteria, something like about 20% of those nodes are going to turn out to be non-cancerous. So the testing isn't perfect. Additional alternatives is PET/CT. Probably right now with FDG tracer, it's probably better than axial imaging alone, although we don't have great data on that. I personally believe it to be more accurate, but you're right. I mean, we're wrong both ways. We're wrong when we assume patients are node-negative and we're wrong sometimes when assume they're node positive.

Kamal Pohar: So that's a bit of a problem in this space then, we're very reliant on cross-sectional imaging. PET may be something that's evolving. And so we may be qualifying patients or upstaging their nodes to a level where they're truly not pathologic.

Brant Inman: Yeah.

Kamal Pohar: Node positive. Okay. So I think we're in agreement here in the conversation that induction chemotherapy, neoadjuvant chemotherapy is important for this patient population who doesn't have metastatic disease outside of the regional lymph nodes. So people have different responses to chemotherapy, and we're talking about platinum therapy here. Most people hopefully are eligible for cisplatin therapy. Some will show radiographic response. Some will not, some will show progression of disease. Where do you think cystectomy has a role there? When after chemotherapies, is everybody eligible for a cystectomy?

Brant Inman: Yeah, I think that's actually a real important point. I think that the patient who has stable disease, meaning no new lymph nodes, no worsening of existing lymph nodes, those patients should be eligible for cystectomy with lymph adenectomy after chemotherapy. The ones I worry about are the ones where we see new disease evolving under chemotherapy, either new lymph nodes or new metastatic sites. And in those patients, I don't believe that radical surgery is going to be curative. And most of the time those patients should be treated with second line systemic agents.

Kamal Pohar: Dr. Lotan, do you do want to pick up the conversation there? You brought up the point that many of these patients have systemic micrometastases and they unfortunately won't be cured by local therapy alone. And we just had a conversation now that systemic therapy plus local therapy in this context, radical cystectomy, by far not everybody is cured. The majority or not. What do you think about alternatives other than radical cystectomy then, if it's not a highly curative operation for everybody, where do we find the balance then? What else can we do?

Yair Lotan: So I think we have to recognize that the field is evolving, right? We know immune therapies likely will be approved in adjuvant therapies. If you do proceed with cystectomy, you don't find disease elsewhere and they're certainly approved in a metastatic setting. And so a lot of our information about prognosis and likelihood of death is based on sort of pre-immune therapy and we're still getting more mature data. So I think the prognosis is maybe a little bit better, even if you don't have a complete response. But I do think that we have to be honest with our patients, and even if we have stable disease, but we think they have disease, those patients who have residual disease in the nodes after induction chemotherapy have a very poor prognosis overall. And cystectomy is a morbid operation. I think we have to start looking at the patient quality of life.

We have to look at the patient's comorbidities. A younger, healthier patient, we want to maximize their likelihood of cure. An older patient who might not do well with cystectomy, we have to really consider, is that how we want them to live out the end of their life? Unless there's a good likelihood of cure. I think there are a couple of alternative options. First of all, the use of just lymphadenectomy, especially with a robotic approach to stage the nodes has been used for prostate cancer. We haven't used it extensively for bladder cancer, but it's not very morbid. One could consider staging lymph node dissection. And if the nodes had had a good response or there's minimal nodal disease, subsequently to do a cystectomy. I don't think that would necessarily keep you from being able to do the operation. The second option is to consider chemoradiation approaches, which are already in the guidelines for treating muscle-invasive bladder cancer. And they could be less morbid approaches, which might not lead to as much debilitation among our patients.

Kamal Pohar: Dr. Inman, despite the fact you take the strong view that radical cystectomy in the appropriate patient who desires it as a fit candidate is probably the likely approach you would favor. Where is the maturity of the data with radiation at this point in time, if you're having a council discussion with a patient about treatment options, how mature is the data of chemoradiation in this space of node-positive disease? And how do you have that conversation with a patient?

Brant Inman: Yeah. For clinically node-positive patients, the data for radiation is very sparse. There are a couple of publications that have looked at this question and have outcomes that are maybe slightly worse than surgery, but it's hard to know the degree to which this is representative of selection biases, where the healthier, fitter, small, smaller volume nodes get operated on, and then the older, sicker patients with worse disease get radiation. And that could explain differences in outcome. But most of the studies that have looked at this seem to suggest that the outcomes with surgery are better. I'm just not convinced that's not due to selection bias. I don't know. There's no randomized data in this space.

Kamal Pohar: Yeah. Dr. Lotan, any comments about radiation in this space, the maturity of the data, any early trials? So the concern with radiation is the actual overall field and the toxicity. We're not talking about targeting the bladder in a situation like this with clinical node-positive disease, the radiation fields need to be extended. Toxicity is a concern. Any of the current trials in this space are excluding N3 patients to limit that radiation field with IMRT techniques. Dr. Lotan, any currently published trials about safety and evaluation of safely being able to deliver higher doses to the pelvis, including the nodes?

Yair Lotan: I don't know that we have a specific trial that's going to give us information. Obviously for high-risk prostate cancer, there are more extended protocols to include the pelvis. There are trials that show that chemoradiation is more effective than radiation alone, but not for more advanced disease. And I think that we're still needing additional information about the extent and safety for those patients. But again, we are talking about a unique population where we don't have a ton of data about the role for cystectomy in patients who are node positive and still have potentially persistent disease. And so a lot of the trials looking at neoadjuvant chemotherapy excluded node-positive patients, clinically node-positive patients. So it's an area that I definitely think we need more work to have a better understanding of what options are best for the patient.

Kamal Pohar: Great. So maybe I'll give a plug to the ECOG-ACRIN trial that's currently ongoing in the United States, of randomizing patients with clinical node-positive disease after chemoradiation with either complete response, partial response or stable disease, plus or minus a checkpoint inhibitor. So something we had brought up earlier about potentially is there a role for immune checkpoint inhibition? So probably an important trial in our field to really start to evaluate the role of radiation in node-positive disease. Maybe we can close on the topic of immune therapy, we brought it up. So I think that's probably a nice way to segue into, we've talked about upfront, we're in agreement that induction chemotherapy, neoadjuvant chemotherapy is important here. We've taken the view that localized therapy is something we would consider in a given patient who's had some degree of response and possibly even stable disease following induction chemotherapy, whether that be cystectomy, whether that be a staging lymphadenectomy to drive further decisions, or whether it be chemoradiation.

Well, as we continue to push additional therapies in this patient population who are very likely to die of their disease with our current paradigm, bringing on immune therapy. So we do have some trials CheckMate, IMvigor, there's the JAVELIN trial, which included node-positive patients without visceral metastases, following response to chemotherapy or stable disease and going on maintenance checkpoint inhibition therapy. Dr. Inman, since Dr. Lotan brought up this topic already to start us off with immune therapy. Where do you think the field is right now of offering immune therapy to patients post cystectomy? Where do you think we are in adding a third area of therapeutics to someone's care?

Brant Inman: It's a great question. So IMvigor010 and CheckMate 274 are the two published trials we have. One is negative for progression-free survival and overall survival. One is positive for progression-free survival, and we don't know about overall survival. And the adjudicating trial is AMBASSADOR, which we don't have the results yet. The trials are very similar and in design different agents. So I think once AMBASSADOR is publish and we have longer-term outcomes from the CheckMate study, we'll have a better feel for it.

The main difference that between those trials, the published two trials, the IMvigor and the CheckMate, is the response rate or efficacy in the control arm, which was much worse in, IMvigor than it was in CheckMate. So that is what explains the difference in efficacy and as for the other question, which is, what about for patients who have advanced disease and using maintenance avelumab, which is what the JAVELIN trial does. I think that does represent probably a standard of care now for patients who've had good results with chemotherapy, and by good results, I mean, stable disease or shrinkage of their tumors, which is a partial or complete response. I think the standard of care now is probably the addition of maintenance avelumab for a year. Whether or not that's going to pan out with longer-term follow-up, I don't know. And I certainly think we need additional studies in that space to clarify.

Kamal Pohar: Dr. Lotan, if you could comment on that for us. So if we take the view that if we have a patient who responds on imaging to induction chemotherapy, there's significant shrinkage of the nodes, or they're no longer measurable. We're talking here of the concept based on the JAVELIN trial that we will not exercise local therapy. You won't recommend radical cystectomy. You won't do radiation, but rather you'll put them on maintenance immune checkpoint inhibition. If I gave you a patient in whom you evaluated the local response as well to chemotherapy by doing by the best tools we have today, a pelvic exam under anesthesia, cytoscopy, a TURBT at that site. And you define a clinical T0 response. How do you feel about not offering local therapy based on the current data and putting the patient on a avelumab maintenance therapy without any local therapy, where do you think we are with the data for that in this patient population?

Yair Lotan: Well, I think we have to recognize the data is quite poor in all regards. I think the truth is that we know that local recurrence in patients who had previously received chemotherapy and refused, the natural history is such that up to 50% will eventually recur. Whether or not immune therapies will keep them from recurring or keep them from progressing is a separate question. The current best data is that even when you don't see anything and you resect, that quite a few of them actually have disease. Maybe 20 to 30%. And so for a younger, healthier patient, I think the best approach is to try to maximize local therapy and treat them with the hope that you're going to cure them. Because I think waiting to see if they recur systemically is likely going to be fatal for them, because if they've already had chemotherapy and they've had immune therapy, they could get Enfortumab Vedotin or one of the other treatments, but their outcome likely would be quite poor.

So I think for a younger, healthier patient, their best chance of cure still probably would be to remove the bladder. I think we need a little bit more information from biomarkers, genetic information. I think that the fact is that maybe we can identify patients who still are more likely to have residual disease and perhaps circulating tumor DNA, or some other markers will help identify which patients might even need systemic immune therapies. But these trials are going to take some years to mature and to validate. I think if you looked at just current data maximizing treatment by removing the bladder and then putting patients in immune therapy is probably their best chance for cure.

Brant Inman: One thing we should say, and I think you raised the really important point, is there is a trial IMvigor011, which is now enrolling, which is using a biomarker-driven approach for adjuvant immunotherapy. So for patients who have high risk disease, positive nodes, extensive cancer, despite neoadjuvant chemotherapy. They don't necessarily need to immediately be treated. They can be monitored with a biomarker. And when the biomarker is positive, they're now being randomized to immunotherapy or observation. And we'll find out, first, if the biomarker is really a reliable predictor of recurrence. And second, if the patient is destined to recur, does immunotherapy work in that setting? Because I think there's many reasons why we wouldn't necessarily want to be giving everybody everything, because there's cost. There's toxicity. And not everybody's benefiting. And I think that if we can use a better strategy and pick the winners and treat the winners hard, but with efficacious treatment, that's the way forward.

Kamal Pohar: Great. Well, I really appreciated the opportunity to interact with the both you, I think those are wonderful points and we look forward to the future where we can do better. Thanks very much.

Yair Lotan: Thank you.