Neha Vapiwala: Hello.
Antoine van der Heijden: Thank you.
Neha Vapiwala: Thank you for having us.
Ashish Kamat: At this year's EAU, we do our rapid-fire debate, which is very well received, but I think one of the highlights, one of the most eagerly anticipated debates, and I say debate, even though we're all friends, because we fashioned it as a debate, was this debate between the two stalwarts on either side, the two of you, one championing that urologists should and do manage a lot of complications from radiation therapy, but pointing that out. And then one on the other side, and it's obvious who had which side, saying, "Well, yes, we appreciate the urologist managing the toxicity, but we as rad oncs also recognize that we should be part of this whole patient journey." It was a great debate, and I said it was a debate, but the two of you were really on the same side. Let's launch that discussion, and at the end of it, I'd love to have a nice little chat with you. Dr. van der Heijden, you're first.
Antoine van der Heijden: Thank you, Ashish, for this kind invitation. At EAU, we were discussing radiation toxicity because it's real. And my title was urologists manage the consequences and what's afterwards. My take-home message at EAU. Complications of bladder irradiation are GU, and they are managed by the urologist. And radiation toxicity actually is clinically a significant problem. It's often irreversible and frequently managed by a urologist and making it a key factor in both patient counseling and treatment selection and not an afterthought. And that's a clear message. What is the downside of radiotherapy? Radiotherapy gives an impaired tissue healing. The latency period is up to 30 years, and the improved cancer survival which we currently have results in more late side effects. The late side effects have a major impact on the quality of life of patients. And especially radiotherapy of the lower abdomen and the pelvis gives GU and GI complications. If we look at the complications here in RAIDER trial, you see that the complications, the incidence of GI complication, is low.
The grade-2-to-3 complications are 5% to 10%, whereas the GU complications also fairly low, about 10% to 15% in grades two to four. Complication incidence is low, but the impact for patients might be very high. What are the radiotherapy induced GU complications? The most common are radiation cystitis, strictures, and fistulas. Very a bit less seen are secondary malignancies. And less common are erectile dysfunction, lower urinary tract dysfunction, bladder fibrosis, and osteonecrosis. And I only want to highlight radiation cystitis because radiation cystitis is the most often seen complication is in about 5% to 10% of patients. Acute radiocystitis is self-limiting in three months and is normally treated with anticholinergics. Chronic radiation cystitis is something different. The main symptom is hematuria. Hematuria and clots. And chronic radiation cystitis is treated by urologists. You see a brief summation of the treatment of chronic radiation cystitis. We have the conservative treatment that's supportive or the bladder irrigation. The first line is to rinse the bladder. The second line is hyperbaric oxygen or formalin or embolization, and the third line is urinary diversion and cystectomy or nephrostomy tubes.
And actually, the third line is obviously done by urologists. Urologists play a central role in both the diagnosis and the treatment of radiation toxicity and complications. My question is, how can urologists and radiation oncologists work better together? Neha, I want to invite you to respond on that.
Neha Vapiwala: Well, thank you, Toine, for really setting the stage so nicely. And thank you, Ashish and the UroToday team for having us back for this very important conversation and really recapping what was, I think, an important and well-received discussion at the EAU meeting this year. Again, my take on this, and I think we all can agree, toxicity does happen, but it's manageable, and radiation oncologists can and should take responsibility. In honor of my surgical oncology friends and colleagues, I want to start with this brilliant quote from the late surgical oncologist, the great Dr. Blake Cady, reminding us that biology is king. Selection of cases is queen. And then our treatments, our surgeries, and our radiation treatments are ultimately the prince and princess here that play a role. And for bladder cancer patients, very much represent true victories in the sense that they represent options for patients who might be eligible for these treatments. But at the end of the day, I would argue that in many cases, it is the king and queen that prevail and that often drive the decision-making, not just for cancer outcomes, but I might argue biology and patient selection also are critical when it comes to treatment complications.
By that, the then extension is, how do we predict better for these treatment complications? That's the holy grail we all seek. I will say age and comorbidities, which matter in the radical cystectomy population, are an even bigger issue, typically, in the radiotherapy population, as these patients are often older and have more comorbidities. A key prerequisite for bladder preservation is good bladder function. And I say good in air quotes because we often need to establish that. Who's determining that? Is it based on patient-reported outcomes? Is extensive urodynamic evaluation performed in all of these patients to really establish that it is, in fact, a bladder worth preserving and not one that will be prone towards longer-term complications? There's obviously a very hot topic right now as well about the role of maximal transurethral resection, and is that always necessary in every case? Might there be patients for whom perhaps this isn't needed, and then that extra instrumentation could be avoided to the extent that that might at any point contribute to longer-term bladder complications? And then really trying to better understand and get at the underlying bladder physiology or, in some cases, pathophysiology.
When you think about that patient that has a long history of bladder outlet obstruction or benign prostatic hypertrophy and increased intravesical pressure over time, what that does to the detrusor muscle and some of the irreversible changes morphologically, the accumulation of collagen over time, and that potential risk for fibrosis, which you then add on potential other factors such as history of stroke, diabetes, just regular aging, and then of course the role of radiotherapy and contributing to the fibrosis, and you can almost create this perfect storm. Perhaps we can do a better job of predicting this and optimizing it. What else can radiation oncologists do, though, to really change the curve on this and think about the biology and predicting this ahead of time? We have elegant work done by colleagues, and this is just one example, of how we might actually use a patient's blood sample and do simple irradiation of the blood sample to establish the rate of radiation-induced lymphocyte apoptosis with some data suggesting that there's an inverse correlation between lymphocyte death that's seen from irradiating this blood sample and the risk that that patient carries of developing late complications, in particular, related to fibrosis. Maybe this is the kind of thing that could be done preemptively to predict for a patient's suitability for, say, a course of bladder preservation.
There's also incredibly important work being done in the prostate cancer space, and this is just another example. This is a very resource-intensive project in which colleagues collected not only serum, urine, and fecal biomarkers before, during, and after a course of radiation therapy for prostate cancer, but they also follow these patients well beyond the completion of their treatment and have patient-reported outcomes all along the way. And what we're learning from some of this preliminary work, and of course this does need to be further validated, is that for patients receiving pelvic radiotherapy, whether it's for prostate cancer, bladder cancer, or other genitourinary malignancies, there can be a central role of a lot of these inflammatory markers, macrophage polarization and other biomarkers, that we could be assessing that might predict for that patient's likelihood of developing longer-term complications. And this might allow for mitigating efforts during treatment as well as extra efforts perhaps after treatment to try and change that natural course and to try and reduce the severity, if not the incidence, of complications. And then when we think about radiation-related complications, at the end of the day, we know that dose and volume absolutely matter.
What received radiation? How much of it received radiation? And this is where all of our technological advances in radiotherapy really come to bear. Adaptive radiotherapy. MRI guidance. Shrinking those margins. But there's more to it than just the technology. We also have to think about the patient as they're getting ready and preparing for a course of bladder preservation. Are they optimized in terms of those comorbidities I mentioned earlier? What's their fitness and nutritional status? What's their cardiovascular health and potential for going on anticoagulants, which of course then can increase the risk of hematuria and many other complications? And what type of psychosocial support are they receiving throughout all of this so that they can be in optimal health? Have they quit smoking, if that's a factor? Again, all of these are factors that radiation oncologists can and should be assessing for and trying to optimize. And then, honestly, the elephant in the room is continuing to follow these patients is critical. We're not going to know about the complications if we're not involved in their care. And there are a lot of post-trial modality therapy bladder preservation guideline recommendations, and a lot of them are fairly standard. How do we move towards a personalized risk-based approach that takes into account some of the factors I just mentioned?
For a given patient who's more versus less at risk for long-term complications, maybe we allocate our resources accordingly and do more frequent versus less frequent surveillance. Use non-invasive means optimizing imaging, particularly MRI, to try and avoid extra instrumentation. And then, of course, predictive molecular biomarkers absolutely can be a critical part of not just looking for cancer recurrence, but perhaps monitoring patients before they reach a state of emergency and end up in Toine's office. And there are examples of multidisciplinary pelvic radiotherapy symptom management clinics that we can follow. At the end of the day, we are here as radiation oncologists to work as part of a team, and we want to always continue to improve the therapeutic index, but we absolutely need our help and need our assistance from our urologic friends. We cannot do this without you. It is important that, as a specialty, we continue to work with you to better understand the biology of these complications, refine patient selection, as Dr. Cady would have us do, continue to improve treatment tolerability by predicting and modifying therapy as needed, following patients more closely and taking responsibility and accountability there, and communicating.
All of us need to communicate better with each other, collaborate, and leverage our respective expertise, so we can really find that optimal balance of responsibility across our specialties from every step, diagnosis through survivorship. And I really want to just echo I think what has already been said, which is that we want to work together and not be in our silos. And that, of course, is the best way to improve patient care. Thank you for having me, and look forward to our discussion.
Ashish Kamat: That was great, both of you. And thank you again for taking the time to put together such thoughtful commentary on the topic. I mean, clearly, obviously when the topic was assigned to you, it was intended to be a debate, but like I said, it's not really a debate. We all do this for our patients, we all work together, but we often will hear from individuals, and sometimes it's individuals with the loudest voice, the strongest social media presence, that will often try to pit one discipline against the other. I mean, whether it's medical oncology versus radiation, whether it's rad oncs versus urologists, et cetera, et cetera. What is your answer to folks that say, "Well, we shouldn't be doing bladder preservation because, if you do bladder preservation, then it's going to only increase the burden on the patient and the urology community,"? Let me put that to you, Toine. What's your recommendation or answer to that question?
Antoine van der Heijden: I think there's a greater interest for trimodal therapy in bladder preservation, and that's due to the impact on the quality of life of patients. For the Netherlands, for example, it was 15 years ago it was 5% to 10%. And if you look now, it's 25% to 30%, and it's still increasing. That has a reason. Because patients do want to keep their bladder. And if you look at the RAIDER trial, the complication rate at the RAIDER trial, it's really low. You have to see 5% to 15% grade-2-to-4 GU-GI complications. If we look at the complications of a radical cystectomy, for example, that is much more and higher complication rate than trimodal therapy. But the thing is, when a patient has a complication, it is very often the urologists that manage it because the patient comes for the regular cystoscopies, for example.
After trimodal therapy, in our clinic, it's normal that urology just follows the patients up for two years every three months with cystoscopy and CT scan every six months. We are the first doctor the patient faces. In that sense, it's also quite logical that we manage the complications. But I think due to that greater interest for trimodal therapy, and it are sometimes not the so ideal patients that we treat. Before, we had a very cut schedule, patient with a very small tumor, TA, no hydronephrosis, no CIS, et cetera, et cetera. But the boundaries are getting wider and wider. Now, it's T3. Maybe small T4A tumor. Patients with unilateral hydronephrosis are accepted. CIS is accepted when it's adjacent to the tumor, but it must not be too extensively. And then my question raised is, what is too extensively? I don't know. We have to be careful that when we treat more patients with trimodal therapy, we will see more complications, so we have to very carefully select those patients and to inform them what might happen. And in that sense, the urologist and radiation oncologists should work together.
Ashish Kamat: I think that's a great point. And I'm going to ask you to comment on that a little bit because one of the things that we have done through the IVCG, and this was at the last year's retreat which, again, you are going to be at this year, is to focus on patient-reported outcomes and patient-reported toxicity from different measurements and actually come up and derive specific toxicity measurement tools for intravesical therapy, for radical cystectomy, obviously for TMT, or even if it's just XRT. But along those lines, one of the things that we heard from patient advocates that are always present is, "Well, which physician am I going to see? I don't want to see both. I mean, if I have to, I will, but if I have to see five different people in follow-up, it's just going to ruin my whole week." From your perspective, again, having done this in multiple arenas, what's your take-home message to your rad-onc colleagues as to counseling patients when they're discussing TMT for bladder cancer? The follow-up schedule? What's your general feel there?
Neha Vapiwala: Sure. No, thank you for that question. And I just want to say I couldn't agree more with Toine's comments earlier as well about just the fact that that teamwork and the reality that typically, of course, our urologic colleagues are the first, usually, to see patients and diagnose them and then provide that initial consultation on everything from what the diagnosis means, what the prognosis may be, and then what the treatment options are, that having that balanced consideration, and ideally in a multidisciplinary tumor board format, when the decision is made, I think radiation oncologists ... Again, every time we encounter our patients, we need to drive home the point that you are being taken care of by a team and not only a team within the radiation oncology department where we have expertise from medical physics. We have PhD-level colleagues that are taking care of the actual treatment machines and monitoring, of course, the accuracy of the treatments we're delivering and helping us develop the plans.
We have, of course, our nursing team. And similarly, we will continue to always confer with our urologic colleagues because, at the end of the day, it's your training and your expertise in urologic issues that we will call upon to help in the care of the patient. And as early and as often as the patient can hear that message and understand we're not doing redundant appointments to make your life difficult, and we're not going to make you visit people unnecessarily, but when we do share your, let's say, ongoing cystoscopic surveillance or when we do decide to keep you seeing your urologist, and we'll alternate blood work and other responsibilities of who's ordering, that there's a thoughtfulness to it, that the patient understands the reason for it. And I would just say, again, to the extent that Toine's earlier comment, which is so true, that we will need to, for those that then go on to have complications, either predictable or unpredictable, the same way in which you in a post-cystectomy setting might have some perioperative complication and might call on the cardiologist or might call on the pulmonologist for assistance with any sort of post-op or perioperative complications, is how we view hopefully our positive relationship and ability to call on our urologic colleagues. That doesn't excuse taking patients who are not a good fit and giving them treatment.
That doesn't excuse poorly rendered treatment. But I'd like to think that those of us who are in this field and in this specialty more than ever are committed to not just offering it to the wrong patient or expanding beyond the appropriate indications. And as long as we're selecting appropriately, having those conversations in a multidisciplinary setting, agreeing that this is an approach that is reasonable for this patient, getting back to patient selection, and counseling the patient that complications may happen, and if so, these are the individuals that would be helping to monitor and treat, then hopefully there isn't a sense of, "Oh, you didn't tell the patient what to expect," and now I'm having to come in and clean up. I think that's where I want to change the narrative and not have it seem like something that we sprung on people, that we sprung it on the patient, or that we sprung it on you. I would like to think it should never be taken that way.
Ashish Kamat: And again, very well articulated by both of you. I think what we all agree on is that we are advocating for the patient, right? And in some ways, everyone here and most of our colleagues are in the same boat. Having talked to folks in the field, either obviously before, during, and after the debate and hearing our online conversations, too, I sense that some of the frustration from the urology side has stemmed from, at least people what have reported is that when the patients are being counseled by our rad-onc colleagues, not everybody is as upfront as you are, maybe, Neha, with telling the patient that there can be complications. And I think from a patient advocacy perspective, what our advocates are saying is, "Please tell us all the complications, whether it's radical cystectomy, BCG, whether it's just putting in a stent. Or if it's TMT, just tell us the complications. Don't try to sugarcoat anything and then have your colleague, in this case, the urologist, be the one to break us the bad news."
And that's what all three of us believe in, but I think that's the message that we as a community need to be sending out. We are in it for the patient. We are in it. If TMT is best for the patient, that's what we would recommend. This is such an interesting and hot topic. We could go on forever, but in the interest of time, I'm going to close it out. Toine, let me give you a final statement, and then we'll let Neha close it off for us.
Antoine van der Heijden: I think the only thing I want to add is that I think it would be wise when urologists also see how radiation oncologists counsel patients and see what they tell them so that we both know what has been said. And it's the same for radiation oncologists. Go with your urologist, and see how patients for a radical cystectomy are being counseled, what we tell the patients, what they can expect, et cetera, et cetera. I think that would be very, very helpful.
Ashish Kamat: We do that here as part of our fellowship program. Many years ago when I was the program director, we initiated that our urologic oncology fellows spend some time with their rad-oncs, and we've asked the rad-oncs to send some of their residents to spend time with us, and those that are bladder focused clearly do. Absolutely agree with that. Neha, last word to you.
Neha Vapiwala: I 100% echo that suggestion of that cross-pollination and cross-training, and that can happen at any point in your career. I'd like to think there's that open door on both sides. Getting back to that patient focus that we, I think, are all really keeping front and center of our conversation, I think we can also, at this point in time, leverage all of the wonderful tools, including what's coming out in AI in terms of patient education. And for a given patient who might learn more visually or who might learn better from written materials, we should be leveraging those opportunities to explain not just that complications happen, but to help provide perspective that maybe this is a rare complication, but if it does happen, it can be severe, and these are the consequences. But at the same time, it's relatively rare. Here's the more common complications.
And whether it's through visual aids, or whether it's through auditory or other forms of learning, I think this is an exciting time for us to all be leveraging those tools so that patients can walk away, particularly those who really have no medical background whatsoever, so that they're not leaving our offices scared and terrified unnecessarily, but they are leaving well-informed with perspective that's honest, that's truthful, that's based on the best available data we have. And this is where my final statement would be. I think real-world data do matter to complement our wonderful clinical trial data, which is, let's face it, a very controlled and special environment and not always reflective. I'd love to partner across the GU world to really say there's what's happening in clinical trials, there's what's published, and there's the reality, and how do we make sure that all of this is presented to patients in a digestible way that's informative but not meant to be choose me versus choose them? That's what we have to get away from.
Ashish Kamat: Absolutely. Thank you both. Always a pleasure.
Neha Vapiwala: Thank you for having.
Antoine van der Heijden: Thank you.