This transcript has been edited for clarity.
Cheryl Lee, MD: Welcome to Medscape InDiscussion. I'm Dr Cheryl Lee, and today we'll be discussing a topic related to bladder cancer, which is very important to urologic oncologists, medical oncologists, and even radiation oncologists. It's about the sequencing and timing of treatment options. Over the past 20 years, our field has really evolved. I think about the considerations we have now for multidisciplinary approaches to treating patients. It's so much more comprehensive than what we've had in the past, particularly for those patients with high-risk disease. The explosion of new systemic drugs over the past 5-10 years has really solidified this kind of multidisciplinary care for high-risk patients, particularly those with muscle-invasive disease. I think we're probably going to confine most of our comments to that setting today. Overall, the issue of timing, and sequencing of treatments and therapies, has become even more important in that context.
How much does sequencing really affect outcomes? What should we be thinking of in terms of treatment timing as it relates to radical surgery or definitive chemoradiation? For expert guidance on these questions, we've invited Dr Matthew Galsky. He's a professor of medicine in hematology and medical oncology, and director of the Genitourinary Medical Oncology Service, at the Tisch Cancer Institute at Mount Sinai in New York City. He also co-directs the Center of Excellence for Bladder Cancer and acts as the associate director for translational research at the Tisch Cancer Institute, again at Mount Sinai in New York City. Welcome, Matt. I'm really excited that you were able to join us today.
Matthew D. Galsky, MD: Thank you, Cheryl. It's my pleasure to be here.
Lee: Before we jump into our main discussion, I'm sure our audience would be interested to learn more about your background. What motivated you to become a physician scientist and devote your career to the subspecialty of bladder cancer? I'm curious about what drove you to focus your research in the area that you have been in, thinking about response and resistance to different novel agents for this disease. It's quite a balancing act: teaching, research, clinical practice. Just wondering how you got involved in this area.
Galsky: I didn't have one of those lightning-bolt moments like a lot of people describe. But during my residency training in internal medicine, I was really drawn to the field of oncology. There were some excellent role models where I trained, and I really felt comfortable with the mix of longitudinal patient care. The emerging science at the time was incredibly exciting. This was a time when signal transduction within cancer cells was really being understood at a different level and exploited in terms of treatment; that was really intriguing to me. I think that's what really led me to pursue oncology. It felt right. I liked caring for patients, getting to know patients/families, and having that longitudinal relationship — mixing cutting-edge science with patient care.
When I started my fellowship in oncology, that's really when I started to think more about genitourinary oncology. Honestly, that was based purely on mentors in the field. I had no particular interest in a certain tumor type before fellowship. It's really the mentors to whom I was exposed, people that you know well — Dean Bajorin, Howard Scher, Kevin Kelly — who exposed me to the field of clinical investigation, and it really solidified my interest in pursuing work in bladder cancer.
Lee: Well, I'm not surprised that with exposure to those giants in genitourinary oncology, you developed an interest in this disease. They're also some folks that I had the great opportunity to work with when I was a fellow at Memorial [Sloan Kettering] many years ago. Within the past decade and a half, bladder cancer treatment has expanded enormously. This includes not only changes in chemotherapy but also immunotherapy, targeted therapies, and other agents. For context, I'm wondering if you could describe your typical approach to new patients with muscle-invasive bladder cancer. Are there any general principles to consider in terms of the timing of treatment to optimize patient outcomes, particularly with this growth in the field and these various systemic agents that we have the opportunities to use?
Galsky: Muscle-invasive bladder cancer is one of the more complex treatment-decision algorithms that I encounter in daily practice, especially when I think about when I was treating patients with other types of cancers. As you know, the treatments that we use with curative intent for muscle-invasive bladder cancer are sometimes associated with a significant treatment-related burden. At the same time, our patient population is one that is often older, with the median age at diagnosis of bladder cancer in the United States in the mid-to-late 70s, and often has morbidities related to their risk factors for bladder cancer — smoking-related comorbidities, not uncommonly. We have to consider these treatments that can be curative but are not without their downside in a patient population that is more at risk for harm, and that creates this really delicate balance.
The first thing that I think about is what we're trying to achieve. If we're trying to achieve cure, then can we achieve cure in a way that minimizes the risk for harm for a patient and tries to maximize the quality of time that they have after the treatment is done. That really is a balance between age, comorbidities, support system, organ function, kidney function — which plays a key role in what we do in terms of systemic treatment for muscle-invasive bladder cancer — and then pairing that with what is most important to an individual patient.
Lee: Maybe I'll approach this as a urologic oncologist when thinking about the patient that I see who comes in and we're having some of those complex decisions. As I talk to someone about surgery — having that be part of the foundation of their care — we start thinking about perioperative chemotherapy, generally in the neoadjuvant sense. That's not always feasible for some with renal insufficiency, some with neuropathy, hearing loss, etc. Maybe we'll start by focusing on that neoadjuvant context and thinking about it from the standpoint of the patient who's cisplatin-eligible vs cisplatin-ineligible. When you see a patient being considered for neoadjuvant treatment, how are you approaching it from that framework?
Galsky: I think you really hit the nail on the head in terms of one of the key considerations — once we move past understanding what's really important to an individual patient and what treatment modality they're willing to undergo, because sometimes someone will come in and right away say, "I'm not having X or Y." Of course, you want to seek to better understand why that is the case, but sometimes that's the case; there's no getting around it and that's what the individual has decided. Once we move beyond that, we really start to think about whether someone can safely receive cisplatin-based neoadjuvant chemotherapy, someone with muscle-invasive bladder cancer. Because if they can, then I certainly encourage that treatment path. I think that when we look at the evidence, we have level 1 evidence from two randomized trials to support a survival benefit with that approach. We can certainly talk about this in more detail, but I don't try to dissect that data in a way that the trials weren't meant to. In other words, I don't think about whether it's a pure T2 tumor or some other clinical criteria to stratify patients, because I don't know that we're that good at determining clinical stage in the first place. If there is someone with clinically localized muscle-invasive bladder cancer who has decided that surgery is the backbone of local curative treatment for them and they are cisplatin-eligible, then I will recommend cisplatin-based neoadjuvant chemotherapy.
Galsky: I don't. I think with some of the recent data that have emerged, maybe I'm a little bit less picky about that. Some of my colleagues have bought into the results of the VESPER trial and really identified that as the final piece of evidence that we should be giving dose-dense MVAC to everyone who can tolerate it. I think there are certain limitations to that study in terms of extrapolation, the way that the chemotherapy was administered, the number of cycles. I still don't think it answers the question definitively, so I see those regimens as probably more similar than different. If it's a younger patient who wants to get treatment done quicker, I have no problems giving dose-dense MVAC, but I don't think it's the regimen that has to be given to everyone.
Lee: For the patient who is cisplatin-ineligible, for many of us on the side of urologic oncology, the issue of primary cystectomy is something that we would talk to patients about in great detail. Is there a role for immunotherapy?
Galsky: Great question. We have many phase 2 studies with neoadjuvant immunotherapy — either single-agent or combination immunotherapy in cisplatin-ineligible patients with muscle-invasive bladder cancer — pretty consistently showing pathologic complete response rates that are competitive with what's been achieved with chemotherapy in the past. That's compelling data, but we need randomized, phase 3 studies to ultimately change practice to show that not only is this intermediate endpoint improved, but patients are living longer and better. Those trials are ongoing now. In fact, those trials are taking longer than was expected, based on the accrual to phase 2 studies in the setting. It's always somewhat harder to randomize, particularly in this setting, to surgery alone vs a neoadjuvant treatment followed by surgery — two pretty disparate treatment paths. So, randomization can sometimes be difficult to swallow, but I think these studies are some of the most important clinical trials in the field of bladder cancer right now. This is really trying to develop a neoadjuvant paradigm where none currently exists. That's a long-winded answer to your question that right now there's not a defined role, but there are very compelling phase 2 data that mean we really need to get the phase 3 studies completed to answer that question.
Lee: I think the interesting part of it, too — even as you think about the phase 3 study — is that we're no longer in a space where surgery is done in isolation. We're looking at neoadjuvant plus surgery vs surgery plus an adjuvant potentially, so that complicates things even further. But I'm excited that we keep extending survival in all of these settings. So, let's say we're moving forward with primary cystectomy. For our patients with clear pathologic demonstration of muscle-invasive disease, perhaps perivesical disease, maybe even N1 disease, what are the opportunities for them at that point?
Galsky: I think that's where the most important data have emerged in the past couple of years. Now we have randomized phase 3 data showing that in a patient like that, who hasn't received neoadjuvant chemotherapy, who has residual pathologic stage T3 or higher or node-positive disease, adjuvant immune checkpoint blockade and adjuvant PD1 blockade significantly improve disease-free survival compared with surgery alone, with a hazard ratio of 0.7. It's not an insignificant benefit. Again, in a scenario in which we didn't have perioperative treatments in the past, that would be a standard consideration these days.
Lee: How long do we expect a patient to be treated with adjuvant therapy in that setting? This is a question that patients are very concerned about. There's this period after surgery when they're recovering — so they've felt the intensity of treatment and recovery — and now they're about to jump into systemic therapy. How long do you tell patients that they're likely to be on adjuvant treatment?
Galsky: I don't take that consideration lightly at all. This is a tremendous burden of treatment that we impose on patients in hoping to cure their bladder cancer. The adjuvant treatment duration in the current generation of immune checkpoint blockade trials has been 1 year of treatment. It's 1 year of treatment because that's how the trials were designed, because we've had difficulty completing adjuvant studies in bladder cancer historically in the first place. Just completing these studies has been an accomplishment. So, trying to think about studies where one had multiple arms with different treatment durations — which would have been ideal — is something that would have been difficult to consider when these studies were designed. Ultimately, we don't know the optimal duration of adjuvant immune checkpoint blockade. It's something that could be sorted out in future clinical trials.
Lee: One of the things we used to always be concerned about in the delivery of adjuvant therapy was the reality check that radical cystectomy is associated with a high rate of postoperative complications. In roughly one third of the patients whom we wanted to treat with adjuvant therapy, they couldn't receive it either because of the complications or because their performance status had declined. What do you think about the issue of postoperative complications and the ability for patients to still be eligible for adjuvant treatments?
Galsky: That is certainly one of the arguments for a neoadjuvant approach, among others. I do think that the introduction of adjuvant immune checkpoint blockade doesn't mitigate those considerations entirely, by any means. But we do think about starting adjuvant immune checkpoint blockade in a patient in whom we might have been a little more hesitant to do so with adjuvant cisplatin-based chemotherapy — for instance, someone whose renal function is borderline and is still sort of improving since surgery. That's a patient who can receive adjuvant immune checkpoint blockade whom we might have had to hold off or not give any adjuvant treatment to in the past.
Lee: I know we're spending a lot of time talking about the perioperative period, but what also happens for these individuals over time, of course, especially in those first couple of years, is that they can experience a recurrence and a distant recurrence. I'm curious about your thoughts for such a patient. Let's say it's someone who has a history of neoadjuvant cisplatin-based chemotherapy, has surgery, and 18 months later they develop a resectable lung nodule — a 2-cm peripheral lung nodule. What is your approach, then, to this patient with metastatic disease? How are we thinking about the sequencing of different agents based on the patient's response?
Galsky: Historically, we've used a little bit of a line in the sand from perioperative treatment to recurrence of 12 months, and it's arbitrary. There are some data to suggest that maybe outcomes are different in those scenarios. But generally, we've used that line in the sand for consideration of whether we should treat someone again with platinum-based chemotherapy or whether we should move on to second-line treatment. In a patient like that, there are a number of considerations that come up. If it's truly oligometastatic disease and it's resectable, then one option, of course, is to treat that surgically or to treat that site with radiation. I actually have a very similar situation with a patient I'm treating now, in whom, based on some of the clinical characteristics, we proceeded with radiation to the solitary metastatic recurrence but had given a couple of cycles of immune checkpoint blockade prior to radiation — to get a sense of whether immune checkpoint blockade as a systemic strategy was going to prove beneficial and should be continued for a period of time after. That's the sequencing that was pursued in that particular patient. Oligometastatic recurrence is not the most common in this disease, but it certainly does occur sometimes.
Lee: Patients are living longer on immune checkpoint blockers, so for the patient who then recurs or progresses on immunotherapy, what is your approach in that individual? I know we have a number of agents in this space even now.
Galsky: We now have a few treatments that are FDA-approved in that particular setting. The choice of the next treatment is informed, in part, by molecular testing. We now have the first targeted therapy in urothelial cancer, based on a recurrent somatic mutation, and that is mutations in fibroblast growth factor receptor 3 — FGFR3. So, that patient certainly should have genomic sequencing done, and if there is an FGFR3 alteration present, then one consideration as a next step would be a small-molecule inhibitor of FGFR3 — erdafitinib, which is orally administered, so a pill. The other option is enfortumab vedotin — an antibody-drug conjugate. Both of those treatments could be considered in that context. Which one to use first? We don't really have great data on the sequencing of those treatments, but it's somewhat driven by patient preference. Whether proceeding with a pill is something that they want to do after having received intravenous treatment previously — it's somewhat dependent on side effects related to prior treatments, in terms of trying to ensure that the next treatment is not going to exacerbate those side effects.
Lee: Well, Matt, this has been an excellent overview of how to think about the timing, particularly around surgery, of using these different systemic agents. I know we're almost out of time, but before we wrap up, is there anything you want to pass along to our listeners?
Galsky: In terms of sequencing of treatments in the perioperative setting, there are new tools that are emerging. You're going to speak more about this in another episode. There are new tools emerging that are going to be paradigm-shifting in this space — specifically, circulating tumor DNA testing — to try to identify who needs treatment in this context. The challenge in the perioperative setting is that unlike in the metastatic setting, where arguably all of our patients need systemic treatment — whether they benefit from it is, unfortunately, a different story — in the perioperative setting, we actually don't know who needs treatment. So we apply these treatments broadly, with the goal being to help a subset of patients. If we can identify who needs treatment, we could employ these treatments in a much more rational way.
Lee: Well, I think what I've taken away from this discussion is that cisplatin-based chemotherapy still is our standard. Also, we have a lot of novel agents that are building upon what we've learned with the use of systemic chemotherapy, and these are being used in the neoadjuvant, adjuvant, and metastatic settings. I'm excited to hear that we're embarking on molecularly guided therapy and greater precision therapy for our patients. Lastly, the multidisciplinary nature of our field is becoming much more comprehensive, not only in the context of localized disease but also in the metastatic setting, as we consider what to do with isolated metastasis or even at the primary site.
I want to thank you again, Matt. I really appreciate you joining us today. We certainly look forward to further discussions on bladder cancer. Thanks for listening. I'm Cheryl Lee for Medscape InDiscussion.
Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial
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Cite this: How to Optimize Treatment Timing in Bladder Cancer - Medscape - Jul 06, 2022.