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Ashish Kamat: Hello everyone. And welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology and Cancer Research at MD Anderson Cancer Center in Houston, Texas. And it is my pleasure to welcome today a who's who cadre of superstars when it comes to bladder cancer. We have with us, Dr. Sima Porten, Ananya Choudhury, Paolo Gontero, and Kamal Pohar, and we are going to replicate today one of the sessions that we had at the EAU 2021 in the controversies in bladder cancer rapid-fire debate session. We are going to be talking about the optimal therapy for a patient who achieves what appears to be a clinical T0 status after neoadjuvant chemotherapy for muscle-invasive bladder cancer. And I'm looking forward to replicating what we did at the EAU, and then we will have some time for Q&A as well. And with that Sima, the stage is yours.

Sima Porten: Awesome. Thanks so much for having us here today. It is really nice to be able to discuss a patient like this, as we are getting asked these questions a lot, lot more by our patients in clinical practice. And so without further delay, this is a 65-year-old gentleman with gross hematuria while starting a new exercise routine. He is really healthy. He has a remote smoking history, excellent GFR, a CT scan shows that his upper tracts are normal. There is no lymphadenopathy, his chest imaging is clear and on cystoscopy, he has a tumor at the dome and positive cytology. Resection was done and everything was visibly completely resected as safely as possible. Bladder biopsies were taken around the bladder time six, including the prostatic urethra, and an exam under anesthesia revealed a mobile bladder. Pathology showed a muscle-invasive bladder cancer with lymphovascular invasion and the random biopsies were negative for carcinoma in situ.

He decides to undergo neoadjuvant chemotherapy followed by a planned cystectomy and was considering a neobladder. He did his neoadjuvant chemotherapy, and he did fairly well. He had four cycles of dose-dense MVAC, and a CT scan after the fourth cycle showed again upper tracts normal, mild dome thickening that was non-specific. I had met with him in the clinic prior to surgery about a month before to kind of talk about any last-minute questions and hopefully finalize what the diversion plan was. And he was getting cold feet. He asked, "Well, my CT looks great. I feel great. Do I really need to have the surgery?" So we ended up doing a repeat TURBT. It showed no residual disease. There was scarring inflammation and cytology was benign. And the question is, what really is the optimal therapy for this patient?

With that, I would love to introduce Dr. Kamal Pohar who will be presenting on making the case for a radical cystectomy.

Kamal Pohar: Sima, thank you very much for that introduction, and I am very much looking forward to the session. I certainly believe that this patient would be best consolidated by radical cystectomy. Now, I think it's very important to recognize that clinical T0 should be considered a misnomer. There are several studies and the literature demonstrates that despite our current clinical tools and abilities, our knowledge of really knowing that a clinical T0 result is truly pT0 is ambiguous. There are two studies that I share here that in centers with considerable experience and expertise, that if you define a clinical T0 response by repeat TURBT before assigning treatment, before radical cystectomy, up to 50% of patients whether they receive neoadjuvant chemotherapy or they did not will have an invasive disease at radical cystectomy. A recent report from Johns Hopkins University also demonstrates that post neoadjuvant chemotherapy just like many other studies when you define a clinical T0 state with a well-performed, carefully evaluated TURBT, almost 30% of patients had invasive disease at radical cystectomy.

So what happens to these patients who have clinical T0 disease if we follow them out? Well, I think a very good study that sets the platform here was from Dr. Herr from Memorial Sloan Kettering Cancer Center more than 10 years ago. Patients who were planning to have radical cystectomy who chose not to, who were carefully evaluated and thought to have clinical T0 disease were followed. Importantly, if you look at the patients who elected this same treatment approach, they are very much like the patients who we see every day with muscle-invasive bladder cancer, many with T3 disease, multiple tumors, larger size tumors. Two-thirds of the patients in follow-up developed some form of recurrent bladder cancer. 40% of them actually had muscle-invasive disease and most of them were at sites away from the original diagnosis of muscle-invasive disease. And the majority of them died of their cancer.

Only 54% of surviving patients still have their bladder intact. Well, clearly those criteria are very concerning. Let's look at a more contemporary publication that's heavily populated by patient selection. This is a combination of a study put together by Memorial Sloan Kettering Cancer Center and Columbia University.  148 patients were highly selected for favorable forms of muscle-invasive bladder cancer, T2, smaller tumors, maximal TURBT. Well sure, bladder cancer recurrence rates are lower. It was only 50% and only 10% had muscle-invasive disease. And certainly, the outcomes are better. Five-year disease-specific survival 90%, salvage cystectomy rate is 18%, and five-year bladder intact rate at 76%. So with heavy patient selection, better results but currently people still die. Let's look at the radiation literature. I think this is a very important publication. It looks at putting together numerous clinical trials done in the field of chemoradiation and or trimodal therapy at managing muscle-invasive bladder cancer.

It looks at different eras in which these patients were treated. Let's start with the first era, 1986 to 1995, with 208 patients. Half of them receive neoadjuvant chemotherapy before trimodality therapy. You'll see the features of the cancer characteristics of these patients very much like a real-world experience like the first study that I pointed out in bullet point A above. Five-year disease-specific survival, only 60%. The risk of a salvage cystectomy, 42%. Bladder intact at five years only 40%, concerning results. Well, of course, patient selection improves the results, just like the study above in bullet B with radical cystectomy. 109 patients in a more modern era heavily selected, most clinical T2, maximal TURBT, no hydronephrosis and we see pretty good results. Five-year disease-specific survival of 84%, risk of salvage cystectomy 16%, bladder intact at 75%. This is only in the context of high selection.

Let's move away from the primary tumor, the primary organ in terms of what happens there. Let's look at the nodes. Well, the first study I'd like to point out is from the [inaudible 00:07:30] Seminole study from the New England Journal of Medicine, a clinical trial performed by SWOG, radical cystectomy alone compared to neoadjuvant chemotherapy plus radical cystectomy for muscle-invasive disease. Regardless of whether neoadjuvant was given or not, when you look at the pathologic results at cystectomy, 20% of patients who were thought to have clinical N0 disease at diagnosis before cystectomy actually had metastatic disease to the nodes. Well, one can look at the degree of lymphadenectomy in these patients. Many had limited node dissections, no node dissections, while study B that I point out looks at a series of patients who had a very extensive lymph node dissection up to the level of the inferior mesenteric artery.

So, if you look at a more complete template of lymphadenectomy, you'll see 58 patients who received gemcitabine cisplatin, 24% had node-positive disease when they were thought to be N0, 58 patients who had MVAC, 40% had node-positive disease not identified clinically. So worrisome that we do not do a good job at staging the nodes. Even if you take the most favorable review, clinical T0 is equivalent to pT0 at radical cystectomy. So 5% of these patients have node-positive disease, even when they are T0.

So the bottom line is radical cystectomy provides the greatest opportunity for cure. Highly selected patients with the most favorable features of muscle-invasive bladder cancer certainly lead to acceptable outcomes with trimodality therapy and active surveillance, but a patient must be willing to accept an avoidable death.

Thank you very much. I am now going to pass on the platform to Dr. Choudhury, who will discuss radiation therapy. Thank you.

Ananya Choudhury: Thank you very much. So I'm going to talk today about whether actually radiotherapy might be a better treatment for this patient. These are my conflicts of interest.  And actually, there is huge underuse of appropriately aggressive therapy for muscle-invasive bladder cancer. This is data based on the NCDB from the U.S. and it shows that out of 29,000 patients who were suitable for radical treatment, actually as patients got older, there was a decrease in the amount of aggressive treatment that was used. And also there was an impact on their socioeconomic background. So clearly we shouldn't really be thinking about not intensifying treatment. We should be treating our bladder cancer patients appropriately and we should be doing this across the board, not just in centers of excellence or centers where there are clinicians who have a particular interest in bladder cancer.

One of the things I often get told is that surgery is better than radiotherapy for the sort of patients presented today.  Well, I think that's a myth and needs to be debunked. There is plenty of data showing that surgery is equivalent to radiotherapy in patients who are suitable for both. There is data at the level of an institute where, as you can see here in a paper from the Princess Margaret Group in Toronto when you match the cohorts using propensity score matching, there is no difference in outcome between radical cystectomy or trimodal therapy. You can also see this data at the level of population data whereby in another study from Ontario, there was no difference between surgery and radiotherapy once known prognostic factors are matched. And this has actually been shown in a meta-analysis as well where the published studies were compared. And even when chemotherapy was given prior to radical cystectomy in this meta-analysis, actually trimodal therapy was superior. So I think for this patient, it's clear that the patient needs to have radical treatment after the neoadjuvant chemotherapy, but I agree that that treatment could either be trimodality treatment or surgery.

I'm often told that the quality of life with radiotherapy can be poor because patients end up with late toxicity from radiotherapy or a shrunken bladder. There is data from the only randomized control trial of radiotherapy versus radical cystectomy which unfortunately did not recruit, so we couldn't answer the question using level 1A data, but it shows that in the vast majority of toxicities there is no difference between radiotherapy and radical cystectomy apart from male sexual problems, where radiotherapy was much better than radical cystectomy in helping men preserve their ability to have sex. And I think most of our male colleagues here would agree that that's a very important endpoint and needs to be taken into consideration.

Late toxicity and quality of life after trimodality to treatment, well, there is a lot of data that shows that this is actually very good. This is data based on an American series, but also from the BC 2001 randomized controlled trial comparing radiotherapy with chemoradiotherapy in a predominantly UK population. And both of these datasets show that GU and GI toxicity is low, with the vast majority of patients undergoing trimodality treatment, not only keeping an intact bladder but keeping a good functioning intact bladder after treatment.

So as a wise man once said to me, for most of us the best bladder you will ever have is the bladder that you're born with. And I think that's the take-home message after this case. Thank you.

And I guess to give the third scenario, I'm now going to invite Professor Gontero to take the stage.

Paolo Gontero: Thank you very much, Professor Choudhury.  Here are my disclosures. According to the current EAU guidelines, the patient that we have heard about would not be entitled to partial surveillance without any consolidated treatment. And the reason for that is because as we heard, clinical T0 does not correspond to a pathological T0 at the radical cystectomy specimen. The other reason is that the response is not deemed durable. And finally, if these patients will have delayed consolidated treatment, this will be too late, so it will jeopardize their survival. Well, I think that these statements are not fully evidence-based. Obviously, if we want to talk about surveillance for a clinical T0 after neoadjuvant chemotherapy, all we got is a case series. And if you look at these series and you look at the cancer-specific survival, we see that up to 70% of these patients will survive.

Obviously, the limitation is that the follow-up is short. It does not go beyond the ... Is actually far less than five years in some series. And you see there is one series that has already been mentioned, with a 90% five-year survival, this is a reflection of selection criteria. And I think this is the key for this type of approach. The other good thing is that up to 70% of the patients in these case series were able to keep their intact bladder. And this is obviously what the patient would like to achieve along with survival when he is asking whether he really needs active treatment after neoadjuvant chemotherapy.

Obviously, we have to assert a fairly high recurrence rate, which is up to 50% of the recurrence rate which will occur at the median time that is quite short, within one year. But the majority of these recurrences will not be muscle-invasive, so potentially amenable for conservative treatment. And if you look at these series, up to 20% of the patients underwent so-called delayed cystectomy. And it's interesting to see that the rate of salvage radical cystectomy after trimodal therapy is the same rate, at 20%. The main criticism is that patients under surveillance will die of the disease.

Well, if we look again at these series, no more than 10% of these patients have an additional cancer-specific death. So this is probably the so-called calculated risks that the patient who opts for this kind of treatment is asked to accept. But we have to be very careful when we look at the cancer-specific deaths to be sure that we do not consider early metastatic disease as a consequence of surveillance because we know that sometimes there is a micrometastatic disease and patients who receive consolidated treatment that still die within two years. And if we look at the results of delayed cystectomy, the Kaplan-Meier curve, if we do cystectomy for muscle-invasive bladder cancer, is excellent.  But even if we do a delayed cystectomy for muscle-invasive recurrence, you see that the curve is not so bad with a 65%, 70% cancer-specific survival at 5 years.

So I think what is really important for this type of approach is the selection. We should exclude patients with hydronephrosis, with multi-focal CIS with tumors that are too large. Preferably they should be a primary, solitary tumor, less than five centimeters, and a strict follow-up has to be adopted in that patients can opt for a delayed cystectomy. So going back to the case, probably this patient that has been presented in theory, has very, very good selection criteria. And in theory, he could have a five-year survival of 90% accepting a 20% risk of delayed cystectomy, but he may be able to keep his bladder in 70% of cases. Thank you very much.

Sima Porten: Thank you everyone for those wonderful points. So I just wanted to give a little conclusion to the case of what happened. Despite the TURBT being clear, and I didn't get a chance to hear Professor Gontero's wonderful presentation. And so I still was pretty nervous about not proceeding with a more definitive option. And we did talk about radiation, but he elected to undergo surgery. And so we did a radical prostatectomy lymph node dissection and neobladder. Clinically he has recovered well, but pathology was interesting. He was indeed pT0, but he was node-positive seven out of 41 nodes. It was the common iliac nodes that were negative, and these were the lower order nodes, operator and external that were positive, negative margins and a micro-focus of Gleason 3+3 prostate cancer. This case was done earlier in my career.

So we are about at five years and he still has no evidence of recurrence of disease and clinically he is doing great. So with that, I have a couple of questions for you again in terms of some nuances of the case and particularly when you kind of see a pathology like this. I'm going to start with Professor Gontero. Have you ever managed a patient, meaning, and not done cystectomy or definitive radiotherapy? And as it stands now, are you comfortable with routinely recommending that? Or is it something you do if a patient really pushes for it and what is sort of your approach to that same question that this patient asked me?

Paolo Gontero: Well. Thank you very much for your question, Sima.  For the time being, I do not recommend surveillance in such a patient. Obviously, I would recommend a consolidated treatment, either cystectomy, as a surgeon, I would prefer a cystectomy with lymphadenectomy and it can happen in this kind of a scenario where you find positive nodes. I think that radiation, consolidated radiation treatment is also a good option in this patient with a solitary lesion and a clinical T0 after neoadjuvant therapy. I would stress the fact that this patient should be restaged with the [inaudib;e 00:22:5] former residual and the multiple biopsies in order to rule out [inaudible 00:22:19] CIS. But at the same time, as a surgeon that performs radical cystectomies, I cannot really believe that a cure of localized muscle-invasive bladder cancer can only be achieved by [inaudible 00:22:34] estimating an organ or radiating the organ, meaning that we add morbidity and trimodal effect to the quality of life.

So in the future, I think that the patient will keep on asking more and more about these options. And I think the time has probably come that we try to improve the evidence that we have at the moment. And probably this kind of approach could be assessed in the setting of a comparative study. I mean, this case was an extremely selected patient. And obviously, if you look at the results of the pathological nodes, I agree that it is a little bit disappointing that he had a relatively massive disease which by the way, was not detected by the CT. But I think that probably this is not the usual case and other cases would turn out to be more favorable.

Sima Porten: Thank you for that. Dr. Pohar what do you think about this situation? What would you need to be able to recommend this to a patient or consider it kind of at the top of your list in terms of management?

Kamal Pohar: Yeah, I appreciate the question and the opportunity to respond to it. I think the presentations of Dr. Choudhury and Dr. Gontero were excellent too. I mean I don't refute the fact that both of these treatment approaches consolidating with radiation or active surveillance or for this given patient are certainly important to discuss. I think I do have patients like this in my clinical practice, not many who are on active surveillance and others that have been consolidated by trimodal therapy. I think the patient selection is key though. And I think that was outlined in the talks, that we are looking at very favorable risk features of muscle-invasive bladder cancer that give you more confidence that your clinical T0 evaluation truly does correlate with a pathologic T0, and the probability that this type of tumor will have pathologic nodal metastases is unlikely.

So choosing patients with smaller tumors, solitary tumors, clinical T2, no hydronephrosis, and no carcinoma in situ, I think the data even though it's a retrospective small series clearly supports the fact that many can do well, but you do have to recognize that there will be some avoidable deaths in that approach. And not everybody consolidated by radical cystectomy will be cured. I understand that, but I think certainly radical cystectomy does provide the opportunity to reduce those avoidable deaths. So I think both treatment approaches other than the one that I supported in this presentation are valuable, but selection criteria drive that decision in my own practice and patient desire obviously is at the top of that list.

Sima Porten: Yeah, I would say that I am really excited to see the longer-term results of some of the trials such as RETAIN and also Memorial Sloan Kettering's trial looking at DNA damage response and kind of stratifying patients from that aspect. We haven't used it in clinical practice here. I send it occasionally for patients who are really pushing for wanting to not have trimodal therapy or consolidation radical cystoprostatectomy after neoadjuvant chemotherapy. And with about 25% of patients actually having an alteration sometimes it helps me convince them to have something more definitive until we have more data. But I think that this type of thing is really exciting.

Dr. Choudhury, a question for you is that, so in this case, where a patient already has had neoadjuvant chemotherapy, what would you recommend in terms of consolidation radiation along with more concurrent chemotherapy or not? Because it's a little different than someone you see right out the bat who sort of picks the pathway of trimodal therapy, correct? How would you alter things in this case or change your considerations on what you would give this patient if indeed he decided to say, look, I will get something definitive but it's not going to be surgery?

Ananya Choudhury: So I suppose I need to give my UK perspective. In the UK, we very rarely do trimodal therapy alone. We give neoadjuvant chemotherapy three cycles prior to either definitive surgery or definitive radiotherapy. So to be absolutely honest, in my practice I'm unlikely to be in that position where I have somebody who was referred to me having had neoadjuvant chemo, and who I would not be expecting to have neoadjuvant chemo. So we would give three cycles of neoadjuvant chemotherapy. We would then give hypofractionated radiotherapy, so radiotherapy is given every four weeks rather than six and a half weeks which is often the standard of care in other countries. There has been a recent meta-analysis of the BCON and BC2001 trials which shows that four weeks is not only non-inferior to six and a half weeks but is actually better for local-regional control.

And then we have a number of radiosensitizers that can be used alongside radiotherapy. We don't always give chemotherapy as a radiosensitizer even though mitomycin C,  5-FU, gemcitabine, and cisplatin all have evidence behind them. We often gave hypoxia modification in the form of carbogen and nicotinamide which has fewer side effects and can be given in patients who are often unfit for systemic chemotherapy. One of the things I guess I find interesting about the idea of not giving any radical treatment other than chemotherapy is there are very few, I won't say any solid tumors, but you might pick me up on that. But there are certainly, I can't think of any solid tumors in which chemotherapy alone kills a significant number of patients. So whether I'm thinking head or neck, lung, pancreas, you name it, any sort of neoadjuvant chemotherapy is pretty much always followed up by local treatment, but we are here to discuss, aren't we? So please correct me if I'm wrong.

Sima Porten: I agree. It's a good point. I'm not aware of any. And I think that brings in important questions like is a repeat TURBT enough, right? Removing all visible disease within the bladder, or do you really need again either surgical or radiotherapy-based definitive treatment in terms of oncologic principles, right? Controlling tissue within the nodal beds and also that has gotten past the organ. And I think that's also where sometimes our limitations of staging become very real in being able to counsel our patients and practice. So I agree, I can't think of another solid tumor where this could be a possible potential. But I'm hopeful that maybe we will be able to find this as a path for some patients in the future.

Ashish Kamat: So those are great points, Sima and Ananya and one of the things that we often forget is that radical TURBT is something that exists, right? So we're not necessarily saying that we do not want to do a local consolidation in a patient when we are sparing the bladder, but not doing TMT. Rather, we are saying that we are taking out the area of the bladder that has the tumor, like a partial nephrectomy or a partial thyroidectomy or a partial lobectomy for lung, or even for the pancreas. You don't always have to take out the entire organ. So, that is one way to look at it. But that brings me to a question and let me start again in the same order. So not to pick on anyone and briefly, Paolo, if you were to do a partial cystectomy on a patient like this, would you then recommend intravesical therapy, say a BCG or something else for this patient?

Because in some ways a partial cystectomy would be like, a radical TUR for T1 or T2 disease, but you've left the rest of the urothelium in place. How do you advise these patients?

Paolo Gontero: Well, I don't think we have any data to support the use of intravesical treatment. You would say neoadjuvant, you are suggesting as adjuvant treatment-

Ashish Kamat: Correct.

Paolo Gontero: I would certainly consider it in a case of nonmuscle invasive recurrence. And this can happen as it has been shown because half of the recurrences, which is also the case after trimodal therapy, that there are some cases of nonmuscle invasive recurrence. And again, we do not have a lot of data on how are the results of intravesical treatment. So I would not recommend the adjuvant intravesical for such a patient should I treat it with a partial cystectomy? And this patient would be amenable to partial cystectomy because he has a solitary tumor on the dome of the bladder. This could be an additional local treatment. I fully support your view that radical TURBT is a kind of local treatment already. And this doesn't happen in other solid tumors. We don't have this opportunity in other solid tumors. But yes, why not? I think also interstitial brachytherapy has been proposed as a kind of alternative to partial cystectomy.

Ashish Kamat: Great. Yeah. And one point I would make for the audience and the listeners is that if you are considering a partial cystectomy, we would definitely do a lymph node dissection at that time as well. Because as Dr. Porten's case presents, the nodes are areas where you could harbor microscopic disease that may not be picked up on any imaging whatsoever. Ananya, a question for you, and I know you and I are going to be chatting in-depth on myths that urologists often face when it comes to radiation therapy and a lot of the reasons why folks will sometimes say, "Well, I can't do it." But to ask you quite bluntly, what are situations in which you would absolutely say, "Okay, this patient should not have radiation and should go on to have surgery instead."

Ananya Choudhury: Thanks, Ashish. As you can imagine, there probably aren't that many patients to who I would absolutely decline to offer radiotherapy, but certainly anybody who has had previous pelvic radiotherapy to any significant dose. I wouldn't say for example I have had patients who've previously had neoadjuvant radiotherapy, or chemo-radiotherapy for rectal cancer for example who then develop bladder cancer. Very importantly, for any patient who has extreme urinary symptoms that affect their quality of life, my main reason for discussing bladder preservation with patients is that they can retain their natural bladder. If retaining their natural bladder is not going to be helpful in any way, shape, or form for them with respect to their quality of life then it's a moot argument really. Most other so-called contraindications, I think actually indicate poor prognosis in general. So I have and continue to treat some patients who have multifocal bladder cancer, who have a diverticulum, and who also have carcinoma in situ. And I guess like any person with a reasonably large practice, I have won and I have losses. But I think that relative contra-indications, I really don't think they are obsolete at all.

Ashish Kamat: Great, thanks for your candor. The situation in the U.S. and the UK is quite different, although as we got closer to the East Coast up near Boston, I guess that's closer to London, practices seem to overlap a little bit. You know we are coming up on time, but I do want to ask one more question, and Kamal and Sima, I'll pose this to both of you or either of you. In the U.S. especially during last year, or even now in COVID times, access to healthcare was really an issue. And even in non-COVID times, we've had patients that come from far away or live in rural areas. And I have actually had patients say, "Just do a radical cystectomy, get it out. I don't have time to come for radiation. I don't have time to come repeatedly for repeated scans. If you do a partial cystectomy, I can't come for intravesical therapy." Would you care to comment on that aspect of things? Does a radical cystectomy, even though upfront much more morbid, provide patients a less intense follow-up schedule afterward or a follow-up that they could even do locally with their PCP?

Kamal Pohar: Yeah, I think that's a very practical point that you bring up and ask for a discussion. I don't think this is that unusual of a practice pattern. I work in a state that we do serve a population that's quite rural and non-urban, and this is not an uncommon dialogue that we have.  And I don't think that is an unreasonable view that the patient takes, that I try to change their mindset by exercising data to try to influence them that, that's not a reasonable approach to treating their disease. So I think that conversation is prudent. And you would prefer in a perfect world that you achieve all the variables of a council fully informed discussion. And the practice of administering neoadjuvant chemotherapy would show a survival benefit. But I think when it gets down to the nitty-gritty of the real-world population and real-world circumstances that affect people based on their socioeconomic factors and age and travel restraints, I think it's very practical that sometimes a radical cystectomy, may end up being the only part of the treatment discussion, and monotherapy.

Ashish Kamat: Sima, what about you? What's your experience?

Sima Porten: Yeah, I think all of those things need to be taken into account when counseling a patient. I would say that we are not as great about looking at these other hidden costs for patients and some financial toxicity. Meaning that sometimes repeat appointments can be a lot more costly depending upon what insurance plan or not insurance plan a patient may have. And I think this factors into my discussions that these are your options. What is most important to me is that you get treated, definitively treated for your muscle-invasive bladder cancer. And this is what this looks like. And potentially these are some ways we can make things less burdensome on you and your family, time off, kids' time off, recovery time. All these other things that we don't really think about impacts patient's lives when they come in for treatment.

And so I think that does factor into my counseling with patients is that these are some of the options, let's look at what your goals are in terms of how you want the next two, five years to look like. Right? And what things are most important to you. And some things that we see as barriers and see if we can work around them. But sometimes it really is that one treatment choice is just more practical for someone's entire whole situation versus another.

Ashish Kamat: Yeah, great points. And again we are having such a great discussion, we could go on forever. But in the interest of time, I want to thank all of you once again for taking time from your busy schedules and sharing with us. This is really an educational effort that reaches out to trainees, folks in practice, and so on and so forth. And again, it's a huge benefit to the community. So thank you everyone for taking the time.

Kamal Pohar: Thank you very much-

Sima Porten: Thank you.

Paolo Gontero: Thank you. Thank you.