Around the Practice: March 24, 2021 - Episode 2

Non-muscle Invasive bladder/urothelial Cancer

Dr. Jason Hafron:

Hello, and welcome to Urology Times, Around the Practice. A live, interactive event featuring the multidisciplinary approach to challenging cases in urologic oncology, posted in partnership with LUGPA. My name is Dr. Jason Hafron, I'm Associate Professor of Urology at Oakland University, William Beaumont School of Medicine. Director of Robotic Surgery at Beaumont Health and Director of Clinical Research at the Michigan Institute of Urology. I'll be moderating this evening's live event, and it's with great pleasure I am joined today by an esteemed panel. I'd like to introduce Dr. Gordon Brown, Associate Clinical Professor of Urology at Rowans School of Medicine, Director of the Center for Advanced Therapeutics at New Jersey Urology, and Director of Robotic Surgery at Kennedy University Medical Centers. I'd also like to introduce my colleague and friend Dr. Sirisha Nandalur, Associate Program Director in the Department of Radiation Oncology at William Beaumont Health System, Assistant Professor of Radiation Oncology at William Beaumont School of Medicine, and Director of Finance and Telemedicine in the Department of Radio- Radiation Oncology at, uh, Beaumont Health.

And finally, uh, Dr. Elan Diamond who's Director of Medical Oncology at the Cancer Center Treatments of New Jersey Urology. With that being said, let's get into our first case. Um, before we get started, just a reminder though, if you have any questions regarding either case, be sure to type them into the panel, um, below. For, and following each case discussion, we'll go over, um, questions that you put through. And throughout this event, we'll be pulling the audience to get background and to make this interactive and see how you would treat each case, so we'll try to have some fun tonight. The first case involves penile urethra cancer with inguinal adenopathy. As we know, penile cancer is a very uncommon malignant disease that affects approximately 1,500 men in the US each year. Penile cancer ca- carries high morbidity and high mortality, unfortunately, um, particularly when it's locally advanced or metastatic. Unfortunately the scientific literature lacks level one evidence, and current guidelines are largely based on retrospective studies and small single center studies.

Despite there's, these limitations, there's been a major paradigm shift in the management of both local and systemic disease. Current guidelines emphasize penile, uh, sparing strategies minimizing morbidity from surgical management and multimodal management of bulky lymph node metastasis. Hopefully we will touch on all these tonight. Let's get started, um, with our first, uh, case. This is a 63 year old man presents the urology with a three month history of a firm painless mass to the left lateral shaft of his penis, occasional discharge, no voiding complaints. Past medical history is positive for hypertension, non-insulin dependent diabetes. Past surgical history is negative. He's allergic to penicillin and you can see the list of medications.

Physical exam, he's overweight, he's obese. He has a positive left inguinal adenopathy, multiple nodes, the largest being 2.5 centimeters non-tender. The GU exam, he's an uncircumcised male, positive phimosis, positive prevalent discharge, positive mass effect from the left, uh, mid-lateral shaft below the glands, um, and below the coronal sulcus. Um, here is some imaging that was obtained, um, it's a, a CT scan of the abdomen and pelvis, and that line denotes the inguinal, uh, left side, uh, adenopathy that's, uh, seen. With that, with that information, I'm gonna turn it over to my colleague, uh, Gordon Brown. Gordon, you know, I gave you the exam, I gave you the history. How, how would you evaluate this patient if he showed up in your clinic, uh, tomorrow?

Gordon Brown:

Yeah, Jason, uh, I guess, first of all thanks for having me, and, uh, it's a pleasure to be here. Uh, you know, so as it relates to the men and the penile cancers, you know, you alluded to paradigm shifts as it relates to organ sparing approaches. Not only do we try to, you know, spare a, you know, penile lane and kind of minimize morbidity as it relates to managing this disease, but adequate tissue sampling of the primary tumor is gonna be essential in determining subsequent treatment strategies. So as it relates to initial staging and workup for a patient like this, usually we'd wanna look at, uh, MRI of his, uh, abdomen and pelvis to, you know, kind of assess local, not only local tumor burden, but also any distant disease that might be suspicious either in his inguinal region or pelvis. Uh, also may consider a CT scan of his chest to rule out any kind of distant, distant metastatic disease.

From my perspective, um, you know, in terms of a surgical approach, at least it was primary tumor, anatomically it's not ideal necessarily for, for, uh, for a penile sparing approach based on its location. Um, but I do think that you could adequately, uh, you know, excise this potentially with reconstruction and get a negative margin. You know, historically we've been taught that the two centimeter negative margin is kind of required. There's, there's I think a substantial body of literature, which really, which suggests that that's probably no longer true, uh, and we can look at margins even in the five millimeter range or less in some, some series, which are more than adequate from a, from a surgical control perspective. I think based on, on the pathology of the primary tumor, that would guide my subsequent kind of evaluation of his inguinal region, uh, obviously in combination with, with his, you know, preoperative imaging studies.

Dr. Jason Hafron:

No, that's great. Thanks Gordon. Some very good points. But before we get, you know, obviously we wanna, uh, sample the, the, the mass, but, you know, and, and try to stage it from a, um, from a histological perspective. I think one of the challenging things with penile cancer is the management of the lymph nodes. And this comes to our first polling question is, how would you initially manage the multiple palpable lymph nodes? Would you treat with antibiotics and reevaluate? Would you do a percutaneous biopsy of the lymph nodes? Would you observe and reevaluate after treatment of the primary, or would you go right and perform a radical inguinal lymphadenectomy? So as you, as, as you see on your screen, just answer these, uh, questions and it will give us an idea of, of where we are with the audience. So again, how would you manage the, uh, multiple palpable lymph nodes on the left side? So we're just, I don't see your screens, but if you could just choose an answer, that would be great.

All right. We can see them on our screen. Um, and basically what we're seeing... Oh, I'll give you a few, we're still seeing responses. So what we're seeing is, you know, I'll send the results I think to the audience. But what you see is 25% of our audience would treat with antibiotics and reevaluate. Half of our audience would do a percutaneous biopsy of the lymph nodes, and another 25% would just go right to that angle- inguinal lymphadenectomy. Gordon, basically do, do you agree with the audience? You know, we, we talked about the biopsy of the primary lesion, which is very important. Before we get into, you know, management and, you know, options for treatment, what would you do with the lymph nodes?

Gordon Brown:

So I, I think at least from my perspective, some of the lymph node management is gonna be dependent upon the, the histology of your primary tumor in this context. Um, so I think if we're assuming this is a T1B or greater primary, or, or one that's associated with LVI, um, or, um, kind of, uh, high grade disease. You know, in that situation, I would be inclined to, to percutaneously biopsy, you know, this area of concern. Uh, historically we've been taught that these have antibiotics in this patient population and then kind of reevaluation that six week kind of interval has been some of the kind of the historical teachings.

Uh, I think some of the, the contemporary literature would argue against, you know, delay as it relates to kind of nodal sampling and further evaluation of the groins in a patient, you know, with this, uh, kind of burden of disease. My, my challenge I have here is that, you know, the traditional kind of, um, you know, cutoffs or, or paradigms that we think about, neoadjuvant therapy in the setting of, of, you know, prior surgical consolidation usually is in that patient with the kind of four centimeter or greater and/or fixed mass, uh, you know, kind of within the pelvis. So it, it, it, we have I think a very clear two and a half centimeter, no, the question is, are there smaller nodes although palpable are they really contributed to by disease or are they contributed to, you know, by, um, by kind of inflammation a- as it relates to kind of the neoadjuvant discussion.

Dr. Jason Hafron:

No, that's, that's very helpful. I think what most people are doing is probably a percutaneous biopsy of the lymph nodes. I agree, we've gotten away with treat with antibiotic reevaluate. But what's also interesting is that when you look at certain, you know, certain studies is that as many as 50% of the palpable inguinal lymph nodes at diagnosis will, will actually go away once you treat the primary, um, and it's something to consider. And, uh, if they have basically palpable lymph nodes surgical after treatment of the primary, 100% of those are typically, uh, metastatic. With that being said, Sirisha, I want to ask your question. Gordon allu- touched on a little bit about surgical resection and, you know, obviously it can impart significant physical, psychological and sexual dysfunction. What about treating let's say a T2 lesion, um, what about treating the primary with, with radiotherapy? Um, what treatment plan would you consider, and is radiation therapy to the primary as good as surgery?

Dr. Sirisha Nandalur:

So definitely for a T2 lesion I think that we can offer radiation therapy. So radiation offers a good penial preserving, uh, treatment option without jeopardizing cure. So you can either use external beam radiation therapy, or penial, uh, brachytherapy, um, primarily for T1, T2 and selected T3 cases. So the data is primarily like you said before, um, retrospective institutional analysis, so that's why it's e- earned itself a category to be on the NCCN guidelines and because of lack of level one evidence. Um, generally we recommend that uncircumcised men are, um, recommended for circumcision prior to doing any radiation. Uh, lymph node assessment, Dr. Brown touched on what you would do as far as lymph nodes. So there's several factors when you're trying to figure out what treatment plan and what parameters you use for radiation therapy. For example, for external beam radiation, you try to treat for greater than 60 gray, um, minimize your treatment breaks and tre- uh, overall to less than 45 days and use fraction sizes greater than or equal to two gray.

Um, in brachytherapy, we look at tumor size, the volume and depth of invasion. Ideally you want your tumors to be less than four centimeters in size, and less than a centimeter, uh, depth of invasion. And generally clinical stage T3s are volumes greater than eight centimeters, um, are reported to have worse outcomes. So once again, touching on external beam, we want doses between 16 gray to 74 gray. Um, and although most of the outcomes between external and brachytherapy are similar, we find that salvage surgery is required more frequently when you pursue the external beam radiotherapy route, um, and penial preservation rates can fall 36 to 66% at five years.

So the way we do penile brachytherapy, you deliver the treatment to the full thickness of the penis using two or three plain, um, implant. Although if you've got a very small tumor, not a patient like this, but a very small tumor superficial or TIS, you can use a single plain implant or, um, plesio, a plesio brachytherapy, which is kind of like a device where it just radiates the superficial aspect. The brachy options throughout the country are going to be LDR pulse dose, or a high dose rate. Um, and high dose rate is probably becoming more common because of the advantages, uh, from a physics perspective.

Um, and so the recommendations are 38.4 gray given twice a day after the implant is done, and gi- given over 12 treatments. So far, brachytherapy data is newer, but what we have available shows it to be a very promising treatment option compared to LDR or pulse dose rate. If you look at the outcomes, the, um, actual, there's multiple single institution data, um, but if you look at the Freedom from Local failure, it's about 87.3% at five years, which is excellent, and 72% at 10 years. The penial preservation rate around 80 to 90% at 10 years and 67%, sorry, at 80 to 90% at five years, and 60 to 70% at 10 years. Um, and the great thing is that salvage procedures are very successful after if needed upwards of 80 to 85% at five to 10 years.

Um, the advantage of brachytherapy once again is you radiate less tissues, so if you had to perform a salvage surgery, it would be less radical, with 75% of those local failures, uh, requiring, or being able to be managed with the partial penectomy. So I think it's a great option for patients, and like you said, there's a lot of potential downsides to having surgery. Now, the side effects of radiation that you would deal with during treatment include [inaudible 00:13:50], which peaks at three weeks, but can be managed, um, with, you know, very supportive treatments. And then longterm side effects can range from ulcer- ulceration or urethrostenosis or necrosis, and I think a lot of it depends on your implant dosimetry and looking at all that.

Dr. Jason Hafron:

No, that's very good data. So I think what you're saying is that we basically would be, you would strongly consider HDR brachytherapy in a situation, um, with a reasonable size lesion that's invasive? Um-

Dr. Sirisha Nandalur:

Yeah. I'm a little biased because I do, you know, really favor HDR brachytherapy, but I think it's a great option. Obviously expertise is, uh, necessary and experienced physics staff to do HDR brachytherapy, but you're able to treat less tissue, um, and potentially [inaudible 00:14:35] the, the chance that you need salvage surgery. You can still, um, end up with a, a less morbid salvage surgery if necessary.

Dr. Jason Hafron:

Now that's interesting. That's great data. Obviously we don't have level one evidence, we don't have randomized control trials, so it makes these decisions very difficult because we just have to go with what our local experiences, or, you know, what, what tools we have. Elon, I wanna talk to you for a second as far as the, you know, let's say he's T2, let's say we did the percutaneous biopsy, you know, and a lot of this is hypothetical. And, um, I know there's been strong evidence for neoadjuvant chemotherapy in patients with initially unresectable disease. But how about patients who are resectable with high volume nodal disease, is there a role for neoadjuvant therapy, you know, chemotherapy? But before you get into the role for neoadjuvant car- chemotherapy, what is the typical chemotherapy regimen, regimen you would consider in a situation like this?

Dr. Elon Diamond:

Yeah, so, uh, that's a very good question. So the typical neoadjuvant chemotherapy regimen that we'd use in a situation like this is TIP, which is Paclitaxel, ifosfamide, ci- uh, cisplatin. Um, the data for that derives from a phase two trial from MD Anderson, which was completed in 2010. It's a small trial, and what they did is they took 30 patients who had either unilateral-

[Inaudible 00:16:00] they took 30 patients who had either unilateral le- uh, uh, inguinal lymph nodes, s- o- two or more, bilateral inguinal nodes, or single node greater than 4 cm. And they treated them with four cycles of neoadjuvant TIP. And what they found in that study was that there was a 50% overall response rate. 10% of those were CRs, and the remainder were partial response.

And the, uh, the time to progression in that, uh, in that patient population was 8.1 months with an overall survival of seven- 17.1 months. When they did a, uh, subset analysis and they looked at the patients who responded, they found that the ones that actually did respond had a overall survival of 38 months. And so, you know, what, what I think this trial is telling us, is that once you have patients who have disease at the level of the inguinal lymph nodes, uh, th- that is really a surrogate marker for u- outcome and likely because that's representing micrometastatic disease. Which if, theoretically speaking, you're sterilizing with neoadjuvant chemotherapy.

Now, the benefits of neoadjuvant chemotherapy in this situation is that you get to surgically downstage your patient. So I would make this, uh, an easier for, surgery for Dr. Brown. And you're getting the chemotherapy in upfront. Rather than in the neoadjuvant setting when a patient's post-op, when they may, may be less likely to tolerate systemic chemotherapy. But there are, there are downsides to this approach as well. So, the regimen is toxic.

Uh, you know, uh, TIP is not an easy regimen to take. It can cause peripheral neuropathy, neutropenia. Um, ifosfamide has been associated with hemorrhagic cystitis, neurologic complications. But actually surprisingly, at least in this 30-patient prospective trial, about 70% of the patients that were enrolled were actually able to complete chemotherapy. So I, I think that, um, if I were seeing this patient and the patient had [inaudible 00:18:06] offer that, that patient this therapy, not simply in the setting of fixed nodes or very large nodes, based on the results of this trial.

Dr. Jason Hafron:

Uh, that's very helpful. So, Gordon, we got some all stars with us. [Saritia 00:18:24] and [Alon 00:18:25] I know is your, one of your partners.

Gordon Brown:

Mm-hmm (affirmative).

Dr. Jason Hafron:

[Inaudible 00:18:28] great arguments for, for neoadjuvant chemotherapy and great arguments for radiation therapy. As a urolo- representing urology, I'm c- I'm with you too, Gordon. What, what w- you know, we, you touched a little bit about surgical therapy, wh- wh- would you consider surgical therapy in, in, in a, in a setting like this?

Gordon Brown:

Yeah. So, so u- I, I would, and, and you know, it's unclear to me again, you know, what his true burden o- of disease is in his groin. So, you know, I, I, I think that some of these nodes are clearly inflammatory and probably not, you know, a metastatic disease. But I had a high degree of suspicion that, that he had, uh, you know, the kinda, the classic extranodal extension, uh, greater than 4 cm and/or fixed mass. I think h- i- he would preclude upfront surgery.

I think in the absence of that, you know, these are commonly associated with concomitant infections at the time of diagnosis, as kinda outlined in the case you presented, [Jason 00:19:20]. And I think that you're having, you know, a fair amount of these probably being reactive nodes that [inaudible 00:19:26]. Now with that, I, I, I think that we would treat his primary lesion with a wide excision, uh, penile sparing approach, and reconstruction. Try to spare his glands to the extent that's possible, which I think would be well-achieved, u- you know, based on location of this.

Uh, and then secondarily, uh, move on and, and tackle his groins, probably in a second setting after determining, you know, his risk from his primary lesion. Uh, you know, u- w- u- biopsy obviously would help us understand that. He would undergo, you know, in this situation, certainly a superficial dissection, uh, uh, on the left. You know, that, that, uh, dissection usually i- is carried from the ASIS, you know, to the pubic tubercle, about 2 cm kinda below the inguinal ligament. Um, and then, you know, develop a flap underneath Scarpa's fascia, and you kinda maintain that to the extent that's possible.

Identify the femoral triangle. Um, whether you maintain the saphenous vein or not, tends to be, uh, little bit dependent upon not only the surgeon involved, um, but also whether you're gonna do a superficial and deep dissection oftentimes. If you can maintain the saphenous vein, that does reduce morbidity, uh, associated with the operation. Specifically post-op, uh, wound faciles and, and edema, the lower extremity.

Uh, you know, our, our, our borders generally speaking are the inguinal ligaments superiorly, the, um, you know, the adductor longus kinda medially, and the sartorius muscle kinda laterally in the thigh. Um, that's kinda the classically described, you know, open superficial and, and then, then subsequently deep dissection. Depending upon whether the superficial nodes are positive. If the superficial nodes are positive on that, uh, ipsilateral side that we suspect, then we're gonna go do a deep dissection on that side, in the superficial contralateral, uh, and dissection.

Uh, and, you know, the, we can progress on our node dissection based on the volume o- of, of positive nodes subsequently. Uh, there has been some reports recently over the last t- 10 to 11 years of approaching these groin dissections with use of, of robotics. Uh, where they're using, uh, access in the kinda mid-thigh portion, right at where the, the point of your triangle for a, uh, uh, j- kind of a classic node dissection would be. A small skin incision and a, a tissue-separating device. Much like a balloon is placed in that space. That potential space is developed. Use three ports.

Uh, it was initially described by Ian Thompson, uh, in his group. And, uh, was kind of, uh, the first larger series of it was produced by, by Surena Matin, uh, at Anderson, where he did te- 10 groins. And subsequently, uh, there's a, a fairly large series of about 50 patients and 100 groins out of India. The operative times are, are about 70 to 90 minutes per groin. Their main length of stay is about, uh, two days. An- and, and importantly, their rates of complications are very low.

So, you know, historically, this groin dissection can be a morbid operation associated with high rates of complications, including the need for re-operation, skin an- flap necrosis, an- and kind of debilitating lower extremity edema. So the, the robotic approach, uh, has, uh, minimized those complications, and it has allowed for, uh, subs- adequate, uh, groin dissection with, with good nodal yield. So I, I, I think that that's a potential alternative, uh, for patients undergoing this operation currently.

So my approach, would yes, it would be to, uh, address the primary tumor first, and then subsequently go on an- and do a superficial and likely deep dissection on this, uh, on his, uh, affected side. And then superef- uh, superficial on his contralateral side to start.

Dr. Jason Hafron:

Gordon, a question just came in through the, the chat boxes. What, what's the role for pelvic, um, uh, lymph node dissection?

Gordon Brown:

Yeah. So p- p- pelvic nodal dissection is usually, uh, uh, uh, done in a situation where you have extranodal extension, uh, on, on the contra- on the same side, or if you have a total of four or more nodes that are positive. Uh, usually in that setting, you proceed onto pelvic nodal dissection.

Dr. Jason Hafron:

Okay. Um, we just have a few more questions. Saritia, what, is there any role for adjuvant radia- radiotherapy? You know, when would you consider ra- u- adjuvant therapy in a p- in a situation?

Dr. Sirisha Nandalur:

So I think there can be, there's definitely a role for adjuvant radiation. We're gonna touch on little bit of the data. But, um, in general, we know that nodal recurrences are associated with very poor outcomes. So any adjuvant treatment goals would be b- ideally to improve those outcomes. There was data presented in 2015 that really define for us the presence of, um, anybody with clinical N3 disease, greater than or equal to three pathologically, uh, involved lymph nodes, or extranodal, um, extension was, had a worse recurrence-free survival. Thus likely, being the basis of why the [NCTN 00:24:12] recommends adjuvant treatment in those patients.

So i- th- the theme of today on penile cancer, is the data available is all single institution reviews. There was one meta-analysis, which we'll touch on, and extrapolation of successful treatment where we have more robust data with other HPV-driven anogenital cancers, as well as oropharynx cancer. So single institution analysis have shown a benefit of adjuvant radiation therapy. Um, in one study there was patients who had more than or equal to two lymph nodes. Um, and there was a recurrence-free survival as long as there was no extranodal extension.

So somebody with likely, just with radiation, more intermediate, high-risk factors. Additionally, [Tangitol 00:24:53] found that pelvic radiation was impr- uh, associated with improved cancer-specific survival and overall survival. But as most retrospective reviews, there was selection bias as well as time bias. Um, there was a larger analysis looking at the NCDB database, uh, where there was 589 men that were evaluated, um, and who underwent inguinal lymph node dissection for Stage 3 penile cancer. 23% of those patients received adjuvant radiation therapy. And on multi-variant analysis, the radiotherapy was associated with improved three and five-year overall survival.

On the flip side, you had this paper published in 2018 in the European Association of Radiology, which was unable to show a benefit in recurrence and survival with radiation. But when you look at th- you know, go fine-comb through the deta- the, the details of the studies they evaluated, it was, the radiation was done '50s, '60s, '70s, and '80s, when we know that our radiotherapy techniques were poor because we were unable to localize tumors as well as we do today with our technology. And then those patients that were studied had a bias towards worse disease, likely confounding the results of that meta- analysis.

Um, we have stronger level evidence d- once again with adjuvant radiation or chemoradiation in patients with anogenital cancers. But this really highlights the importance and the need for stronger data in patients with penile cancer, which I'm hoping that we get with the [InPACT 00:26:16] trial, that I know you'll touch on a little bit.

Ultimately, what we do and recommend for, um, adjuvant treatment, is patients who are at high-risk of local recurrence, which would be the extranodal extension, more than three lymph nodes, and adjuvant chemoradiation might actually reduce the risk of recurrence and improved survival as well. Um, a- a- as Doctor Gordon touched on, you know, there's a, uh, role for potential pelvic lymph node dissection, but as in [vulvar 00:26:40] cancer, we found that pelvic radiotherapy... In a study where it was pelvic radiation versus pelvic, uh, dissection, and those patients with positive got the pelvic radiotherapy, there was a benefit of pelvic radiation, um, and, and the InPACT trial will hopefully give us the results of that as well. And, um, change the paradigm in how we treat these patients adjuvantly.

With regards to nodes, we generally treat the pelvis to 45 gray if there is no gross disease. And ideally somewhere close to si- biological equivalents of 60 to 63 if there is gross disease. The current oath and protocol allows you to go up to 54. A lot of it, you know, we're trying to reduce bio-toxicity and we have to be careful with some of those organs. Um, but, you know, using something like intensity modulated radiation really helps minimize toxicity.

Dr. Jason Hafron:

Now that, that's great. Thank you, Saritia. So Alon, Saritia makes, you know, there's some data to support radiation. You know, it's obviously a little confusing and, uh, fuzzy because we don't have that category one. I just want you to touch on, you know, the role for adjuvant, uh, chemotherapy, or, um... And then, you know, Saritia touched on it, can you just tell the audience, u- uh, explain what the, the, the Phase 3l, uh, InPACT trial is? Uh, InPACT is I-n-P-A-C-T trials is, is about?

Dr. Elon Diamond:

Yeah, absolutely. So, um, you know, uh, in keeping with our theme from today, there really is no good data for adjuvant chemotherapy and penile cancer. There was a retrospective review, uh, case series of these patients who did not receive pre-operative chemotherapy and were treated with adjuvant TIP or 5-FU cisplatin. And what they found really i- is that there's a fi- uh, uh, a 40% reduction in the risk of death in this patient population. But we have to take that data with a grain of salt because those patients who were treated with adjuvant chemotherapy tended to be younger. They had less aggressive disease histology overall when you parse through the data. And they actually refused adjuvant radiation, so that may have tipped the scales over in terms of having a greater survival benefit than th- the, than the general population.

But for patients who have not received neoadjuvant chemotherapy, we would have u- very similar criteria for selection that we'd have for radiation. So patients who have extranodal extension, uh, you know, pelvic nodal involvement, or patient with bilateral, bilateral positive inguinal lymph nodes after surgery. And there is no data to guide between the choice of adjuvant radiation or adjuvant chemotherapy. Um, the, the InPACT trial that we were referencing before actually doesn't necessarily touch so much on the adjuvant space, but really seeks to answer the question of what the ideal pre-operative therapy is for patients with intermediate and high-risk penile cancer.

So this trial is a Phase 3, randomized trial with an adaptive design where they take patients with intermediate risk penile cancer, which is defined as patients with, um, up to two inguinal lymph nodes. And those patients in that cohort are randomized to either inguinal lymph node dissection, uh, neoadjuvant chemotherapy followed by inguinal lymph node dissection, or neoadjuvant chemotherapy radiation followed by inguinal lymph node dissection. There's a high-risk cohort patient, uh, cohort of patients that's also included in the study. And in that high-risk, which is basically anything that's greater that that intermediate-risk group, those patients are randomized to either neoadjuvant chemotherapy with TIP followed by ly- uh, lymph node dissection or neoadjuvant chemoradiation.

There's a second randomization for that high-risk cohort, where those patients are randomized to either a pelvic, a prophylactic pelvic lymph node dissection or no pelvic lymph node dissection. And so, this is a, this is a fairly ambitious trial 'cause it's 400 patients. But that will provide us with the Level 1 evidence that we need, to actually s- make meaningful statements about what the peri-operative management of these patients should be.

Dr. Jason Hafron:

Yeah. Uh, hopefully, we'll, the, we'll be able to accrue that trial. Um, I think, uh, it will, like you said, answer the sequencing questions, how to best treat these patients with, you know, Level, hopefully, Level 1 evidence. I think what we learned today, clearly, it's a complicated disease limited by poor data. That, but I think the key is working like we are to- tonight, is working with, you know, y- y- all your consultants. The hematology oncologists working closely with your radons. And the urologists figuring out what's the best plan for each of these patients

Also, if you are located where there are Centers of Excellence, this is an uncommon disease. It's not unreasonable to send it to one of these centers that will see this disease on a more regular basis, as something to also consider. With that being said, let's just move onto our, uh, second case. Um, that was a great discussion. So we go from the most uncommon cancer that we see in urology to bladder carcinoma, which is the most common malignancy of the urinary tract. Approximately 75 to 80% of the patients we see with bladder cancer have superficial bladder cancer, uh, TACIS or T1. What's really exciting, and this started in 2013, there's been a concerted, it started actually at the [AUA 00:32:00]. I was actually at this meeting. There was a concerted effort by the FDA-

Actually, at this meeting, there was a concerted effort by the FDA, by, uh, urologists, medical oncologists, radiation oncologists, pharma, uh, the NCI to really develop and strategize how to improve the quality of, of, uh, bladder cancer care and to develop, you know, clinical trials that will lead to drug approvals, and now we're starting to see some of those results w-, in, in literally eight years. You know, there's, uh, some recent approvals that we'll touch on and a lot of, uh, really exciting drugs that are near approval or will be out shortly.

So, let's just get into this first case, or second case, but let's get into it. This is a, you know, typical, you know, average urologist case where we see a 58-year-old white male, healthy, presents with asymptomatic gross hematuria, uh, to the office. Um, he opted, he underwent upper tract, uh, workup, which was negative, standard, you know, for gross hematuria, then underwent a flexible cystoscopy. Uh, timeline here is, obviously, critical i-, in superficial bladder cancer.

The office flexible cystoscopy showed an erythematous area in the right lateral wall and a positive papillary tumor in the posterior wall. Um, he subsequently underwent a transurethral section of the bladder tumor and EUA, and pathology revealed a carcinoma in situ in the right lateral bladder wall, as well as a, a TA, grade 3, in the posterior bladder wall, so we're seeing, uh, two areas.

He underwent, uh, which is standard AUA guidelines, induction round of intravesical BCG x six weeks, and then he underwent, uh, six weeks later, his three-month cystoscopy, um, which with bladder biopsy, which showed, uh, CIS at the, uh, right lateral bladder wall. I'm going to get the, bring a question up to the audience. Um, I ask that you, uh, answer what you do, so we have, uh, basically superficial bladder cancer, CISTA, with a recurrence at the first cysto, the three-month cysto. Would you consider BCG maintenance i-, in this patient? We'll give it a second.

So, whi-, while the, while the audience is answering, I'm going to put Gordon on the spot. You know, Gordon and I just went and reviewed the case a few nights ago. Recurrent CIS at the three-month, the first cysto, te-, tell me, is, you know, is this BCG failure? Is this pa-... What, what would you do with this patient and, you know, just ta-, talk out loud your thought process on, on when, when you come across this situation.

Gordon Brown:

Sure. So, I, I think, you know, trying to understand h-, the, um, response patterns of patients with high-risk non-muscle invasive bladder cancer is important in trying to, uh, uh, adequately treat them, uh, both, you know, knowing when to pivot from their existing treatment and knowing when not to stop a treatment that may still work, I think, are two important concepts, uh, to kind of maximally manage this patient population. It can, it can get a little bit tricky, I think, a l-, little bit quickly, you know, in some of these patients.

So, from my perspective, with pers-, you know, I, I think a lot of this has been, I think, formalized by, by Ashish Kamat, you know, um, in his work from MD Anderson in bringing, you know, some, a lot more form and structure t-, to kind of the realm of, of non-muscle invasive bladder cancer, and we'll talk about that, I think, in subsequent slides to help us understand, uh, kind of which buckets patients fall in to help us maybe make better clinical decisions about these patients as it relates to their BCG responsiveness.

In this patient, you know, who presents with CIS alone after induction, um, you know, uh, these patients have, if they continue with additional BCG, a reinduction course, potentially, or maintenance, they have a significant response rate at six months of followup. So, 50% of these patients would be potentially expected to, uh, respond within six months at their subsequent kind of follow-up cystoscopy and biopsy. So, from my perspective, with CIS alone, no papillary disease, no disease progression in this patient population, I would be inclined to continue with BCG therapy, uh, and, and reevaluate them at six months.

You know, no, it's a good point, and this is kind of a unique case, and it's a good teaching point about, you know, um, how to define BCG unresponsive. Just looking at the poll question, 66% said they would not do maintenance, uh, BCG. Uh, um, 33% said they would do, uh, BCG maintenance. I think the key here is what you kind of alluded to, and we'll talk about. At three months, CIC, no, you know, progression, is this a failure of BCG?

Would you go right to maintenance, which I think is what you're saying as opposed to, and I'll go to the next slide, is what was done in this case was, the patient received a second, uh, round of induction BCG.

Yeah. I, I, I think second round of re-, of reinduction or maintenance, both would be, I'd be comfortable with both, but I wouldn't give up on BCG quite yet, you know. So, so, Ashish published a, a paper in JCO in 2016, trying to really kind of articulate a-, and give form and structure to the definitions of BCG responsiveness in patients with non-muscle invasive disease, uh, and I think that has subsequently served as the, um, you know, the kind of, the hallmark for the FDA guidance, which helps us kind of formulate clinical trials and get patients onto these trials in a timely fashion. So, the way that he looked at it was based on BCG intolerance, what he called BCG refractory, BCG relapsing, or BCG unresponsive.

So, that intolerant patient, as one would expect, is that patient who doesn't really tolerate, uh, you know, the therapy due basically contributed to early adverse effects. That BCG refractory patient is really defined as somebody who has persistent high-grade disease, uh, you know, after six months of initiation of induction therapy or somebody who progresses i-, in grade or stage after three months of induction, okay? So, this patient really hasn't technically met that definition yet.

Um, he also, he goes on to find BCG relapsing in somebody who has recurrence after achieving disease-free state at six months, uh, and those patients who are unresponsive really are kind of a combination of refractory and relapsing. So, trying to understand and synthesize some of these definitions, I think, will help us better restratify these patient populations, uh, and, and treat them, potentially, you know, more effectively one, and two, uh, hopefully accrue to our many ongoing clinical trials in this space to really find much needed additional therapies for these, you know, high-risk superficial patients.

Dr. Jason Hafron:

Yeah, Gordon, I totally agree. You know, I think for, for the audience, it's really important that they understand the definitions of BCG failure, whi-, which you talked about, intolerance, refractory, le-, relapsing, etc. I think that's really key, and we really got to get more comfortable with these definitions to appropriately treat these patients. With that being said, you know, the patient went on to his, uh, cystoscopy and biopsy which was, fortunately, negative in September of 2020. Um, and then, he basically got his first round of maintenance BCG x three, you know, got his three weeks maintenance after his, uh, two induction courses. Um, you know, you touched a little bit on maintenance. Do you, what do you think about maintenance? Do you use maintenance routinely in your patients, Gordon?

Gordon Brown:

Uh, I, I do. So, um, you know, the initial SWAG data was, was done with up to three years of maintenance therapy, you know, induction maintenance at, at three months, uh, weekly x three and then maintenance at six months weekly x three and then every six months thereafter for up to three years. Uh, in the context of BCG shortage, obviously, you know, we don't do that kind of, um, of, of maintenance protocols any longer, but I do a six plus three regimen right now, um, then we reevaluate those patients at six months. You know, if those patients fail, uh, we have, you know, several ongoing clinical trials which make them appropriate to, to enroll into or to pivot onto subsequent, you know, intravesical therapies, which are either FDA-approved or even off-label therapies in some cases.

Um, but, but I think, um, so I do use maintenance, yes, and to me, I think, uh, it's a critical part, i-, if possible, to try to, you know, kind of improve outcomes associated with BCG, uh, use to achieve maximal kind of response downstream and, hopefully, save these patients' bladders, if possible.

Dr. Jason Hafron:

Yeah, I th-, I like to use maintenance, as well and I, you know, you referenced the SWAG trial. I think what's critical and just a couple of key data points in the SWAG trial was, it improved recurrence-free survival by 20%. What, what also, we have to keep in mind and this is something we see day to day in the clinic, only 16% tolerated the, the full course of maintenance, so I know you probably, you know, we try to do it a lot of times. Frequently, patients can't tolerate it but, if we can get them through maintenance, we can im-, improve, uh, recurrence-free survival.

Just going back to the case, he goes back for his, uh, you know, surveillance cystoscopy December of 2020. Cystoscopy shows, unfortunately, erythema, positive cytology, and we see re-, recurrent CIS. Um, [inaudible 00:41:57], you know, recurrent CIS, you know, can... Is there, you know, an option for radiation therapy in, in superficial... I-, is it, is it, can we consider it, su-, radiation therapy for superficial bladder cancer with CIS?

Dr. Sirisha Nandalur:

So, I'm going to touch on a couple of things. Um, we can talk about CIS, but we'll also talk about just T, uh, T1s, as well, uh, bladder cancer. So, just as a background, you know, treatment for muscle-invasive bladder cancer with selective bladder preservation using tri-modality therapy, which is the max TURBT, chemotherapy, either CIS fi-, or 5FU mitomycin, along with radiation with prompt cystectomy for recurrence has been established as an effe-, effective alternative to upfront radical cystectomies, um, and this has been published in protocols, as well as single institution report.

So, interestingly, the pres-, presence of extensive CIS prior to therapy, um, was initially associated with lower rates of, um, complete response to trimodality therapy or radiotherapy alone with higher rates of recurrence, so there is a suggestion that, if you have extensive CIS, that it could be considered a relative contraindication, not absolute, but relative contraindication to, uh, trimodality therapy, but it doesn't affect survival. So, radiation therapy, with or without chemotherapy, may be of limited benefit in patients with pure CIS but, if you switch the, you know, equation to high-grade non-muscle invasive bladder cancer, I think there's good data, um, for, potentially, the use of, um, bladder preservation.

So, there was, Wiesen colleagues looked at 141 patients with high-risk T1 bladder cancer treated with radiation therapy, um, or, uh, platinum-base chemoradiotherapy and found that, uh, tumor recurrence after complete response was fairly low at five to 10 years. Um, 48 patients, of the... All of their patients did actually have CIS and, in that study, there was no difference of, uh, recurrence when compared to patients without CIS. Um, you know, previous mul-, multi- institutional randomized data out of the UK, uh, didn't show a benefit for radiation alone for T1, grade 3s. However, if you add chemotherapy, like they did in Germany, we found that the ten-year progression-free survival rate was 71%, 10-year disease survi-, disease, uh, specific survival 70%, um, and there's data out of Harvard that also supports the use of tri-modality therapy for T1, grade 3.

Um, there was the current closed protocol of RTOG 0926, which I know both you and I accrue to. Um, the, we're waiting for the results where they treated the entire bladder to 61, uh, .2 grade with either chemotherapy options, and I think that this, uh, the outcome of this trial may actually establish an alternative organ-sparing approach to in-, to intravesical's chemotherapy failure patients prior to resorting to a cystectomy, um, but pure CIS, I think, is a little bit more difficult.

Dr. Jason Hafron:

I think what we also have to stress is that, you know, according to AUA guidelines, American Urological Association, and probably the standard of care, would, i-, this patient should be offered a cystectomy. Um, recurrent CIS, the outcomes are very good for these patients. They tend to do very well, but the real-, if they fail two, two lines of induction therapy, but the reality is that, you know, Gordon will attest to us is is, no one's lining up in our offices to have their bladders removed. Um, frequently, these patients are older.

There's morbidity associated with the cystectomy. It's a big operation. It's tough for, for patients to go for it, um, but I, we can't ever forget that these patients should be offered a cystectomy. Unfortunately, a lot of them will decline, but we have a very healthy man, uh, he's 58 years old, who would be an excellent candidate for a cystectomy, um, something that definitely has to be offered to each one of these patients with recurrent CIS after failure of, of two cycles of induction BCG.

I'm going to go to our next poll question, and this is kind of what Gordon touched on is, how would you define this patient's BCG failure? Is he BCG relapsing, is he BCG intolerant, is he BCG refractory, or is he BCG resistant? Just for the sake of time, Gordon, why don't you, you know, while the audience is answering this, just go, you know, rapid fire. Define each of these for the audience.

Gordon Brown:

Sure, so BCG in, uh, BCG refractory is persistent high-grade cancer which is, you know, usually present six months after the start of induction therapy or, you know, that, uh, tumor which progresses, either in greater stage, usually within three months after the start of induction. Uh, our, our current patient didn't meet that, that definition because they didn't progress i-, in grade or, or stage of disease. Um, that BCG relapsing patient i-, is that patient who has recurrence after, uh, this disease, after achieving a disease-free interval, um, state at six months, so anybody who recurs after six months, uh, usually within the one-year time frame, is considered to be BCG re-, relapsing.

Those patients who are intolerant, I think that's self-explanatory. They, obviously, can't receive, uh, therapy due to treatment-related side effects, and the unresponsive group really kind of, you know, combines both the BCG refractory, as well as the BCG relapsing patient population where you have, uh, those tumors who recur within six months of the last BCG exposure, so that's somebody, really, who is, you know, an early kind of failure. Um, so, generally speaking...

Dr. Jason Hafron:

What would you, what would you call this guy?

Gordon Brown:

Yeah, so for, for, for me, I, I would call him BCG unresponsive...

Dr. Jason Hafron:

Okay.

Gordon Brown:

... because he, he occurred, he recurred within six months of his last BCG exposure, meaning an early recurrence.

Dr. Jason Hafron:

Okay. Yeah, and we can see the results of the audience. They called the BCG ref-, relapsing, so clearly not refractory which...

Gordon Brown:

Yeah.

Dr. Jason Hafron:

... can sometimes be confus-..

... so clearly not refractory, which can-

Gordon Brown:

Yeah.

Dr. Jason Hafron:

... sometimes be confusing, but it's definitely BCG re- relapsing. Um, that leads us to our next question, poll question is, how would you manage this patient with recurrent CIS after two courses of induction BCD- G, would you offer this patient a third course of BCG? Would you manage this patient with a radical cystectomy? Would you offer them Pembrolizumab or Keytruda, or would you consider some of the sequentials, and I just put a couple of these up, Gemcitabine and Docetaxel or BCG plus interferon.

Dr. Jason Hafron:

So we already said, Gordon, I'll, I'll let you talk about this. Would you offer this patient a radical cystectomy?

Gordon Brown:

Yeah, I, I think it's part of the discussion especially in a 59 year old healthy guy, you can do a neobladder on him and, you know, he would do I th- I think very well. Uh, I think that that discussion is gonna be met with, with some challenges quite honestly early on, six months after his diagnosis. It's a morbid operation, it's a big recovery, and then it's significant, uh, you know, uh, potentially morbidity and even mortality, you know, uh, frankly. So, uh, I think it's not something that, that anybody undertakes, uh, lightly. I think that's part of your discussion. However, I think most oftentimes patients are gonna move on to some other second line intravesical therapy before standing up and having their bladder removed, oftentimes multiple intravesical therapies as we've seen from, from the published literature.

Gordon Brown:

Um, I wouldn't give him a third li- third induction of BCG. There's very good data out there to suggest that simply increases risk of disease progression and even conventionally death and as such situation. Uh, I wouldn't give him BCG interferon because the, you know, the data out there is, is, the outcomes are comparable to BCG alone, you know, and kind of a more contemporary series. Um, I think Alon could probably better speak to Pembro, but the Pembro data, the CRS at three months, or somewhere in the 40 or 41% range, that would be a very reasonable potential for him in CIS only situation.

Um, and, and quite honestly, the, the, the data from Michael Donald and Betaloc from Hopkins looking at the sequential use of, of Gem and, and Doce, I think is very compelling data quite honestly. Um, and, and that's a bladder preservation, you know, strategy utilizing, uh, you know, uh, a gram of Gemcitabine in 37 and a half milligrams of, uh, of Docetaxel in sequential fashion. Um, and, and I think that their, their responses have been pretty remarkable. Um, so I think that's a very valid option as well, you know, in this patient population. And, and lastly, I think accruing into an ongoing clinical trial would be a reasonable option as well. Um, we have a couple of good ongoing clinical trials and a couple of, of, uh, products coming to the marketplace, uh, in the near future.

Dr. Jason Hafron:

Before we get, before we get to that, let's just, you know, those are great points. I w- I wanna get to Alon, you know, Alon you work at New Jersey urology, have a very integrated model, you know, you know, you guys are doing tremendous work. You know, if this patient was at, uh, NJCU, what about Pembro, you know, for recurrent CIS, what, what is the data, you know, would you consider it in this patient?

Dr. Elon Diamond:

So I would, well, if this patient were sitting in front of me in my office, I would console him that radical cystectomy is really the preferred option. And I would tell him that with radical cystectomy you'd have a greater than 70%, uh, five-year cancer specific survival. Now Pembrolizumab, we have ex- a fairly reasonable experience with it in the metastatic setting at this point where it's used for cisplatin ineligible patients, or even in the second line, we ha- we have have excellent responses. So, uh, Arjun Balar, um, uh, out of NYU, uh, conducted a, uh, phase two clinical trial, KEYNOTE-057, where they had two cohorts of patients, and cohort A was patients with BCG unresponsive carcinoma, and cohort B had high- grade TA or T1 lesions. And the data for the cohort A has actually been reported already.

In cohort A, they had 103 patients, and what they found that at three months the complete response rate, and this was the primary endpoint of that study was 41%, and that's based on the, uh, updated, uh, reporting this trial from ASCO GU 2021. They also had a median duration of response of 16.2 months. And when they looked at the subset of patients who were the complete responders, they, 50%, 57% rather had a duration of response more than 12 months, but we really don't know the long-term implications or the long-term outcomes of this therapy.

In that trial with the updated, uh, uh, data, about 8% of patients were actually upstaged on therapy, so they, you know, clearly didn't respond. Um, but I would tell the patient that this is an option with the caveat that we don't know what the long-term responses are, but it seems that with this approach we can at least spare some patients a radical cystectomy. Now we also have to consider that there's potential toxicity for, um, immune checkpoint inhibitor therapy. So, um, patients can have pneumonitis, hepatitis, endocrinopathies, um, neurologic complications, immune-related colitis. So this is something that is not common, but these are potentially serious side effects.

Um, the other thing is that this is potentially associated with a significant cost. So there was an analysis where they, uh, estimated how much, uh, Pembroli- Pembrolizumab would cost in a patient who was responding, and it was about $300,000, but you have to understand that that's only in the, the cohort that has an ongoing response. And the way that these patients were treated in KEYNOTE-057 is that they received therapy every three weeks for a total of two years if we maintain their complete response. If they have recurrent disease at any point in the trial, they were taken off and offered radical cystectomy afterwards as a salvage therapy. But I, but I would offer it to him with the caveat that in this young healthy man surgery would be s- would be preferable.

Dr. Jason Hafron:

No, those are great points Alon, and, uh, thank you. That's good information. Pembro is exciting, but it definitely has its role, probably not a great choice in, in a young healthy guy. I agree with Gordon, we'll probably would try to steer them towards a cystectomy or a sequential, um, therapy intravesical if he wasn't up for ready for his, the cystectomy. Um, that being said, and Gordon touched on it, and Alon if you wanna touch on it, um, you know, because of this concerted effort to improve the quality of, of bladder cancer treatments the, you know, collaboration between urologist, oncologist and, you know, pharma and everything, and the FDA, we got a lot of great trials that have read out with pending approvals. Do you wanna highlight some of the things that stand out, you know, are we headed, you know, it seems like we're headed towards space. Maybe you may, I might just being too bold or BCG may be obsolete in the future. But what, for, for the audience should be looking out for, what trials should they, you know, what drugs are potentially gonna be coming pending, uh, FDA approvals?

Dr. Elon Diamond:

Yeah. So there are, there are, um, uh, two standouts, um, that have been read out in clinical trials already. One of them was a phase three single arm trial with a drug called NATA FER gene, and NATA FER gene is really a very interesting therapy, and what it is, it's a, uh, it's an inactive add no virus vector with a, that delivers interferon alpha 2b/cDNA to the bladder intravascularly. And so what it basically does is it turns the bladder into an interferon generator. And what they found is that the, the complete response rates at three months are fairly good, they are 53% with a 24% maintained CR rate at 12 months.

And the way that this has given it's actually fairly convenient for patients where it's given every three months for a total of four years. And so that's, that's something that patients may be able to keep up with in terms of a regimen. There's of course no randomized data, you know, comparing this to other options, but it does compare favorably. The other, um, the other interesting therapy that has been read out, and this is in the VISTA Trial is, uh, an agent called oportuzumab monatox, which is also an intravascular therapy.

And what this is, is a antibody drug conjugate of a monoclonal antibody to FKM, which is a fused to a pseudomonas aerug- inosa, aeruginosa endotoxin A. So it basically delivers this directly to the bladder, uh, uh, bladder wall. And what they found is that, uh, in, in this trial, in the VISTA Trial, there was a 40% CR rate and a 17%, 12- 12 month maintain CR rate. So the, the, um, the CR rates at three months and long-term outcomes seem to be fairly similar between NATA FER gene, uh, oportuzumab monatox and even Pembrolizumab, uh, they all have, you know, similar rates of efficacy. The downside potentially of the oportuzumab monatox is that it's given once or twice a week for 12 weeks, um, and then every two weeks for a total of two years. That would be something that might tip the scales away from that kind of therapy for patients in terms of a, a long-term strategy.

Uh, in terms of, um, uh, the ongoing clinical trials, there is a lot of, there are a lot of trials that are focusing on combination therapy. So, um, there's the KEYNOTE-676, which is a phase three trial of Pembrolizumab in combination with BCG, uh, in patients who, uh, have high-risk disease, or are BCG refractory, with the idea that the BCG is gonna potentiate the, uh, the, um, the efficacy of Pembrolizumab b- by making this a inflammatory immune environment. Um, there's a, there's a similar trial Checkmate, uh, 7G8, which is a phase two trial of a similar drug to, uh, Pembro. This has Nivolumab which is another PD-1 inhibitor with a BCG in both B- in BCG unresponsive, uh, patients. There is a trial of, um, BCG and ALT-803, which is called the QUILT Trial, which, uh, ALT-803 is an IL-15 super agonist, um, so that might be something that's a promising, uh, avenue. So all these trials remain to be read out, but it's really building on our experience with BCG and trying to potentiate the efficacy of immune checkpoint inhibitors that we currently have.

Gordon Brown:

The only thing I w- I would add to that, and that was excellent Alon. Uh, w- would be that there's a SWOG 1602 which actually is looking at the Tokyo strain of, of BCG. So, you know, if that in combination with the PPD booster run by [inaudible 00:58:55]. So I think if that reads out to be po- you know, positive, or at least comparable to contemporary BCG studies, it gives us a whole other supply of BCG in our marketplace, which we currently don't have, which I think could be paradigm changing in itself.

Dr. Jason Hafron:

No, they, that Alon and Gordon, and Sarisha, that, that, such great points. Bladder cancer is such an exciting space, so many good things are happening, so many new treatment options that will definitely benefit our patients, um, in the future. Unfortunately, we are out of time. If you'd like to watch this again, it will be available on demand, uh, Urology Times in the coming days, so look out for it. I wanna thank, you know, everybody for, for, for joining us tonight, uh, the audience and participating in today's event. Um, and then if you could, if you have a chance, pl- please provide feedback around the practice, uh, is a recurring monthly, uh, uh, tumor board, and we need feedback to get better. Uh, we hope to see you next month on Stallman on April 21st at 5:00 P- PM Eastern, where we will be discussing cases on metastatic castration resistant prostate cancer that has failed or did not tolerate Docetaxel. And we will also talk about high risk renal cell, uh, carcinoma following resection. Thank you all for joining us, we'll see you next time and goodnight.