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Ashish Kamat: Welcome. I have the pleasure of having a good friend and a leader in bladder cancer here with us today, Dr. Brant Inman. He is Associate Professor of Urology and Co-Director of the Prostate and Urology Cancer Center at Duke University in the US. Welcome, Brant.

Brant Inman: Thank you, Ashish.

Ashish Kamat: Brant, we had an excellent session here at the EAU, and you were an integral part of it. One of the topics that we touched upon was the role of the surgeon in the management of locally advanced and metastatic bladder cancer. Can you elucidate a little bit more of your thoughts and comments from that session and more for our audience?

Brant Inman: Yeah. Our discussion centered around the role of surgery in the management of patients with metastatic disease. Generally, patients with metastatic disease are managed with systemic therapies. Chemotherapy, and now immunotherapies. The role of surgery has sometimes been underplayed or forgotten. I think the purpose of the debate was to highlight that, in fact, surgery does have a role, and in select patients, it can be curative. In fact, with a much higher cure rate than you would expect from systemic therapies. I think the trick there is who? Who benefits? How do you select? That's what we were trying to discuss, is when is it relevant and indicated, and when is it best not done.

Ashish Kamat: Correct. Right. Let's take this patient that presents to you with lymph node-positive disease. Bladder cancer, muscle invasive, imaging shows a puffed lymph node, that you biopsy and is positive. What is your treatment paradigm for these patients that have, say, pelvic lymph nodes and maybe also a lymph node right by the common iliac muscles?

Brant Inman: Yeah. For us, the first question is are they a candidate for cystectomy? If the patient is healthy enough to undergo a cystectomy, and this is the only site of disease, basically pelvic disease, our approach generally is we consider this patient potentially curable until proven otherwise. For us, we typically would manage this patient with neoadjuvant chemotherapy. The flavor of which might vary. In a younger, healthier patient, we tend to use dose-dense MVAC. In an older, sicker patient, we might use gem cis. Typically, we would give probably three cycles, reimage. If we see progression of disease, so worsening new nodes, growth of existing nodes, then generally those patients are probably not best served by surgery. But in patients who see responses, shrinkage of the nodes or disappearance, we might actually continue to six cycles at that point, and then consolidate with surgery. Those patients, in our experience, are potentially curable, whereas if you don't remove those tumors, very few of those patients will be cured. The role of cystectomy with extended nodes and resection of the nodal burden that you saw in the imaging I think probably represents the patients best opportunity for cure, so multimodal management.

It is possible, also, to use radiation in those settings, although I think the data's much less clear because not as many places have experience with managing those. I think surgery probably remains the modality with which there's the largest evidence for node-positive disease.

Ashish Kamat: Right, and that's been my bias with these patients, too, because clearing out the nodal burden clearly can get some patients to be cured. I'm curious as to your thoughts on imaging. You mentioned imaging. What do you think is the role of say PET imaging in these patients?

Brant Inman: Yeah, actually we've been very impressed with PET CT. We don't do PET alone but always fused with CT, so that we have anatomic imaging, as well. We use in almost all patients with muscle invasive disease, that's how we stage them. If they've already been staged with multiple imaging already with bone, lung, and abdominal imaging, then I probably wouldn't repeat a PET. But in patients who've only had an abdominal CT, which is very common, I'll stage the lung, bone and restage the abdomen with PET. It's actually surprising how frequent you'll find a small nodal disease on a PET that you just wouldn't have appreciated well, particularly in the retroperitoneum on regular imaging. We do use PET scan, and I think it increases the sensitivity for metastatic disease.

Ashish Kamat: You mentioned the retroperitoneum, so let's move to the scenario where you have a patient that has similar nodal burden in the pelvis, and then has skip legions up in the retroperitoneum up close to the hilum of the kidneys, in that nodal area. When you give these patients chemotherapy, let's assume he or she responds well, and these nodes shrink dramatically and the PET CT converts. There is a body of evidence that suggests that leaving those nodes alone also is sufficient treatment.

Brant Inman: Mm-hmm.

Ashish Kamat: There's a body of evidence that suggests you should do full RPLND. What's your thought about those two ...

Brant Inman: Yeah. Well, I'm generally less enthusiastic about the role of surgery in curing people who have disease in more than one compartment. For example, isolated disease in the pelvis, to me, is different than pelvic plus retroperitoneum. Now we have two compartments, two anatomical areas. Similarly, if you had pelvic disease and something in the neck or in the chest, we tend to view those patients as having much poorer results, so I'm less enthusiastic. That being said, in patients who are relatively young and fit, we would generally, if we're going to go to cystectomy and there was retroperitoneal disease, we would probably counsel the patient that it's reasonable to consider. The morbidity of these operations is not small because your incision is much larger now, and these nodes are in my experience after chemo, especially in the retroperitoneum, it could be just like testicular cancer, fairly fibrotic and stuck to the vessels. There's a higher risk of complications and it takes time. This surgery, a cystectomy that might take you three or four hours is now turning into a six or seven-hour operation. That's important consideration, especially in the elderly.

For the younger, fitter patients, we tend to take the approach of resecting those. But I'll tell you that, in my experience, there's not great evidence that suggests benefit. The more disease you have, the higher disease burden, the less likely surgery is that to cure.

Ashish Kamat: Right. Another scenario that often faces members of our audience that are viewing this is a patient that has metastatic disease, gets chemotherapy, has a nice complete response. Let's assume it's one or two areas in the lung, maybe a few lymph nodes in the retroperitoneum, and then, of course, the bladder itself with the tumor. This patient now has a 6 to 12-month window, where the metastatic burden is quiet. Then, the patient comes to you and says, "Doc, should I have my bladder taken out?" What is your thought process and counseling process there?

Brant Inman: That particular patient is tricky because you're talking about a patient who now has disease in the chest, the retroperitoneum, and the pelvis, so three compartments are involved. For me, those patients rarely benefit from surgery unless their bladder function is poor. For example, if they have obstructed hydronephrosis, so there's a quality of life issue. They're leaving with stents or PCNs, or they're bleeding. That might be a patient in which we would perform cystectomy in the absence of resecting metastatic disease, so more for palliation. In that setting, we'd be more likely to use radiation, if the bladder function was good. If the bladder function was poor, we'd be more likely to use surgery. That's a very different scenario to us than in the context of where you have solitary metachronous metastases. For example, for someone who has a cystectomy, and then 9, 12, 24 months later has now a new solitary lung legion. We worry usually pretty significantly about it being a second primary lung tumor because smoking is obviously the cause of both of those cancers, or the dominant cause anyway, so we generally biopsy. If it's not a lung carcinoma, and it's a bladder carcinoma, and it's limited, we do consider resecting metastases.

We talked about in the session site is important. The best responses are seen in lymph node only and lung metastases, better when solitary. Okay if one or two, but not generally very effective if there's five or six. Worse for brain, but still kind of in the intermediate range. Then, the worst outcomes are for bone and liver. We generally don't resect bone. We would generally eradiate solitary bony metastases in bladder cancer. We generally, also, with liver would use ablation or radiation. But for lung, and nodes, and brain ... Brain could be either or, but lung and nodes often will be using surgery in those setting because the outcomes are very good. The median survival with solitary lung metastasis for bladder is somewhere in the range of four years, and that's much better than any systemic therapy can give I think.

Ashish Kamat: All right. Right, and you mentioned brain. Fortunately, brain is rare, but when it occurs, you should always think about small cell carcinoma.

Brant Inman: Yes.

Ashish Kamat: That's just a little snippet for our audience. Do you think that the immune-oncology era with checkpoint inhibition is going to change your thinking about the role of surgery in metastatic disease?

Brant Inman: Yeah, it's changing the way I think about surgery as a treatment for cancer. The ideal scenario for an immunotherapy is to have a source of antigen present in the patient while that immunotherapy is being given. In surgery, once we've removed the cancer, the bulk of the source of the antigen against which we are trying to immunize the patient is gone. I think that the ideal role for immunotherapy is prior to removal of an organ because you have an optimal situation there to sensitize the patient to the antigens that the tumor has. I also think that the way we treat the tumor might change. Rather than remove a mass, it might be better to make it die on the vine. As it's dying, it's releasing a lot of important factors that might additionally sensitize the patient and essentially immunize them. We're really interested in this concept at Duke, and we're working on a number of new ways of getting rid of tumors without surgery. I don't know if long ...

Certainly, for large masses this is unlikely to get rid of the mass, but for smaller tumors ... For example, you can imagine a scenario in the bladder where you have a two-centimeter muscle invasive tumor, and certainly a non-muscle invasive disease. Where if you had a method of making that tumor go away slowly over time, dying or wilting, and as it's dying and wilting, the immune system is there and it's unleashed because now you're using either a checkpoint inhibitor or a checkpoint stimulator, one of the two, to sort of favor a productive immune response. I think in that context you have the best chance possible for durable long term cures. I think of the treatment of cancer as having two components. One, getting rid of the cancer you have, and two, preventing the recurrence that you might get in the future. Knowing the timing I think is what's going to be important here. I'm actually very excited about the concept of neoadjuvant checkpoint inhibitors. You were one of the early ones to do this with CTLA4, a more toxic agent for sure. But I think the concept is there, and it makes a lot of sense to do it prior rather than after you've removed a mass, I think.

Ashish Kamat: Yeah, absolutely. You raise some really great points. We could go on chatting about this forever, but I think we'll have to call it a close. Thank you very much for taking the time. It's always a pleasure chatting with you, Brant.

Brant Inman: Okay, great.