Optimizing Surgical Options for patients with Bladder Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase 1 and Sarcoma programs. Today I'm happy to be joined by Dr. Byron Lee, a urologist in Cleveland Clinic's Glickman Urological and Kidney Institute. He's here today to talk to us about optimizing surgical management for patients with bladder cancer, so welcome, Byron.

Byron Lee, MD, PhD: Thank you. I'm really, really happy to be here, Dale.

Dale Shepard, MD, PhD: Happy to have you here. Let's start out, give us a little idea what's your role here at Cleveland Clinic?

Byron Lee, MD, PhD: Yeah, so I'm a bladder cancer specialist here in the Glickman Urological and Kidney Institute, so I see, manage, and operate on bladder cancer patients. I don't do very much of any of the other cancers, the other genitourinary cancers anymore. I've cut down my practice on kidney and testes, and mainly focusing on bladder cancer patients. I do that about two days out of the week. The other three days out of the week I'm doing research. I have a small lab at Lerner Research Institute where I investigate the genomics and epigenomics of bladder cancer and how they affect initiation, response to treatment, and progression of the disease.

Dale Shepard, MD, PhD: Excellent. We're going to primarily focus on muscle invasive bladder cancer and how we surgically manage that. Let's just start off in a very broad way because we have a lot of different types of people who might be listening in terms of their expertise. Open versus robotic surgery. Where is the field right now? Tell us a little bit about the difference between the two.

Byron Lee, MD, PhD: Yeah, so open surgery refers to making an incision in the belly. How long the incision is kind of depends on the surgeon, but it's usually a midline incision and what happens is that self-retaining retractors are placed and then the hands go inside the belly to operate. This is the traditional way that we've done it for many, many, many years. What's more recently been used is robotic surgery to remove the bladder, and the reason why this has moved towards robotics is because open surgery, for the longest time, was associated with a number of complications, especially for this patient population that we're talking about.

These are patients with multiple medical co-morbidities who have a hard time getting through surgery and recovering from surgery, and so they oftentimes get readmitted with dehydration, for example, infections, and other issues. The trend towards robotics is basically us thinking about a different way to do surgery for these patients to minimize the impact of the surgery on these patients so that they can recover more quickly. Robotic surgery basically involves making very small incisions in the belly.

These are incisions that are approximately eight to 12 millimeters or so, and there are usually about five or six of them in the belly. We do it with five here. What we do is we blow the belly up full of carbon dioxide to create working space in the belly. We fit working instruments through these small incisions, attach these instruments to a surgical robot, and the surgeon actually does not sit next to the patient, actually sits at a surgical console to manipulate these instruments to carry out the entire surgery.

Dale Shepard, MD, PhD: When you take the bladder out urine has to go somewhere. There's different ways that you can sort of divert that urine, extracorporeal, intracorporeal. Tell us a little bit about the difference.

Byron Lee, MD, PhD: Initially during the experience for robotic cystectomy, the extirpative portion was done robotically, but surgeons would make an incision just around the belly button area to do the bowel work, which is what you're referring to as the urinary diversion. What that means essentially is to take a piece of small intestine, usually the terminal ileum, isolate it away from the rest of the GI tract, reconnect the GI tract. The back end of that piece of ileum is hooked up to the ureters, which is the thin tubes that carry urine from the kidney to the bladder.

Now that they're disconnected they have to hook it up to something, so this would be the terminal ileum in this situation. Then the front end, depending on how you configure the urinary diversion is either hooked up to the urethra, which is the natural opening to the outside world, or to the surface of the skin right on the abdomen, and that type of diversion is called an ileal conduit. There's a third diversion called the Indiana Pouch, which uses a piece of large intestine as well and a continent catheterizable channel is hooked up to the skin, which you catheterize every few hours to empty the pouch of urine.

Dale Shepard, MD, PhD: All of these different surgical options, some of these patients, as you've already mentioned, they come in and may have a lot of other medical issues. How do you decide what's right for what patient?

Byron Lee, MD, PhD: It's tough, and we have a very, very long conversation with the patient. I think the biggest decision that they make with respect to surgery is the choice of urinary diversion, and there's a lot of data to suggest that whichever diversion that the patients choose is probably the right one for them. Some patients really prioritize body image, and so a neobladder is probably the right diversion for them, but they have to be dedicated to taking care of the neobladder, and that involves a number of things that we talk to the patients extensively about.

Other patients want something that's very, very simple and they don't care about body image as much, and so the ileal conduit's probably right for them. The important thing about the ileal conduit is it doesn't really limit you from all the activities that you would otherwise do anyway, and that's how we counsel the patients. Patient counseling is probably the most important part of this, and so they get a chance to decide what's best for them and then we kind of carry out whatever they want. There are some strong contra-indications for doing a continent diversion like a neobladder, which we will mention to the patient and tell them why we can't do a neobladder for them, but otherwise it's really patient choice.

Dale Shepard, MD, PhD: When we think about these, what kind of comparisons have you done between procedures on things like recurrence, either local or distant, hospital stay, complications? What does that look like?

Byron Lee, MD, PhD: Yeah, so one of the things that we really looked at in the beginning of our experience is to compare robotic surgery and open surgery. Now this has been done in the literature before in basically two randomized controlled trials. There's one randomized controlled trial at Memorial Sloan Kettering. That was published in European Urology in 2015, and they looked at basically 56 robotic cases and 62 open cases, and what they found was that the operating room time was higher for robotic cases, which is not surprising, but the estimated blood loss was much lower for the robotic series.

It didn't really change their complication rate or their hospital stay. Now when we talk about the RAZOR trial, that's a multi-center trial that involved a larger number of patients, and essentially what they found were similar things, so lower blood loss for the robotic cases, longer surgery time for the robotic cases, fewer transfusions for the robotic cases, but they did notice a slightly shorter hospital stay for the robotic group.

Now we looked at our data and we felt that it didn't really reflect our experience at all, and when we switched from open to robotic we were able to dramatically reduce complications as well, so we published our series in, I think 2020, that reflected this. Unfortunately this was a retrospective series, so again, limited by all the biases that are known and unknown to a retrospective series, but what we found was again, lower blood loss, decreased length of stay, lower complication rate. In fact early on in this experience we had a 20% lower complication rate for robotic surgery and about a 17% lower readmission rate.

Dale Shepard, MD, PhD: When we think about complications that happen and decreased complication rate, was it complications across the board? Are there particular complications that you can minimize by going with a robotic approach?

Byron Lee, MD, PhD: Yeah, I think there were complications across the board, but I can tell you the most frequent complications that we experience are kidney injury due to dehydration. That's a very common thing. Patients struggle hydrating themselves probably for the first few weeks after surgery, and so they frequently get readmitted for this reason. The other complication that we typically see after this is urinary tract infections and other infections. Now with robotic surgery, obviously you're not making a longer incision so the rate of wound complications, we barely ever see wound complications anymore actually, and urinary tract infections we typically use prophylactic antibiotics to prevent this while the ureteral stints are still in place.

Dale Shepard, MD, PhD: Are there differences in pain medication use?

Byron Lee, MD, PhD: Absolutely. It's hard to tell because during this entire era, what we've done was we've also moved to an ERAS protocol, and ERAS stands for enhanced recovery after surgery, and part of that protocol involves use of a number of non-narcotic pain medications. These are things like lidocaine patches, NSAIDs, et cetera, and so narcotic use was being minimized through other means as well, but I think the robotic surgery probably helped it.

Dale Shepard, MD, PhD: When we think about surgical approaches, what are the gaps? What are the things that as you look at how we're doing the procedures now could be improved to improve patient outcomes?

Byron Lee, MD, PhD: That's a great question, Dale. I think one of the leaps that we have made more recently was the switch from extracorporeal to intracorporeal urinary diversion. I want to spend just a couple of minutes on that. What that means is instead of making that midline incision after the extirpative portion of the procedure to do the bowel work, what we've done is moved toward doing the entire procedure robotically so the bowel work and the urinary diversion is done entirely using the surgical robot.

There's no other big incision other than extending one of the incisions a little bit just to get the specimen out. As you can imagine, you can't get a bladder and a prostate out through a 12 millimeter incision. That's just not possible, while leaving everything intact. Other than that, we've moved to this intracorporeal approach. I think it does help the patients as well. It improves their short term perioperative outcomes, okay? I think there are other exciting things that are coming in terms of surgical technique.

Surgical navigation is, for example, one of them, where AXL imaging can be overlaid upon the surgical field. I think this is coming in the near future so that we have a better understanding of areas of the cancer that we may be close to even though we may not visibly see it, and that also helps with the robot because with the robot you have to be clued into visual cues a lot. What I mean by that is you don't have any tactile feedback from moving the instruments, and what you're seeing is how the tissue deforms in relation to how hard you're pulling the tissue, for example. I think surgical navigation with enhanced imaging would be very, very helpful in these kind of scenarios where you're not exactly sure the extent of the cancer just by the deformation of the tissue.

Dale Shepard, MD, PhD: The technology is crazy these days. Of course my kids, they play video games. Is there any incorporation thing like haptics or anything to be able to actually feel what's going on in the surgical field?

Byron Lee, MD, PhD: I think that would be amazing, but I don't know anything that's kind of coming across the horizon to provide that feedback for the surgeons.

Dale Shepard, MD, PhD: When we think about the multidisciplinary nature of most cancers, one thing that seems to be always a concern is people coming in for neoadjuvant therapy before surgery. How do we make progress in that area?

Byron Lee, MD, PhD: Yeah, I mean I think having a multidisciplinary program like we have the one here is incredibly important because we're surgeons and this is our expertise here, and we can provide all the details with respect to how we're going to do the surgery to the patients. But we have some understanding, of course, in systemic therapy, before and after surgery, we know the data, but usually the medical oncologist, for example, is the best person to talk to the patient about these kind of things.

The medical oncologist, and Dr. Gupta is the one who's taking the lead here and she's done a wonderful job of this. She's broadened the number of trials, for example in the neoadjuvant space that are incredibly helpful for the patients. One of the trials, for example, looks at Enfortumab with Pembrolizumab in the setting for patients who are not eligible for Cisplatin. I think that's a patient population that's very much underserved when it comes to neoadjuvant treatment. We don't hesitate at all sending patients over to medical oncology to discuss these things because it can potentially improve their outcomes.

Dale Shepard, MD, PhD: A couple of other areas, the first not necessarily straight up surgical, non-muscle invasive bladder cancer, of course, is the bulk of bladder cancer. I guess what's the current state of things in terms of it got hit really hard with shortages of BCG?

Byron Lee, MD, PhD: Yeah.

Dale Shepard, MD, PhD: Where are we now and how do we get around these sorts of things? It seems like such a crazy thing to have essentially treatment stop in the way that it did.

Byron Lee, MD, PhD: Yeah, I'm fighting that battle right now, Dale, and it's incredibly tough to fight. BCG shortage has been a real struggle with us. What's problematic is the supply is uneven. What that means is that I can't predict what's going to happen next month, the month after that, and while our patient population with non-muscle invasive bladder cancer continues to grow, I can't tell them for certain "you're going to get the treatment that you need for the kind of cancer that you have." BCG's been around for I don't know, 40, 50 years now. It's probably still the best drug. It's the very first immunotherapy, I think, for cancer, and it's the best drug for intermediate high risk non-muscle invasive bladder cancer, which the bulk of our bladder cancer patients have.

MB Anderson published a recent series on it, an updated series on it and how BCG works and it's just amazing. These patients do incredibly well after BCG, but we're having a shortage and so we have to find different ways to overcome that. One obviously, Merck is increasing the supply for BCG. Other things that we are doing are trying to predict how patients respond to BCG. Why is this important? Well, there are certain patients with just some kind of intrinsic resistant, their tumors have some kind of intrinsic resistance to BCG, and potentially those patients will be better served either with a different medication or if they are high risk, maybe with a cystectomy, for example.

We also have to find other ways to augment BCG response, especially in those patients who are recurring after BCG so that maybe we can identify a compound or drug target that would say, "Hey, look, you had BCG, but the cancer's coming back. You would otherwise be in a BCG refractory state, but adding this to BCG would again, make BCG useful in you." Patients who are in the BCG refractory state, there are a number of different compounds in this area that are just coming online. We're all very excited about that. That's a whole other podcast in itself, I'm sure. I'm not going to talk too much about that. The future is bright in this field, but we got to get beyond this.

Dale Shepard, MD, PhD: Traditionally surgery for muscle invasive bladder cancer, back to that, would be radical cystectomy. Tell me a little bit about thoughts in terms of bladder preservation and where the field is in that particular area.

Byron Lee, MD, PhD: Yeah. This is a great, great topic, Dale, and as you and I both know, a lot of cancer care is risk stratification and tailoring our approach to the patient. Probably the biggest experience on bladder preservation, the way it's done now, which is trimodality therapy, the combination of radical TURBT, transurethral resection of the bladder tumor, with concurrent chemotherapy and radiation that's provided by medical oncology and radiation oncology. The way it's practiced now the best data probably come from Massachusetts General Hospital, and they published this in 2017.

The bottom line from this study is that if you select the patients very, very carefully, their outcomes are almost equivalent to cystectomy, and they get to keep their bladders, which patients, they love that. Nobody wants to lose their bladder to bladder cancer, I can tell you that. I mean, it's a big deal to patients, not only just going through the surgery, but you know, it's a life changing thing. They're different for the rest of their lives. Now there are a number of trials that are ongoing and coming online that combine different types of systemic therapy in an effort to improve the outcomes for trimodality therapy, and those are all very exciting.

One, there's immunotherapy in the space now, and another trial is looking at a TROP2 inhibitor, Sacituzumab, in combination with chemo and radiation. I'm anxiously awaiting the results of these trials as well and I find them to be very exciting. One way that we're thinking about doing bladder sparing here at Cleveland Clinic is to kind of update the experience with something called partial cystectomy. Now for a long time, partial cystectomy has been kind of derided as an inferior oncologic control operation for patients with muscle invasive bladder cancer, but I got to tell you, Dale, most of the studies were published in an era where neoadjuvant chemotherapy wasn't routinely used.

In fact, there were not some of these newer agents that we use for neoadjuvant treatment as well. The other thing that's changed significantly over time is surgical technique, for example robotic technique. There are other things that have changed, like the use of Cysview, for example, to augment cystoscopy to detect more bladder tumors or smaller bladder tumors that would otherwise escape and cause a local recurrence. I think what we're trying to do now is to put together a concept as to how to investigate partial cystectomy in this new era and add it to all the options that the patients can choose for bladder sparing.

Dale Shepard, MD, PhD: That sounds pretty promising, and I guess since we have an opportunity to pick your brain as a urologist for bladder cancer and surgical approaches, last thing I'm going to ask about from that standpoint would be there are other tumors, colon cancers and prostate cancer or some consideration and as you just said, losing your bladder's a big deal. But what's the current thinking about resection of the bladder in the studying of metastatic disease, so resecting the primary?

Byron Lee, MD, PhD: Yeah, great question, Dale. I think controlling the primary, in our setting, is incredibly important. One of the biggest things that patients come back to the hospital for is gross hematuria, renal failure. Even if it does nothing in terms of improving their cancer control outcomes, this is a big palliative portion of what we do as surgeons. You know, we've had patients where they just couldn't receive any more systemic treatment because they were bleeding through treatment, and we would help them by going in and resecting everything as much as we could so that we can get everything clean, they're not bleeding, so they can continue to have their systemic treatment which they would otherwise not be getting. That's our main role in this situation, but I think it's incredibly helpful for these patients.

Dale Shepard, MD, PhD: Well, you've given us some great insight in a number of areas of surgical management of bladder cancer, and we appreciate you joining us today.

Byron Lee, MD, PhD: Thank you, Dale. Really appreciate that opportunity to share our thoughts.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

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