Ashish Kamat: Welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urology at MD Anderson Cancer Center in Houston, Texas. It's my pleasure today to welcome Dr. Renu Eapen, who is a urologist at Peter Mac Cancer Center and the Olivia Newton-John Cancer Center and Austin Health. Joining us today all the way from Australia, welcome Renu.

Renu Eapen: Hello there good morning. Or good evening to you guys. Thanks for having me.

Ashish Kamat: Absolutely. We've been chatting about bladder cancer and cystectomy and women and everything, so that seemed to come together based on your interest in this particular field. I thought it'd be wonderful for you to first presenting and then discussing with us, for the benefit of our audience, the various points to consider both for patients and practitioners when it comes to choices of diversion for women after radical cystectomy. Go ahead, Renu. Take it away.

Renu Eapen: Fantastic. Thank you, Ashish. Again, thank you for this invitation to talk about a topic that I think is really understudied, and that's really looking at outcomes of women after radical cystectomy and how that really influences the choice of diversion in these women. As you all know, bladder cancer is common. It's one of the most common cancers worldwide with an incidence of about 500,000 a year. We know that radical cystectomy is really the standard of care for muscle-invasive bladder cancer or recurrent high-risk nonmuscle-invasive bladder cancer. We know that there are gender-related differences in both oncological and functional outcomes after a radical cystectomy and diversion, but the data really is quite contradictory.

There is a growing body of evidence via med analysis, population-based studies, and collaborative systematic reviews that suggest that female gender may be associated with worse oncological outcomes. Women tend to present with more advanced disease at the time of diagnosis, and they tend to have a higher risk of recurrence and progression and death after treatment as well. The evidence for gender-specific differences in terms of functional outcomes really is lacking, but we know from small series that there are differences in urinary and sexual function and health-related quality of life between men and women.

Why are there these gender differences? Well, there are multiple explanations for this. Firstly, there may be social determinants such as delays in diagnosis and access to treatment. There may be various healthcare disparities based on issues that are influenced by gender. Women tend to have a lower rate of referrals to urologists. There could be a perception that urologists really are doctors for male problems. Women tend to have multiple courses of antibiotics prior to the diagnosis of bladder cancer. In fact, having a diagnosis of a UTI has been found to be a predictor of a delay in bladder cancer diagnosis. There are also biological determinants and so the genetic factors that drive a disease initiation are different in men and women. Women tend to have variant histologies, so based on molecular subtypes with squamous or sarcomatoid histology that is associated with worse stage and survival.

The response treatment may be different, and it's thought that the hormonal axis, which may be different, which may be important in bladder cancer development and progression, is different between men and women. In terms of urinary diversion choices, we know that there are traditionally three different choices. The most common ones really are the ileal conduit or the incontinent diversion and the orthotopic neobladder, which is the continent diversion. Continent cutaneous reservoirs are also used, although less commonly than the other two, in my experience. Whereas, a conduit is really a straightforward option for both physicians and patients. When it comes to continent diversion, such as a neobladder, patient selection becomes really important.

We all know about the advantages of a neobladder, but it's important to highlight to patients the main disadvantages and this includes incontinence, it includes chronic retention requiring self-catheterization, metabolic consequences, and the need for quite strict training regimes. As with anything, the selection really comes down to patient factors, disease factors, and surgeon factors. While age is not necessarily a contraindication, patients should be of good general health and their comorbidities should be taken into account. They should have reasonable physical and cognitive capacity and they should be motivated and be compliant with training programs. In terms of disease factors, the extent of disease at the bladder neck and in men, the prostatic apex should be taken into consideration and certain factors are important. It's been shown that surgeon experience can actually predict the post-procedure quality of life. Surgeon volume and experience is also important.

When looking at functional outcomes in women after radical cystectomy, you're really looking at three main domains and that's urinary function, sexual function and health-related quality of life. The data in this regard is really limited. The reason for this is that women are excluded from many series. The sample sizes are often very small. A lot of studies don't use validated measuring tools or questionnaires, and there's a lot of variation in reporting and in surgical technique. There are a few studies that really assess women alone, and in studies that combine genders, although initially, gender appears to be a predictor for worse outcomes, when it's included in multivariable models with other factors such as age and preoperative continence, gender tends to lose significance.

The first systematic review really was by Smith's group and published in 2017. This was the first systematic review that looked at functional outcomes in women after radical cystectomy and any type of diversion. They looked at about 55 studies and all these studies had a high risk of bias. They ranged in sample size, inclusion criteria, follow-up time and it really meant that they weren't able to do a meaningful meta-analysis. Less than half the studies used standardized instruments, but what they found was the rate of daytime and nighttime incontinence were about 20% each and the rate of hyper-continence or chronic retention was about 10 to 20%. Sexual function was generally poor in those undergoing routine radical cystectomy, but it was slightly better in genitalia sparing surgery. Health-related quality of life, there were minimal differences between diversion types, but certainly significant compared to the general population and the sort of recurring issues were emotional issues, role functioning, appetite, fatigue in women.

Kim's group looked at 142 patients after cystectomy in neobladder formation and it was a mix of men and women with only a small proportion of women, only 23 women. The group classified these women, these patients, according to urodynamic voiding parameters of their neobladders. They identified the ideal group, which had good bladder capacity, normal compliance, and emptied well with low residual volumes. Group two had low capacity and higher rates of incontinence with lower compliance. Group three was on the other side of the spectrum with large residual volumes, and they found that women were more likely to belong to group two or three, so they were more likely to be incontinent or at all have chronic retention and need catheterization. In their multi-varied analysis, they found that age and male gender actually predicted for the ideal urodynamic voiding pattern in the neobladders.

What about pelvic organ preserving surgery? Now we all know that radical cystectomy is really a different technique in women than in men. Historically, women have undergone a full pelvic exenteration, including removing the bladder, the uterus, ovaries, anterior vaginal wall, and now with advancements in imaging and in neoadjuvant chemotherapy and surgical technique, there's been a move from full pelvic exenteration to considering women for pelvic organ preserving or nerve preserving surgery. Again, the data is really scarce, but it is thought to improve continence rates, although studies have shown varying outcomes depending on the time points at which this is assessed. The techniques were also thought to improve sexual function by preserving the entry of the vagina wall and the lateral neovascular bundles of the vagina and blood supply to the clitoris.

Again, there's a lot of heterogeneity in the data surrounding pelvic organ preserving surgery and the data is really quite embryonic and really you need prospective trials in this regard, but this group published in 2017, they did a systematic review to look at the effects of pelvic organ preservation on functional and oncological outcomes in women compared to radical cystectomy and compared to standard radical cystectomy and neobladder formation. They reviewed 15 studies including over 870 women and they saw that in the studies that looked at sexual function about 86% of women were able to resume sexual activity within six months of surgery with a median sexual satisfaction score of over 85%. In terms of urinary function, the data was really widely ranging. Continence rates were varied between 40 to 100% and the catheterization rates varied between 10 and 80%. From an oncological point of view, the cancer-specific and overall survival were really comparable.

Zippe's group in 2004 published about sexual function in a small cohort of women, 27 women who underwent radical cystectomy, and they use the validated female sexual function index, or the FSFI. These women underwent a range of diversions, neobladders, cutaneous continent diversion, and ileal conduit. They found that only about 48% of women were able to have successful vaginal intercourse, 22% had vaginal pain, and overall over 50% of women had decreased satisfaction with their sexual function since radical cystectomy with the main issues being an inability to achieve orgasm, decreased lubrication, et cetera. The same group then did a subset analysis two years later looking at patients post-nerve-sparing radical cystectomy and neobladder formation. They found that most patients in the non-nerve sparing group ultimately discontinued sexual activity and the study showed that while all domains of sexual function had declined in the non-nerve-sparing group, the FSFI scores were able to be preserved in women who underwent nerve-sparing radical cystectomy.

Looking at health-related quality of life in women after radical cystectomy, most of these studies combined genders. When you compare neobladder versus conduit diversion, there are really minimal differences seen, and gender has not been seen to be a significant predictor of quality of life. Goldberg's group published in 2015, looking at longterm quality of life outcomes. That's a minimum of one-year post-surgery compared between patients who've had radical cystectomy followed by a conduit diversion and those having a neobladder diversion. They looked at urinary function, sexual function, and level of bother using the bladder cancer index questionnaire. They found that when it came to urinary function, the conduit group scored better, with bother scores being equal in the two groups. When it came to sexual function, the neobladder group scored better with bother scores being less in the neobladder group than in the conduit group.

With time patients tended to have improved urinary function, worsening sexual function, but they were less likely to be bothered by that decline in sexual function. This group concluded that when you're counseling patients who are electing to have neobladder reconstruction, they should really be warned about the risk of bother from urinary incontinence and the risk of sexual dysfunction. In those who are electing to have conduit diversions, they can be fairly reassured that their expected quality of life won't be significantly compromised.

Looking specifically at the quality of life after a neobladder, Zahran's group in 2014 published looking at 72 women post cystectomy and neobladder with a one year follow up. They divided patients into three groups, so those who were completely continent, those who nighttime incontinence and those who had chronic urinary retention, and they found that women who had nighttime incontinence had a worse overall quality of life than those that were continent or those who required catheterization. Nighttime incontinence really had a negative impact on most domains of quality of life.

Looking at the quality of life after ileal conduit, this group in 2018 compared outcomes of men and women after a radical cystectomy and ileal conduit diversion, and only about a third of these patients were women. They found that while sexual function was worse in men undergoing an ileal conduit, women tended to experience a greater burden in terms of postoperative cognitive function and in terms of future perspectives.

There are many things to consider when it comes to women undergoing radical cystectomy. We know that gender negatively can affect oncological outcome after treatment for bladder cancer. We also can see that characterization of functional outcomes, urinary, sexual, and health-related quality of life is really poor. It can be seen that nighttime incontinence and sexual dissatisfaction definitely negatively impact the quality of life and the recurring theme seemed to be a difficulty with lubrication, difficulty with orgasm, and painful intercourse when it comes to sexual dysfunction.

There is some early evidence to show that pelvic organ preservation and nerve-sparing techniques at the time of cystectomy in very carefully selected patients may help to mitigate some of these effects. For instance, preserving the urethra can help to maintain clitoral blood flow that may help with orgasm, preserving the anterior vaginal and lateral nerve bundles may help with sensation, lubrication. Preserving the ovaries in younger women may help with estrogen-mediated vascularization of the female pelvic organs. Knowing how gender affects outcomes can make it a possible target to improve outcomes just by modifying techniques, but there are main major gaps in knowledge in this area, and we definitely need further prospective trials to fill those gaps.

Ashish Kamat: That was really well done, Renu, and a lot of information in a very short time. Could I ask you a few questions? It's one of those things where when you sit down and you talk to a patient and you're actually counseling them one-on-one over the last 20 years, my conversation with the patients really changed in the way I portrayed the different diversions. Could I have you walk our audience through how you would counsel, say, a relatively healthy 63-year-old woman who's needing a radical cystectomy for T2 disease and has good expected outcomes after the surgery?

Renu Eapen: Yeah. I think when counseling patients it's important to tailor it to that particular patient. I think before giving them advice or recommendations on what their diversion techniques are, it's important to know what's important to them. It's important to find out what their quality of life is like, what their current urinary, sexual function is like, and what their expectations are after the surgery. I think a lot of it is about managing expectations.

I've always been told in my training that nobody should ever talk you into doing a neobladder and you should never talk a patient into doing a neobladder. If a continent diversion is appropriate for them based on their disease characteristics, because oncological outcome is really the most important thing, then I pitch all options to them and give them the pros and cons. Really it takes quite a motivated patient wanting a continent diversion to really proceed in that way. It should be a joint decision with the patient and with the surgeon. I tend to start my counseling by really finding out what's important to them and what would give them the greatest level of satisfaction after surgery, and I let that sort of guide the conversation.

Ashish Kamat: I'm sure you, just like I get the question, so that's all well and good doc, but what would you do if you were me?

Renu Eapen: I answer that very honestly. For me, I think, if my disease permitted it, then I would want a well-created neobladder. I would honestly say that to them in a patient who was considering a neobladder and I would tell them why and I would say that, although despite there are these issues with a neobladder, these are the things that I'm willing to do to make it work. It's a longterm, lifelong investment. I answer that question very honestly, actually.

Ashish Kamat: That's good. It's funny because there are patients that will come and see me from different centers in the US and elsewhere and say, "Oh, when I went to this place, they said, absolutely, you should never have a neobladder. You should only have a conduit", or I went to this place and they said, "Oh, if you don't have a neobladder, then you're just going to hold up in your room and never be able to enjoy life and you'll just die a miserable death." I think what you said about presenting a fair and balanced viewpoint on each of the diversions and letting the patient choose what he or she, in this case, she, would like to do is absolutely critical. Have you ever felt the need to counsel a patient against a selection that she might be making? If so, what sort of parameters do you use to make that decision?

Renu Eapen: The answer is yes. Some patients come to you wanting a neobladder, and they've been told previously that they shouldn't have one and they want to hear the answer, yes, I can get a neobladder in. I find that these are actually quite motivated patients. From a motivation and compliance point of view, they are ideal patients, but the thing that deters me often is their disease. Especially when it comes to women, because although women, you want to give them a neobladder if they can and they want one, the disease is often quite advanced and women often present with nasty disease and it's usually the disease parameters that tend to deter me from recommending a neobladder.

Ashish Kamat: Okay. Do you ever look at the patient's other factors such as potentially their ability to keep appointments or follow-up... Not necessarily socio-economic status, but some of the limitations that their lifestyle would impose upon them when you're making these treatment recommendation decisions?

Renu Eapen: Oh, yeah. Absolutely. I think that comes under the motivation and compliance point of view and their ability to understand what's going on with it; their ability to keep appointments, their ability to seek further information about the diversion choices, I think all gives you an indication of how compliant these patients are. Certainly, if I can see that a patient is not quite fitting into that category, then I make sure that I address their preconceived ideas about what a neobladder might be, and really make sure that they understand that a neobladder is something that requires a lot of effort from them. Some of my mentors here in Melbourne use the analogy of a conduit versus neobladder as having a Volvo versus a Rolls-Royce. Volvo's easy maintenance. It doesn't really matter if you bang it anywhere, but a Rolls-Royce while it's amazing, it takes a lot of investment care and effort to look after it. I often think that patients who come in demanding one over the other have some preconceived ideas that you really need to try and address, debunk some of the myths, and make sure they know what the reality is.

Ashish Kamat: That's an interesting analogy. I hadn't quite heard it put that way. Almost makes me think that you would prefer to drive a Rolls-Royce versus a Volvo. Is that what you're hinting at?

Renu Eapen: Of course, but I think a Volvo that you can just park anywhere, fit into tight spaces, it doesn't matter if it gets a little bit scratched. It's a load off your mind. You don't have to worry about it.

Ashish Kamat: Oh, absolutely. Yeah.

Renu Eapen: That's what a conduit is. It's an easy solution.

Ashish Kamat: Yeah. Often times, it is obvious what the patient's comfort level is. I've had patients who are in their 20's who have disease where they're not expected really, even though we think we'll get them cured with metastatic disease may not live many years, and they select a conduit because they don't want to train a neobladder and put in the time if they're not sure they're going to have a long life. Low and behold, some of them are many years out and still alive and the amount of physical activity, some of them are triathletes and doing stuff with a conduit. A lot of it is, as you said, a mental thing. We could chat forever, but obviously, in the interest of time, we do have to wrap up. Any closing thoughts for our listeners?

Renu Eapen: With any sort of cancer surgery, you want to consider the triad or the four things that are most important in the outcome of that surgery, oncological outcome, and then functional outcomes. In this case, urinary function, sexual function, they're all important, and I think the main thing when it comes to counseling patients is to find out what their expectations are and then address those and tailor it to that particular patient. There's no right fit for everyone.

Ashish Kamat: Well said. Very well said. Thank you once again for taking the time during this crazy 2020 that we have, spending time with us talking about this important issue. Stay safe and stay well.

Renu Eapen: Thank you so much for having me, Ashish. Really appreciate it.