Patrick Hensley: Hello, and welcome to the UroToday coverage of the International Bladder Cancer Group Bladder Cancer Forum at the AUA 2022 in New Orleans. I'm Patrick Hensley. I'm a urologic oncology fellow at the University of Texas MD Anderson Cancer Center, and today we'll be discussing the role of risk-stratified neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer who are undergoing radical cystectomy. I have two esteemed colleagues and guests with us today, Dr. Arlene Siefker-Radtke, Professor of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center, and Dr. Shilpa Gupta, Associate Professor of Genitourinary Medical Oncology at the Cleveland Clinic in Cleveland, Ohio. Dr. Siefker-Radtke, Dr. Gupta, thank you for joining us, and welcome.

Arlene Siefker-Radtke: Thank you for having us.

Shilpa Gupta: Thank you for having us.

Patrick Hensley: I'd like to kick off the discussion with a short case vignette to set the stage for the discussion. We have a 65-year-old otherwise healthy female who is diagnosed with a three-centimeter clinical stage T2 muscle-invasive bladder cancer. On review of the pathology specimen, there's no adverse histologic features, including lymphovascular invasion, variant histology. Clinical T2, small completely resected muscle-invasive bladder tumor referred to your clinic to discuss the role of neoadjuvant chemotherapy. Dr. Siefker-Radtke, I'd like to start with you. If you could, talk to us a little bit about the rationale for upfront surgery in such a low-risk patient and some of the data to support that rationale and that approach.

Arlene Siefker-Radtke: Sure. Thank you so much, Patrick. As we all know, systemic chemotherapy can be very challenging for bladder cancer patients to receive. It can lead to long-term side effects like peripheral neuropathy, heart disease, which can occur long-term, hypertension, which can occur in the setting of cisplatin. In fact, over half of patients with bladder tumors are not even candidates for the current standard of care cisplatin-based chemotherapy due to poor kidney function. Chemotherapy is challenging, and if we can spare people the side effects of chemotherapy, I think we are doing them a wonderful thing.

At MD Anderson, for several decades, we've been using a high-risk, low-risk approach. This approach has been able to help us select for patients at highest risk of extra organ extension. When we use these risk factors, which include lymphovascular invasion, a three-dimensional mass on exam under anesthesia, variant histology, such as micropapillary and small cell histology, or hydronephrosis. When we have patients with these criteria who go to initial surgery, we see upstaging in over 80% of patients, but when these factors are absent, we find that we can take patients to upfront surgery and spare over half of them the riggers of systemic chemotherapy.

Now the challenge of course is always the risk for upstaging, but what we've observed is when we have a patient who's upstaged at the time of surgery, we would then give them adjuvant chemotherapy with similar survival outcomes. This technique was explored on a clinical trial that was run by Dr. Randy Millikan back in the day, and published in the Journal of Clinical Oncology, showing that whether we gave chemotherapy preoperatively or post-surgery in this high-risk cohort, we saw a similar survival fraction. I think the ability to spare patients the toxicity of chemotherapy and especially the long-term side effects of therapy is a wonderful thing to do.

Patrick Hensley: Absolutely. Thank you for your insight. I'll turn to Dr. Gupta. If you would please, indulge us on the indication for upfront neoadjuvant chemotherapy as a standard of care for all patients with muscle-invasive bladder cancer.

Shilpa Gupta: Yeah. I agree with Arlene. If we can spare patients chemotherapy, we should. I think in the current standard of care, we don't have the tools which can tell us for sure what is the risk of upstaging or not. The imaging is subpar at best, and if we have more precision-based approaches using subtyping models and then decide whether chemotherapy will be useful or not. These are all exploratory at this point. I think the point is well taken that chemotherapy's hard, but if a patient needs it in the adjuvant setting, it's as hard. In fact, sometimes postoperatively patients are not in a state to get chemotherapy for whatever reason, or they may be too frail, and before surgery, they are probably fitter.

That's the rationale for doing upfront, but I think this is where the use of novel biomarkers comes in. Dr. [inaudible 00:05:01] is leading a trial through the Alliance where he's using the molecular correlates to see if some patients can actually be spared surgery or if they have those DDR alterations and respond to chemo, but chemo is still the integral part of this. We also saw that in the CheckMate 274 trial patients got nivolumab and that's now approved because it improved disease re-survival. However, patients who had prior neoadjuvant chemotherapy and still had residual disease were the ones who benefited most. I think this really needs more investigation, and the goal should be to offer as less therapy as possible. In the current standard of care, I would say it's still recommended.

Patrick Hensley: Absolutely. In the [inaudible 00:05:50] SWOG trial published by Dr. Grossman in 2003, the data indicated that the patients with clinical T3B disease benefited the most from neoadjuvant chemotherapy, while the clinical T2 patients benefited relatively less. Do you see that our current inability to accurately clinically stage patients in terms of TUR by manual examination, current imaging modalities, the inaccuracies of our clinical staging system, does that limit our ability to more broadly implement a risk-stratified approach? I'll start with Dr. Siefker Radtke.

Arlene Siefker-Radtke: Well, that is the greatest challenge that we face, Patrick. Clearly, the tools that we have to accurately stage patients are completely inadequate for telling us what the final stage will be at surgery. With each approach, whether it's chemotherapy first versus surgery first, there's risk for each. We have patients who have chemotherapy and don't make it to surgery. They have a heart attack or some other serious life-threatening infection that takes time for them to recover. With the initial surgery approach, we have patients who have positive margins at surgery or don't recover well from surgery to receive that adjuvant treatment, which is why risk stratification is absolutely needed. The current factors that we use, really, I'd like to see much better factors. Use of imaging could be very helpful if we could accurately estimate a true stage two versus stage three or greater tumor since it really is that T3B stage three disease that has the highest rates of progression and relapse with surgery alone.

Yet even with the current staging modalities, including MRI, there appear to be some inadequacies. We don't have good validation sets. Does an MRI scan adequately predict whether that patient is truly muscle invasive, superficial, or extending beyond the wall of the bladder? I think as a urologist and a medical oncologist, we've all had patients where post-TUR they have a scan and you'd bet a paycheck that there's tumor there, but then when you repeat a scan six weeks later, you see all of that inflammation has resolved and all of that thickening has gone away, and the TUR from the specimen actually showed no tumor. We are limited in our abilities to adequately stage and accurately predict that pathologic stage and really do the best job selecting the correct patient for the correct treatment. We need more work.

Patrick Hensley: Absolutely. I'll ask the same question to Dr. Gupta. What do you think are the biggest limitations in our current staging modalities, and maybe you could shed some light and on how patients are adequately worked up in stage at Cleveland Clinic, for example, in a multidisciplinary fashion.

Shilpa Gupta: Yeah. I agree with Arlene. We don't have adequate tools. We are using the same tools we've been using for so many decades, and the risk of upstaging is the biggest disservice that we can do to a patient. We need better imaging modalities. Like in prostate cancer, now we have PSMA PET. Hopefully, we'll have something like that in bladder, and I think there's an unmet need to integrate biomarkers with imaging to develop signatures as to what's the probability this patient may have upstaging or not sure. Until we get there, I think we have to deal with what we have and make the best decisions for the patient. We typically use a CT or an MRI for our patients for staging workup, and we have several trials in the perioperative space, including both for cisplatin eligible and cisplatin ineligible patients with immunotherapy antibody, drug conjugates, which we try to enroll patients on. I would like to obviously see more patients getting some kind of perioperative therapy, which currently is not the case at our institution. I don't know how it is, Arlene, in your experience.

Arlene Siefker-Radtke: Well, it all depends on the patients who are referred, their risk factors, whether they can tolerate chemotherapy or not. We have patients who come in who clearly need chemotherapy, but unfortunately, their physical condition is such that we fear they won't be able to handle both chemotherapy and surgery. At the moment, surgery still has a cure fraction, even in that cohort of patients. Chemotherapy alone does not. We do have patients who are very frail, indeed. They can get an operation. Not necessarily two things with the addition of chemotherapy, but what the field really needs is what if we had a treatment that was tolerable at 100% of patients and cured 100% of patients, or as Shilpa even mentioned, now we no longer need to do a cystectomy. Well, that would be a beautiful thing. I think in that event, we'd probably all be out of a job. They'd be doing this at Walmart.

Patrick Hensley: That's right.

Arlene Siefker-Radtke: We're working toward that. That's a lofty goal, and I hope to push myself into retirement by achieving that.

Patrick Hensley: Dr. Gupta, you mentioned a couple times biomarkers. There's a push to use biomarkers as an adjunct to associate platinum sensitivity or chemo-sensitivity in a broader sense to the clinical factors that Dr. Siefker Radtke has mentioned. Where do you see DNA damage response, gene alterations, molecular subtyping, these type of genetic biomarkers playing a role moving forward into our ability to triage patients for upfront chemotherapy or even post-cystectomy recurrence chemotherapy?

Shilpa Gupta: Yeah. We've learned from Dr. Plimack's work about these DNA-altered tumors that respond better to cisplatin, and the Alliance trial is selecting patients based on that to minimize the risk of poor selection. We have that trial open. We find not a lot of patients obviously have that, so it's still an unmet need to develop more comprehensive biomarkers, and subtyping, I think, is really an interesting area, although it's not really being applied prime time, but in SWOG, they're now going to lead a trial called the Subtype Study based on the subtypes patients may get, FGFR inhibitor or chemotherapy or immunotherapy. I think that is the way to move forward. Until then, even if we see the subtyping report, we are not changing our standard of care, but it's a good step in the right direction.

Patrick Hensley: Absolutely. That step towards personalized, tumor-specific biology-driven care. Dr. Siefker Radtke, how do you foresee in the next five, 10 years implementing some of these biomarkers into your practice?

Arlene Siefker-Radtke: Well, biomarkers, I think, are going to play a growing role. As Shilpa mentioned, we now have targeted therapies for FGFR three alterations. There are a lot of other trials studying novel agents in the setting of alternate mutations, looking at DDR, DNA mismatch repair genes. Can we start predicting patients who benefit from chemo? Maybe we can even avoid surgery in some of those patients, but it really will take a personalized approach. As a result of personalization, we will need large cooperative groups who are able to do these trials and enroll the number of patients in each type of subtype and mutation to really validate this work. It really does require that validation, whether it's validation of MRI imaging, validation of the use of FGF, validation of the use of a biomarker subtype to predict who needs treatment and who does not. There's a lot of work for us in our future and for a lot of other young investigators like yourself, Patrick.

Patrick Hensley: Absolutely. The last thing I'd like to discuss is the role of variant histologic differentiation and chemo-sensitivity, and specifically in the neoadjuvant setting. Dr. Gupta, maybe we'll start with you. How in your practice ... do you have any anecdotes in terms of platinum sensitivity for various subtypes of variant histologic differentiation? It seems like in our retrospective series that we rely heavily on, they are lumped in one umbrella category as variant histology. Well, we know that there's a very disparate biology when you look at the various subtypes, so how do you manage those in your practice and where do you think the data is leading towards chemo-sensitivity in the various subtypes?

Shilpa Gupta: Yeah, that's a great question. I wish we did trials which are more inclusive. Currently, you'll see trials limiting the percent of variant histology variants. If a patient has 52% variant, they can't really go on their routine trials. I think we need to be more open-minded with these newer novel drug therapy trials, and in my experience, patients who have variant histology, they really benefit from the chemotherapy, immunotherapy combination trials. We've seen that, but unfortunately, when we put a cut-off of so much percent, which really is not based on great science, in my opinion, we are not able to explore. Then we keep doing the same thing that we study in the trials, pure histologies but try to apply that data in the real world to patients with variant histology. I think we need to have more inclusive trials because if anything, patients with variant histology are the ones who need more of these novel combinations because chemotherapy alone is not going to be the answer for that.

Patrick Hensley: Sure. Dr. Siefker Radtke, any comments on inherent chemo-sensitivity to varying histology? Is the data compelling? Do we need more fleshed-out studies? How do you manage those patients?

Arlene Siefker-Radtke: Well, our current strategy of using that percent is really quite antiquated. We did a mapping study. This was done by Bogdan Czerniak at MD Anderson, where he looked at micropapillary patients, took pieces of tissue from the micropapillary component, microdissected the areas that were urothelial cancer. We all say, oh, the percent matters, but what he found is even in the plain old urothelial cancer compartment, by gene expression, it most closely resembled that micropapillary subtype. We've also seen neuroendocrine tumors. They respond very well to chemotherapy and should receive a neoadjuvant small cell treatment approach. Yet we can see a similar marker pattern in a group of patients without small cell features. Variants, perhaps, present extremes in subtype. We see patients who have the molecular changes consistent with what is seen in variants, but we do not see that variant histology.

I think we really need that personalized strategy where we enroll all patients on these trials, allow the subtypes to tell us where they're going to go. Will they respond to immunotherapy? Do they respond to chemotherapy? At the moment, I do believe small cell tumors need more of that small cell type therapy. The bladder treatments or typical urothelial cancer treatments appear inadequate, but for the other subtypes, I think they should be combined together. I think we will find there are some that respond better to chemotherapy like the SWOG inter-group data, where they looked at mixed histology with squamous and adenocarcinomas. Actually, it appeared that group appeared to be doing better in the neoadjuvant setting.

As we start lumping all variant histologies as bad histology, there are actually some that might be in the chemosensitive group, such as variant mixed urothelial with adenocarcinoma, mixed urothelial with squamous tumors, I think the small cell phenotype needs more of a small cell therapy, and at the moment we still don't know what to do with those mixed micropapillary sarcomatoid and plasmacytoid, but we start seeing patterns. CDH1 mutations and deletions in plasmacytoid, HER2 expression in micropapillary. We might find that these variants are actually the groups who need a particular treatment.

Patrick Hensley: Absolutely. As we conclude, I just want to give you each the opportunity to provide some pearls of wisdom and maybe a call to action where you think this field is going in terms of a risk-stratified approach to systemic therapy and timing of surgery and how that fits in. Dr. Gupta, I'll start with you.

Shilpa Gupta: I think we need what we have, iSpy, in breast cancer. We need that for bladder cancer. You can't do trials that take years and years to enroll, and then when the answer finally comes, it's probably an outdated treatment. We need something based on quick turnouts of pathologic response rates and then move forward in a larger trial. If breast cancer can do it, we can do it in bladder cancer too. I think Arlene has said so many times, it's molecularly driven disease, but we are still using the same old chemotherapy for everybody, and I think we need to move away from that approach.

Patrick Hensley: Thank you. Any closing remarks, Dr. Siefker-Radtke?

Arlene Siefker-Radtke: Well, I think it's becoming clear that bladder cancer is no longer just one disease. It's actually composed of multiple diseases. As we gain the ability to tease out those multiple differences and the ability to target each, that's when we are going to see the true extension of life and long-term benefit for our bladder cancer patients.

Patrick Hensley: Well, thank you both very much for your time, Dr. Shilpa Gupta, Cleveland Clinic, Dr. Arlene Siefker-Radtke, MD Anderson. Thank you for your time and your expertise and your words of wisdom, and thank you for joining us for our ongoing coverage of the International Bladder Cancer Group, Bladder Cancer Forum at the AUA 2022.