Sima Porten: Hello everyone. Welcome today to our conversations, discussing the realities of bladder cancer in women. And I am really pleased to be here with three great friends and colleagues in urologic oncology. My name is Sima Porten. I'm an associate professor at UCSF and a urologic oncologist that specializes in urothelial carcinoma. And I will have my colleagues introduce themselves as well, starting with Dr. Schuckman.

Anne K. Schuckman: Hi. Thank you so much, Sima and thanks for the opportunity to participate today. My name is Anne Schuckman. I'm also an associate professor at University of Southern California in Los Angeles, specializing in bladder cancer and urothelial carcinoma.

Kristen Scarpato: Hi, I'm Kristen Scarpato. I'm a urologic oncologist at Vanderbilt. I'm an associate professor of urology, and I am really thrilled to be here for this important discussion today.

Svetlana Avulova: Thank you, Sima. And I am Svetlana Avulova. I've been honored to be trained by some of the people on this call. I'm an assistant professor of urologic oncology at Albany Medical Center, and I also treat all urothelial carcinoma.

Sima Porten: Thank you all for being here. So I thought we'd start with a case to kind of highlight some of our patient stories in women who present with bladder cancer. And although we're going to discuss the realities and issues with diagnosis, we'll also today be discussing a path forward, right? What's important when we talk about caring for these patients and how to improve care, and I think it's going to be a fantastic discussion. So I saw a healthy 51 year old woman who has about six months of UTI symptoms. And I say, UTI in quotes. She has urgency frequency burning. Maybe she saw a little blood when she has these symptoms, but things kind of have a waxing and waning presentation. So she was initially treated with empiric antibiotics without a urine culture. She's had four of these episodes, two of them she did have a culture, but they had this like mixed growth that we see. It's sort of this annoying mixed urogenital flora, right?

And after her fourth course of antibiotics with no improvement, she was referred to one of my colleagues, a general urologist, and he did a workup and it revealed a muscle invasive tumor consistent with clinical T3 disease. She had a pretty large growth on her right lateral wall. She had staging imaging, no lymphadenopathy, no metastasis. She is healthy. She has a partner. She has children. She's sexually active. And she's currently having irregular periods kind of in a, like a perimenopausal status at the time that she sees me. Dr. Scarpato what are your thoughts regarding this presentation? Can you describe a bit about the incidence of bladder cancer and some of the challenges in diagnosing women and comment a bit on oncologic outcomes in response to treatment for women who are facing the diagnosis of muscle invasive bladder cancer?

Kristen Scarpato: Yeah. Thank you, Sima. First of all, my heart hurts with this scenario, because unfortunately we see this not rarely, and this is a young, healthy woman who now has a significant health problem. I think considering the epidemiology of bladder cancer is really important. So first let's just start with the incidents. We can expect 20,000 new cases of bladder cancer to be diagnosed in women in the United States out of about a total of 80,000 new diagnoses. And we can expect about 5,000 bladder cancer related deaths in women in the United States out of about 17,000 total expected deaths this year. And so a woman has about a one in 89 chance of being diagnosed with bladder cancer over the course of her lifetime. I think the epidemiology of bladder cancer sort of contributes to part of the problem with delays in diagnosis in women. We think of bladder cancer as being a disease of the aging.

The average age of diagnosis is mid 70s. Here's a woman who's 51 years of age. And so it might not be on the forefront of her provider's mind that she may have bladder cancer. Secondly, we think of bladder cancer as a disease of exposures. And in this scenario, this woman is healthy. She likely has not been a heavy smoker based on what you told us. And she likely has not had significant environmental exposures that would make us be thinking about bladder cancer. And I think most importantly, bladder cancers often thought of as a disease of men. We know that nearly three quarters of the cases of bladder cancer that are diagnosed are going to occur in men. So why is that? Smoking as we talked about number one, two, and three diagnosis, or cause for diagnosis of bladder cancer, really big risk factor, but there are gender related disparities that persist even when you're controlling for smoking.

And so there may be differences in the way that women and men metabolize carcinogens, there may be differences related to hormonal production or androgen receptor presence, but that epidemiology, I think contributes to some of the challenges with diagnosis. And so we certainly have to have bladder cancer on the list of possible diagnosis for women in order to make the diagnosis. And so I thought there would be one sort of scenario to highlight that there's some data to support. Putting the UTI like symptoms aside, which we know is a common presentation for women, let's just think about microscopic hematuria. Right. There's a lot of evidence about the management of microscopic hematuria contributing to outcomes. We have guidelines that clearly delineate how we should manage patients with microscopic hematuria, but there's evidence to show that this prompt standardized diagnostic evaluation is different in men and women. And men are more likely to undergo recommended workup for microscopic hematuria than women are.

And so this completed evaluation leads to a diagnosis, more commonly in men than in women who are not having the appropriate diagnostic workup and this delayed or incomplete workup has downstream implications for diagnosis. And then just a couple of other points about outcomes related to staging. Just first and foremost, we should say right off the bat that women fare worse than men stage for stage. Secondly, women are more likely to have advanced tumors with higher stage at presentation than men are. And bladder cancer has a less favorable prognosis in women than in men. And so this is sort of across the board with even non muscle invasive bladder cancer, but certainly with muscle invasive bladder cancer. There's also evidence to suggest that there's excess mortality in the first two years after diagnosis for women than for men. And so certainly we can't discount the impact of the delay in diagnosis, which we know is a significant contributing factor, but there may be issues related to women being more likely to present with non urothelial tumors and variant histology, which can be more challenging to treat.

And then different responses to therapy. There is evidence that shows that women don't respond the same way to men for chemotherapy in the management of urothelial carcinoma, but also sort of tied to that, there's evidence that shows that women are less likely to receive chemotherapy than their male counterparts, which is unfortunate. And there's also some indication that women who are included in clinical trial may actually do as good as men if they receive the treatment that should be given in the cases of advanced bladder cancer. So I mean all this to say, I'll just summarize to say that we need to have the diagnosis of bladder cancer on our radar when we're treating women. We need to initiate a prompt and thorough diagnostic workup. And then finally we need to offer timely, appropriate and often aggressive therapy for these women.

Sima Porten: Yeah, I think that your summary kind of really hits home to the point in terms of having a really high index of suspicion for the like folks out there listening. Right. And to really chase down the workup in an appropriate way. And a lot of the other points your sort of saying. So good thing is, is that she does get guideline based neoadjuvant chemotherapy that cisplatinum based. She has a fantastic response and she's now here to discuss surgery and urinary diversion. And so this is kind of moving into the part of the conversation of how do you manage these patients? And what are the things that you think of? And how is the care of women changing in terms of the treatment of muscle invasive bladder cancer?

So I'm going to pose this question to Dr. Schuckman. And how would you counsel this woman who's in your office? Kind of really focus in on the anatomy and do we have oncologic equipoise for organ sparing? What does that mean? Is it like a single definition or are there like different variations of that? And what are some of the reasons why I would say more recently, this is kind of become more part of the discussion? Like why is it important? So I'll let you take it away.

Anne K. Schuckman: Great. Thank you so much, Sima. I just, I did have one thought on the UTI portion of this woman's presentation that I just thought we should highlight maybe is that just because somebody has a UTI doesn't mean they can't have bladder cancer and that oftentimes women will have recurrent UTIs and bladder cancer because all those bugs are kind of hiding in the tumor. And I think in men that often gets worked up and leads to the diagnosis, whereas in women, it's just assumed it's normal. So I'm sure we can talk about that a little more in the discussion, but I think that it's pretty important as well. So going back to your question. So, this woman presented with a T3 tumor, and it sounds like based on what you said, the location of the tumor was potentially a little more lateral and extending towards the side wall, whereas it wasn't really in the posterior wall of the bladder or involving the vagina, she did receive neoadjuvant chemotherapy.

And I think that the first step after this is really a good clinical evaluation to determine whether she is an appropriate candidate for any sort of organ sparing surgery. And so what does that mean? I think there's some obvious times when that may not be appropriate. So if somebody has tumor involving the vaginal wall, potentially a tumor involving the bladder, neck or urethra that may limit our options a little bit, but if the bimanual exam is normal and it seems that she's had a fairly complete response to therapy, then I think women in this day and age have lots and lots of options.

So the things I like to take into account are first and foremost, patient preference. I talk to all patients about whether they would prefer to have a continent or an incontinent diversion. For this very young woman I would certainly encourage her to have a continent diversion, but for me that means really two options that can mean the patient would be a candidate for a neobladder, or the patient would be a candidate for a continent cutaneous urinary diversion. And I think maybe I'm a little biased. I really do encourage a lot of women to consider a continent cutaneous diversion, which is catheterizing through the belly button. And we talk about the pluses and minuses of a neobladder versus that in great detail.

Some of the things that I might consider are their willingness to catheterize through the urethra versus through the belly button and take into account the pretty high percentage of women with the neobladder who may need to catheterize. So I think that's one portion of the discussion, but maybe focusing a little more on organ sparing and some of the things we wanted to discuss today. I'd like to consider all women to be candidates for organ sparing. And what does that even mean? For many people that may mean just sparing a portion of the vagina and that's all. And I think historically that was considered organ sparing. And I don't consider that to really be an organ sparing operation anymore.

So I think moving forward from there, we can consider sparing the entire vagina. We can certainly consider sparing the uterus, the fallopian tubes, and the ovaries. And I think that that is what I would consider to be full organ sparing at this point. Whether we do that or not really sometimes depends on patient preference, if there's no cancer issues in terms of location of tumor. Sometimes depends, obviously many patients have had prior hysterectomies, et cetera.

If a tumor is located in the posterior wall, we may need to discuss some removal of the anterior vaginal wall. But I think you can still preserve quite a bit of vaginal length at that point. In terms of equipoise and asking about studies and whether organ sparing is a good or appropriate idea for cancer cure, I think that's a tricky question. Because there's no definition of organ sparing, studies have looked at lots of different versions of these scenarios that I just discussed. And there's some really nice work actually out of Vanderbilt that Sam Chang did looking at complete organ sparing surgery in women who are reconstructed with neobladders and in the end actually found that there was no difference in the rate of local recurrence of disease. I think it's really important. People are scared about leaving these organs in because of fear of recurrence, but multiple series have shown that really female organs are only involved in about two to 5% of cases of bladder cancer, which is a very, very low number.

So I think that again, there are multiple series showing its appropriate, and I think we'll get a little more into functional benefits later, but there are also multiple series showing that continents and sexual functions certainly are better if we're able to spare these organs. To address your last question, talking about some of the hormonal benefits. So people used to take out ovaries all the time for fear of ovarian cancer developing down the road. And really the College of Obstetrics and Gynecology is quite against this idea. And we know that even in postmenopausal women leaving ovaries in has quite a few hormonal benefits and that all cause mortality is this increased about 13% in women who have [inaudible 00:15:50]. It's a huge number and that's associated with heart disease and stroke and sort of maybe underappreciated value of hormones that ovaries may be contributing even in the post menopausal state.

And the College of Obstetrics and Gynecology recommends, if anything, just removing fallopian tubes to still limit the risk of ovarian cancer developing down the road. So I think that's really important and really, potentially practice changing as the ovaries are almost never involved in bladder cancer patients. So I think we can move maybe forward from there, unless you have other questions about that for now.

Sima Porten: No, I think that was a really nice summary and also highlighting a little bit of the newer data, right? In terms of the importance of still preserving ovaries, even if a patient is in that peri or postmenopausal setting. And I do think that's again, new and sort of practice changing and kind of has come to the forefront. Because a lot of, even my patients themselves sort of say, I don't need them anymore. Just-

Anne K. Schuckman: Take everything out.

Sima Porten: Have negative margins. Take it all out.

Anne K. Schuckman: Absolutely.

Sima Porten: And I would say that I end up having more of a conversation. I think where we go a little bit more in depth is some of my patients who have a very strong family history or personal history of BRCA alterations. And I think though that might be another whole conversation we could probably have regarding how to incorporate that in. And so I think in moving on, she actually has a successful full organ sparing surgery for everything, uterus, ovaries, and the full vagina, and she elected to have a neobladder and we could also probably have a huge discussion about continent diversions as well. But Dr. Avulova, what do you think? I know you've done a lot of research looking at this and I think this part gets missed a lot, even in those of us who see a lot of women with muscle invasive bladder cancer and are sort of counseling.

I think actually this gets missed a lot for bladder cancer patients in general, but in terms of survivorship and going forward specifically for women, what do you discuss? Right. They're back at the appointment. They're learning to take care of their neobladder. What are some of the things that they could expect to experience in the next couple of years and also longer into the future? And then what are some of the tips or things that you discuss with your patients who are women in terms of like the survivorship from a sexual function perspective? I think with men, we naturally talk about erections, right, and all of the things that we can do to bring that back when they're ready. But I would say sometimes you hear an absence of that when we talk about survivorship for women. So what are your thoughts in that aspect?

Svetlana Avulova: Yes. Dr. Porten, thank you. So, first of all, I would say the survivorship period, it starts at that first visit when you diagnose them with muscle invasive bladder cancer. And I think that's important to set that stage because you need to make sure that you're giving your patient hope because I often tell my patients, what's the point of us doing all this, if you're not going to enjoy your life after the fact. Right. And so survivorship really starts the day you get that cancer diagnosis. Because the thing that the patients are thinking about is their living will, their power of attorney, all of the terrible things that come along with a cancer diagnosis. And the last thing they think about is, am I going to be able to have penetrative intercourse? No, they're not thinking about that. So you kind of have to really set the page and provide hope for them and set the expectations.

And in order to do that, you really have to, as you so diligently did ask them like, where are they now? What is their baseline, right? Like where are they starting from? So are they sexually active? Do they have a partner? What issues are they having now with, for example, sexual activity? You mentioned she was perimenopausal. So is she going through genital urinary syndrome of menopause? Has anyone addressed that? Is she on topical estrogen already?

Oftentimes women who are going through GSM, they have vaginal atrophy, they have dyspareunia. Sometimes they have a little bit of vaginal bleeding and spotting. And this is also to Dr. Scarpato's point, how a lot of these diagnoses keep getting missed because, I tell women just an aside, like, yeah, this could all be GSM, but it could also be bladder cancer. So this is why we're doing all this. But so to set the expectation and set the stage and kind of establish a baseline. So what have they done in the past? What is their issue now? Are they using any topical medications, such as estrogen? A lot of women are very, very wary of any sort of estrogen because of the studies that came out with oral hormone replacement therapy.

But I try to reassure them that vaginal topical estrogen is perfectly safe. And even in discussion with medical oncologists in the absence of any sort of family history of breast cancer or BRCA mutations, it's completely safe. However, if there is some sort of, a lot of women, for example, they've lived nine lives, right? They've had already a breast cancer diagnosis and maybe in their 30s, God forbid, or maybe in their 40s. And now this is a new thing. And they're wary of any estrogen, like forget it estrogen, no way. Well, introduce them to a new topical DHEA vaginal suppository, which has been approved and is actually effective or equally as effective as vaginal estrogen. And also steer them away and caution them from things like MonaLisa laser fiber, which actually recent studies have shown doesn't work that well. Right. And if you go back to the society for menopause, you will note what their recommendations are, which is topical vaginal estrogen.

And if there is any sort of concern for breast cancer, then vaginal DHEA suppositories. So, again, you set the stage, you set the expectations, you see what's working for them now, and what's not. And then after Dr. Schuckman has done this amazing surgery, spared all of these organs, now what? They come to you at three months, they have that scan and they think, oh yeah, I get a good report. Okay, that's it, no cancer. But then reengage them with that conversation. Ask them, how's it going? They are not going to want to bring that up on their own because they're shy. They want to be a good patient. They want you to give them a good report. And the last thing most 50, 60 year old women want to talk about is sex because society has made it not okay for women to talk about sex for whatever reason.

So you have to be the person that engages them in that because they want you to ask as their physician, they want you to ask, so you have to ask. And then maybe at three months, they're just not ready. They just finally got over having diarrhea or managing their neobladder or pouching their ostomy, they're just not ready. And so whenever you see them again, whether it's six months, or nine months, or 12 months, again, keep asking them. Be that annoying sort of nuisance and ask them, how's it going? Are you engaging in intercourse? Because, and remind them, as we often do for our male patients, one of the risk factors of cardiovascular disease, the first symptom is erectile dysfunction. So we all know that if someone is having erectile dysfunction, we are sending them to the cardiologist, because if something's wrong down there, it's got to be wrong with your heart.

Well, tell these women that it's normal and healthy that once you start having that urge, that increased libido, which they will, if they're feeling good, that it's normal to have these feelings. And again, reengage them in terms of resources, potentially that they can refer to you, that you can refer them to rather. Now, one of the main things that people always say, well, I am not a sexologist. I am not a sex therapist. I don't have time. I have a busy surgical practice. Absolutely. I don't expect you to be. If you don't have social workers who are sex therapists in your practice, then refer them to ISSWSH. So this is the International Society of Sexual of Health for Women. And they have lots of resources where you can look up online, a sexual health counselor, which is perfectly safe. And most women again, are thinking, I'm not going to look online and look for a sex therapist.

That's taboo. No, this is a society. You have to be a licensed sexual therapist in order to provide this therapy. This is perfectly acceptable. And now that we're also mobile engaged and love interacting with our smartphones, there's actually an application that is being used called Lisa Health, which is all about postmenopausal, perimenopausal, GSM type symptoms. And it's very discreet. It's an app that you can download on your phone. And actually certain institutions are partnering with Lisa Health to provide this sort of bridge in the knowledge gap, because we really don't have as surgeons to spend this time to talk about it. But what we can do is we can bring it up to the forefront. We can make sure the patient understand it's perfectly normal and healthy to talk about this. And if we don't have time or the resources, we refer them to these perfectly acceptable websites or mobile applications.

Sima Porten: I think you brought up a lot of good points. I really like that point about starting the conversation early and starting to talk about this stuff at the first visit. And then also like lot of the practical tips, right? Because many people do say that I only have a limited amount of time and I actually don't know what to do. But I think you brought up some actual true tips in terms of what you can do and where you can refer in terms of getting patients the resources they need. I think we are close to our time. I wanted to take this time to thank you guys for joining me here for this conversation. And I know we could probably go for another couple hours on all the different aspects and parts of this journey for these patients that we are passionate about. But I really appreciate you guys being here with me today, and I hope to do this again sometimes soon.