Ashish Kamat: Welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from MD Anderson Cancer Center in Houston. Today it's my distinct pleasure to welcome Neema Navai, who is an Associate Professor in the Department of Urology here at MD Anderson Cancer Center. Neema is a good friend, a colleague, and a true rising star in many aspects of urologic oncology. But one particular thing that he has focused a lot of attention and detail on is consolidation surgery, and consolidation therapy, for patients who have metastatic, minimally or otherwise, bladder cancer. So really excited to hear what you have to say today, Neema, and thanks for taking the time and joining us today.

Neema Navai: Yeah. Thank you, Ashish. It's my distinct pleasure to be invited. I really look forward to bringing some, hopefully, clarity to a topic that I think is sorely needing it. Thank you to the group at UroToday for extending this invitation.

As you know, we've worked together for a number of years, and I've been fortunate enough to learn from your mentorship, and try to apply that, as I onboarded as a faculty at MD Anderson. One of the places where I found my intellect drawn, to identify a new avenue of research potential in the bladder cancer world, was this area of minimally metastatic and metastatic bladder cancer, and where we can apply surgical therapy, in particular, for that patient population. I think to set the stage, I'm going to go through, briefly, a patient scenario, because I think it really illustrates the dilemma.

In my practice, I had a 61-year-old, extremely healthy woman, who had no prior smoking history. To no fault of her own, she had developed a really bad, an aggressive bladder cancer. At the time of diagnosis, she was found to have a very concerning lymph node in the pelvis, almost two centimeters in size, and by all measures, was deemed clinically lymph node-positive. For this bladder cancer, she was originally told by an outside institution that she essentially had an incurable disease, and they could prolong her life potentially with chemotherapy. That would be their main driver and treatment planning.

Well, she clearly wanted to get additional information. She came and saw our group. I found it a very challenging discussion because, there are some assumptions and arguments of the rationale for when we would include surgery and the treatment plan for this type of patient. But a lot of it really is based on minimally informative or incomplete data. What we think we know is that limited pelvic nodal disease may be cured with surgery with the addition of chemotherapy, but that's been largely driven by patients who are found to have node-positive disease at the time of surgery but did not have a concern for node-positive disease before they got to the operating room.

We also suspect that surgery in the setting of clinically node-positive disease, so that would fit the story of our patient, should only really be reserved for those patients where the chemotherapy renders them a complete responder. The question there is whether or not the surgery actually augments their cure rate, or if the chemotherapy has done all of the heavy lifting. On the heels of that, those with a pathologic complete response rate, so they had the surgery and there's no residual disease, they have exceptional survival. But that doesn't tell us that surgery was actually an important part of their therapeutic plan.

The last dogmatic statement is that consolidation in the setting of residual disease does not benefit a patient. I would argue that there is perhaps some rationale to suggest that that's not true, and similar to the way we treat chemo-resistant testicular cancer, there may actually be a role in curing limited local chemoresistant disease.

Some data that's recently come to light that helps inform this topic came from two large population-based studies published in JCO in 2016. what they found were patients that had cystectomy in their treatment plan, that initially presented with pelvic nodal disease, did better than those patients who did not have surgery as their treatment plan. So cystectomy was an improvement over chemotherapy alone. In patients with metastatic disease, that same survival advantage was seen with high-intensity local therapy, which broadened the consolidation to include high-intensity radiation therapy.

It was modest, but nevertheless, it was an important early signal. We've looked to try to find data that supports refining the selection criteria for these patients. There was another population study that published on the SEER data set for clinically node-positive patients, that similarly found, when you include radical cystectomy in the treatment plan, as opposed to chemotherapy alone, there is a survival advantage.

Our group then started to publish on this topic. We found what we suspected was a unique phenotype within this population. That was those patients with only single sites of metastasis. This was a relatively small study, although many of the studies in this space are. These patients had majority retroperitoneal nodal disease, so not local metastatic disease, but regional metastatic disease; they underwent consolidated therapy. Those patients had only had a single site of metastatic disease. Their survival was significantly better, and there were some longterm survivors, as compared to those that had multiple sites of metastatic disease.

We also look to see if there was a benefit in examining the response to chemotherapy in these patients prior to surgery. Clearly those that had a complete response, or at the very least a partial response, fared better than those that only had stable disease.

Our current knowledge has been looked at in a robust systematic review published by our group. What we find here is a very common thread which is, longterm survivals in this group hover right around the 35% range. This may give us a clue as to the impact of both systemic therapy, as well as surgical therapy. We've taken it a step further and examined a robust population of patients at MD Anderson. Our group has done both the clinical study and the translational study in this space to identify those patients that are likely to benefit and helping us inform selection criteria moving forward for definitive clinical trial.

In our study, we looked at over 130 patients, some of whom had preoperative biopsies. In those patients that did have biopsy-proven lymph node-positive disease, what we find is about 35% of those will be rendered to have a complete pathologic response at the time of radical cystectomy. Interestingly in this study, what we find is that those who did have a biopsy and the biopsy was negative, the rates of pathologic complete response are largely similar. Except for the scenario where the patient does not have a biopsy, and they're rendered clinically node-positive by imaging alone. You see an enrichment for pathologic complete responses, largely owed to likely overstaging.

How do these patients fare? Well, again, pathology is the driver. If they've had a complete response to their systemic therapy, and all disease is eradicated to at least nonmuscle-invasive or lower, they have excellent long-term survival. These are patients with metastatic disease into lymph nodes, and we're seeing survival above 85%. Unfortunately, those patients that have residual disease, especially in the lymph nodes, do very poorly.

Our translational component in this study looked at whether or not there were biological signatures of chemotherapy response in the lymph node, different than looking at biological response within the bladder. What we found is a clear dichotomization for those patients that are complete responders, versus not. We look forward to informing future definitive trials based on this work.

On the heels of that, we've been working with a cooperative group, SWOG, to develop a clinical trial, which hopefully will get through their robust selection criteria for trials and be activated. This would be a randomized trial to examine patients that initially present with lymph node-positive disease, and then randomize those patients with partial responses or stable disease, to either include radical cystectomy, or go onto observation or second-line therapy, and ensuring that we're not avoiding potentially curative therapy in those who have robust responses. All patients with a complete response would undergo surgical consolidation.

Our patient, fortunately, did quite well after chemotherapy and was able to move forward with her surgery. She did have a complete response in her lymph node, but not in her bladder. She had residual muscle-invasive disease in the bladder. She's a year and a half out from surgery and currently without evidence of disease, and our fingers are crossed that she has a different outcome than what we've seen in some of our retrospective work.

In conclusion, I would draw your attention to that the role of surgery in clinically node-positive bladder cancer remains unproven, despite robust practice patterns that do include it in the treatment plan. Persistent post-chemotherapy nodal disease is a clear red flag, and lower burdens of disease tend to fare better. The clinical response of a patient may be informative, but there's more work to be done there. Hopefully, biomarkers of the underlying biology will help inform when, and how, we should include surgical consolidation in this patient population.

Obviously, thank you to our many patients who are included in these trials, as well as the robust research group, and my colleagues, Dr. Kamat and Dr. Dinney, and our wonderful group of PAs, who've helped take care of these patients as well.

Ashish Kamat: Great. Thank you so much, Neema. That was a really concise and precise summation of the topic. If I could ask you a couple of questions. When we face these patients in our clinic, for example, how would you recommend we counsel these patients that have minimal burden of metastatic disease? What do you say to the patients?

Neema Navai: Yeah, I think it's an extremely challenging conversation. Because obviously from a patient perspective, they're looking for the home run cure. I think the truth is we just don't know. I suspect that one of the largest drivers is their response to chemotherapy. The way I approach that conversation is, that in the paradigm of treatment, clearly they need to start with systemic therapy, and that's going to help us tailor the next step. If they have a really robust clinical response to their systemic therapy, I do think that there are a large number of longterm survivors in that patient population. But we need to see that first before we start having the conversation around surgery.

Ashish Kamat: You've done a lot of work in imaging, and are leading some studies looking at MRI and others with staging. How do you incorporate that, and/or other modalities such as PET in your decision making and in counseling of patients?

Neema Navai: Yeah. I think it's a really important tool in many circumstances because as you know, many times the potential for metastatic disease is not clearly evident. You might have a marginally enlarged lymph node in the pelvis that's not amenable to a biopsy. In those circumstances, I think before you assume that a patient must be notably metastatic, it can be helpful to use PET imaging. I think PET imaging for the primary tumors is clearly not helpful, but for nodal disease, it can be helpful in certain circumstances.

MRI is another one. There is slightly better data than CT imaging, as far as nodal staging with MRI, as opposed to CT imaging, so that can be a useful tool. I do use them in very select circumstances, but I don't use them across the board in all of these patients. I do try, however, to get node biopsies whenever possible.

Ashish Kamat: Do you have a selection criterion based on what you would say, select a patient to get PET imaging, or MRI, or standard CT urograms?

Neema Navai: Yeah, absolutely. For me, in my practice, what I found is those patients that have two centimeters or greater lymph nodes in the landing zone for bladder cancer are usually sufficient to call based on imaging alone. If they're between one and two centimeters and not amenable to a biopsy, that's usually where I would include PET imaging or MRI imaging potentially to augment my clinical decision making.

Ashish Kamat: Yeah. My practice is quite similar as you know. If somebody has metastatic disease, node-positive disease, and has an apparent good response to chemotherapy, but the nodes haven't shrunk, I've oftentimes relied on PET imaging to help clarify that situation. What's your practice? Do you go with PET? Do you do biopsies? Do you do both?

Neema Navai: Yeah. I think it's an excellent clinical scenario that you bring up, which is the dilemma after systemic therapy. Many times, and we found this actually in our cohort, not all patients that have a pathologic complete response have a radiographic complete response. And it just may be that their lymph node is not going to shrink, despite the disease being eliminated. If possible, I do actually prefer getting tissue. A repeat nodal biopsy, if it hasn't been done, or a nodal biopsy at the time of decision making for surgery after systemic therapy. But that's also a great time to use PET if needed. I do worry a little bit about the smaller lymph nodes though, where PET imaging just may not have the resolution you need to clarify it. I think we have a pretty similar practice pattern there, but I would try to get biopsies in many of those cases.

Ashish Kamat: A few more questions, if you would. With JAVELIN being reported recently, and the maintenance therapy with IOs, if somebody responds to chemotherapy and presents in your clinic and says, "Hey, Dr. Navai, I've responded to the chemotherapy. Initially, we planned to do surgery as consolidative therapy, but I've heard about the study that looks at IO, and does maintenance therapy, now that I've responded. Which one is better?" How would you address that question?

Neema Navai: I'd call an audible, it's a tough one. I think the jury's out still, to some degree, and the inclusion of surgery is really the jury's out in that setting. There are some very limited data in the breast cancer world that suggests that surgical consolidation or local definitive therapy may actually be harmful in nodal metastatic disease when it comes to IO responses. There's not really any data that suggests that that's true in the bladder cancer world, but that does worry me to some degree. As far as the continuation of maintenance therapy after surgical consolidation, I think we just don't know enough yet.

Ashish Kamat: Okay, very valid points. Just switching gears for the last question, what's your approach towards frank metastatic disease, if it's oligometastatic?

Neema Navai: The data out there really suggests these patients have poor survival. Because of that, we've been really hesitant to offer surgical consolidation in those patients, outside of very unique, durable, complete responses to systemic therapy. And that has happened. I've had a couple of patients where they presented with distant visceral metastatic disease. They had a complete response to systemic therapy, and maintained a complete response for many months, and then had a local-only recurrence. They had an invasive recurrence in the bladder and remained without evidence of disease distantly. In those patients, I have offered radical cystectomy, but it's very, very few and far between.

Ashish Kamat: Do you go after those metastatic sites? Do you have a selection criteria for the patients for surgical consolidation, now say a solitary lung nodule or liver mets?

Neema Navai: Yeah. There is some data on method cystectomy and actually our group has published on it previously. I think if it is oligometastatic in a surgically amenable site, it can be consolidated surgically. Usually, that's going to be lung, it's probably the most common distance site where that comes up. But again, these are pretty rare scenarios and I think you do have to bring the disease under control systemically first.

Ashish Kamat: Right. Exactly. I think nowadays with so many choices for our patients when it comes to consolidative immunotherapy after chemotherapy, and surgery, and cryo, and what have you; hopefully the needle is moving forward in the right direction.

Neema Navai: Absolutely.

Ashish Kamat: Neema, obviously this has been a wonderful discussion and I have so many questions I could chat with you about. I'm sure we'll do it offline. But in the interest of time, if I could ask you to share some closing thoughts with our audience?

Neema Navai: Yeah, absolutely. I think the one thing that I would love to emphasize is that this disease state is not a death sentence. There's actually a remarkable, sizable minority. About 35% of patients that present with metastatic bladder cancer, especially those that have node-only metastatic disease, are likely to become long-term survivors with the right combination of therapy, which would include systemic therapy and potentially surgical consolidation. I hope that we get enough advocates out there to inform the definitive trial so that we can actually test whether or not we need to do the surgery in these patients.

Lastly, my sincere hope is that we'll have better biomarkers that will inform the future direction for bladder cancer care across all stages but most particularly in the patients with node metastatic disease.

Ashish Kamat: Yeah, no, I agree 100%. The trial needs to be done and should be done, and best of luck to you in that endeavor. Once again, thank you so much for taking the time to be part of this really important educational activity. Neema, stay safe, and stay well.

Neema Navai: Yeah, you as well. Thank you so much for the opportunity. It's been a pleasure.