Transcription:

Andrew Wilner, MD: Welcome to GW Doc Pod, a peer to peer podcast for medical professionals with The George Washington University Hospital. I'm your host, Dr. Andrew Wilner. I invite you to listen in as we discuss updates in the treatment of muscle-invasive bladder cancer, such as immunotherapy and robotic surgery.

My guest today is Dr. Michael Whalen, Associate Professor of Urology at The George Washington University School of Medicine & Health Sciences and Chief of Urologic Oncology at The George Washington University Hospital. Welcome, Dr. Whalen.

Michael Whalen, MD: Thanks for having me.

Andrew Wilner, MD: Dr. Whalen, thank you for joining us. We spoke on a prior podcast about prostate cancer, and today we are moving up the urinary tract to discuss bladder cancer. How common is it?

Michael Whalen, MD: Bladder cancer is actually the fourth most common cancer in men. And it's a smoking-related cancer, meaning that cigarettes and tobacco history play a role in the generation of the disease. Most people think of smoking-related cancers being like lung cancer. But bladder cancer is fairly common, yet it is not as widely kind of spoken about or known.

Andrew Wilner, MD: Right. So my take on that is the kidneys filter the blood. There's toxins in the smoke, and they all end up in the bladder and just sit there all day, you know, until you go and pee. And somehow that's not a healthy thing for the bladder. Is that kind of what it boils down to?

Michael Whalen, MD: Exactly. Yes. All the carcinogens that are filtered into the urine bathe the inner lining of the bladder and can lead to cumulative oxidative stress and damaging the DNA of the cells that line the bladder. Whenever there's a smoking history, there's risk for the lining becoming cancerous down the road even for people who have a remote smoking history, you know, who haven't smoked in many, many years, you know, there's still that risk. Certainly something to bring up with your doctor and it's important as you're seeing your primary care doctor, even before you get to the urologist, to talk about smoking history because your primary care doctor will do a urinalysis and make sure there's not blood in the urine. So it's actually a common referral to the urologist for what we call microscopic hematuria, finding trace amounts or microscopic amounts of blood in the urine and that prompts further workup such as imaging with a CT scan or even an endoscopic evaluation of the bladder, which is performed by the urology specialist in the office, giving numbing medicine and a gulp of courage. It's actually. You know, not so unpleasant to have you know, but the camera's put into the urethra and the bladder is inspected to make sure there's not tumors.

The majority of bladder tumors are not invading into the muscle layer of the bladder about 75% of the time. But about 25% of the time, the tumor can be invading into the muscle layer and that makes it more difficult to treat and requires usually multiple modes of treatment. Any time we see blood in the urine that a patient can see, you know, which is called gross hematuria, or, you know, the urine looks red or wine-colored or like fruit punch sometimes with blood clots that pass, we get very concerned that there may be an underlying tumor.

Andrew Wilner, MD: Yeah, that will definitely get anyone's attention. Before we proceed with the workup, are there any other risk factors for bladder cancer besides smoking? Does it matter what you eat or drink or where you live or if you're a man or a woman? Or is smoking the big thing?

Michael Whalen, MD: So it's more predominant in men. There are some occupational exposures with certain chemicals like benzene or aromatic amines or even dyes like aniline dyes that are used in the textile industry, or even hair dyes for people who have worked as hairdressers. Given a lot of contemporary regulations in reducing exposure to these chemicals, and It's not as common in this day and age, although, you know, I do have patients who have been exposed to various chemicals, like even in the gardening industry who had developed bladder tumors at a young age and we couldn't really find any culprit except for that.

Also any history of radiation to the pelvis, like for people who've had prior things like cervical cancer or other gynecologic or even colon malignancies maybe at higher risk or even men who have had prostate cancer that have gotten radiation, they're at increased risk for developing tumors in the bladder as well. There is not as robust a genetic component as for prostate cancer, for example, but that's being further elucidated and understood these days.

Andrew Wilner, MD: Okay. So from the patient's point of view, if there's blood in the urine, it's off to the doctor right away and probably to the urologist. Or if just during a checkup the doctor finds microscopic hematuria and then you're going to proceed with a workup. So what's the first thing you would do? I think you mentioned a cystoscopy. Is that the number one test or is there something before that?

Michael Whalen, MD: The very first thing we would do is to make sure there's not an infection as the cause of the bleeding. You know, that can be associated with certain symptoms like burning, frequency, urgency, and once that's ruled out as well as potential benign causes like prostate enlargement, usually we'll do imaging. These are either a renal and bladder ultrasound or a CT scan, and then a cystoscopy, which is, as I said, an endoscopic evaluation of the bladder sometimes because small polyps go unseen on traditional imaging.

Andrew Wilner, MD: Okay. So you found a bladder cancer, what happens next?

Michael Whalen, MD: Typically, it requires a biopsy and this is an excisional biopsy done endoscopically under anesthesia. And we want to assess the aggressiveness of the cells and also the depth of invasion into the bladder wall. That's usually done as an outpatient procedure as an endoscopy, as I said. And then once we get that information, we will be able to understand what the next steps are and we want to determine whether there has been invasion into the muscle layer of the bladder.

Andrew Wilner, MD: You know, somehow the surgeons, they always seem to want to remove the problem, but I mean, can you remove the bladder?

Michael Whalen, MD: Yes. And in fact, that is the standard approach for people who are fit to undergo surgery along with usually systemic therapies such as chemotherapy or immunotherapy. Once the disease has invaded into the muscle, there can be microscopic cells that get into the lymphatic system or the blood system, and have a tendency to spread to the lymph nodes. So about 30% of the time, if there's muscle invasion, there's also lymphatic involvement. So we get concerned that we're limited in our ability to go in endoscopically and just shave out the tumor, for example, because it may already have spread. So there's where multi-disciplinary collaboration among the urologist and the medical oncologist and sometimes even the radiation oncologist come into play.

At GW, we have a multidisciplinary genito urinary cancer clinic, where we enlist the services of each of these types of specialists to understand and develop personalized and precision medicine treatment approach to handling the patient's disease. And there's been a lot of advancements in the realm of systemic therapy, not only giving chemotherapy, but also immunotherapy.

Now, bladder removal is a big surgery. And you may wonder why that is. I mean, there's been no replacement bladder sort of developed in the same way that we have replacement kidneys, you know, like dialysis or even cardiac assist devices sort of replacement hearts. There's been no artificial way to store urine without transmitting pressure up to the kidneys and leading to progressive kidney failure. And there's not really like a bladder replacement that can be grown. There are some institutions doing tissue engineering and bioengineering using biologically-based scaffolds and trying to grow tissue on them. But it's far from prime time at this point.

As I said, the majority of bladder cancers are non-muscle invasive, so it can be managed with shaving out the tumor, you know, understanding and staging it and then giving actually medicine inside the bladder, usually with a catheter temporarily. But then for those with muscle invasive disease, we get concerned that the disease may spread and unlike prostate cancer, which is a very slow-growing disease, bladder cancer if it spreads is incurable and can be rapidly lethal, you know, and it's like advanced kidney cancer, you know, one of the genitourinary cancers that has a high mortality rate associated with it if it's locally advanced or spreads.

Andrew Wilner, MD: All right. So that sounds nasty. So blood in the urine, you go to the doctor that day so that you can catch this thing early. Like all cancers, you do a lot better if you get it early, before it invades other tissues than late. Now, you mentioned immunotherapy. What's that all about?

Michael Whalen, MD: So immunotherapy is a type of systemic therapy that's growing in understanding use for various cancers. It makes use of the fact that the immune system is constantly monitoring for any cancer cells in the body and often kind of keeping them at bay and mobilizing killer cells to destroy any incipient or newly-formed tumors. Cancer cells can evolve the ability to kind of elude or evade the immune system by expressing certain proteins on the cancer cell surface that turns off T-cells. It's been understood through, you know, pioneering work at major cancer centers about this immuno-oncology pathway. And there have been drugs developed, antibodies, against these proteins that the cancer cells manifest and also the receptor proteins on the immune cells that basically takes the brakes off the immune system and allows it to re-recognize the tumor cells. The advantage of these is that there's less toxicity and less side effects than associated with traditional chemotherapy. And there's immense efforts to integrate these immunotherapies into the treatment of bladder cancer.

Most of the work has been done in advanced and metastatic bladder cancer for patients who have no other option. But because of the multi-institutional collaborations afforded by the various national cooperative oncology groups, such as the Southwest Oncology Group, Eastern Cooperative Oncology Group, we've been able to make strides in bumping up these therapies earlier and earlier in the treatment pathway. So, you know, offering them not only to advanced or metastatic patients, but to patients who have localized disease in the bladder, which has started to the muscle. And the hope here is that we can give the systemic therapy and have less side effects.

The work has been done after having surgery to remove the bladder and there's been work done as well to give these therapies before bladder is removed and the outcomes are very promising. It seems like the tumor responses and the shrinkage rate or the complete response rates are similar to chemotherapy and they have a better side effect profile. And we're even starting to do trials to understand which patients may not have to have their bladders removed. You know, I do surgery and robotic surgery, which is called the radical cystectomy to remove the bladder and rebuild a urinary diversion out of intestine. But, you know, I'd love to not have to do that. And it's an ongoing efforts at multiple institutions across the country, and even internationally to understand how these immunotherapies may factor in before the surgery process and even potentially in place of the surgery.

You know, it's sort of not ready for prime time and it's important to discuss the possibility of, you know, any patient's candidacy for these things with their oncologist and their urologist and their urological oncologist. But, you know, clinical trial enrollment is paramount in this setting. So we can study these things and understand how future generations can benefit from the information that we derive.

Andrew Wilner, MD: Do you have these collaborative arrangements at George Washington Hospital and clinical trials available there?

Michael Whalen, MD: Yes. One in particular is called the ambassador trial, which is giving the medication pembrolizumab after a radical cystectomy. And we're always in works with the clinical trial office to open new trials. And I would like to see some in the neoadjuvant space as well, meaning, you know, prior to surgery. I mean, one of the limitations with having the ambassador trial open and, you know, we don't want to compete with our own trials, right? So we have to make sure that we have enough patients to enroll. But there are some very promising ones, single institutions, small numbers of patients that seem promising and, you know, once that traction is gained and, you know, those results are published, then those trials are usually expanded to involve other institutions. And I'm very eager and excited to get GW involved in that.

Andrew Wilner, MD: Now, before we started recording this episode, we were chatting and you mentioned something about gene therapy and identifying abnormal genes. Where does that fit in?

Michael Whalen, MD: So with prostate cancer, there are commercially available genomic profiling or gene expression profiling that can be run on a mRNA. The bladder cancer space is trending in that direction and there's been something called the Cancer Genome Atlas, which has done whole exome sequencing of the basically genome of bladder tumors that are muscle invasive and come up with five different subtypes that are genetically based.

There's been a few trials looking at how these subtypes respond to various treatments and no consensus or sort of unanimous say right now is part of the reason that there's no commercially available assay, meaning like you can't just take the tumor cells and, you know, extract the DNA and then run this thing and get a profile and know exactly how it's going to behave. But that work is being moved forward. And more and more trials were being done.

There was something called the COXEN Trial, which looked at a co-expression analysis of various in vitro tumors and developed a signature that was then validated in multiple bladder cancer cohorts. And then there was a randomized trial done through some of the methodological limitations of that study. There was no definitive predominant signature that could predict who would respond to chemotherapy. That was the intention of that trial. So, you know, more work has to be done, but we're growing in our understanding about how the underlying genetics of the tumor might predict who will respond to various treatments. And it's important that we don't want to give someone chemotherapy, that's going to hype toxicity and side effects associated with it if they're not going to respond. And more importantly, if we can get a gene profile, that'll say, "Okay, you know, patient A, you're more likely to respond to chemo. Patient B, you're more likely to respond to this new immunotherapy," then, you know, that would be great. And then we can better tailor based on the data which systemic therapy a person will get. Or conversely, if we say, "Listen, each of these medicines doesn't look like it's going to work based on your genes, then we'll go right to surgery because we don't want to waste time exposing you to toxic chemotherapy if it's not going to work and, you know, give the tumor a chance to grow and potentially spread."

So, there's a lot of efforts being done and we don't quite have, the smoking gun signal right now. But it's an exciting time for us clinicians and researchers to be able to utilize these findings and kind of share in the dialogue with our patients about what's going on so that we can kind of poise them on the cutting edge to be able to really utilize this understanding derived at other institutions and implement it at our own institution.

Andrew Wilner, MD: Okay. Well, Dr. Whalen, we're just about out of time. Is there anything else you'd like to add before we close?

Michael Whalen, MD: For patients, again, any blood in the urine is concerning. You want to rule out a urinary infection. And if that's ruled out, then, you know, bladder tumors unfortunately should be on the differential. So make sure you talk to your primary care doctor about being referred appropriately to a specialist. And although, I never liked having these conversations with patients, we have a lot of tools in our toolkit to be able to treat the disease and even cure it.

Andrew Wilner, MD: Oh, well, that's pretty exciting. Dr. Whalen, I want to thank you for this great discussion about the modern approaches to bladder cancer treatment utilized at George Washington University Hospital.

Michael Whalen, MD: Thanks for having me.

That concludes this episode of GW Doc Pod, a peer to peer podcast for medical professionals with The George Washington University Hospital. To refer your patient please call 1-888-4GW-DOCS. If you have a question for one of our specialists please email physicianrelations@gwu-hospital.com

Disclaimer: Physicians are independent practitioners who are not employees or agents of The George Washington University Hospital. The hospital shall not be liable for actions or treatments provided by physicians. Individual results may vary. There are risks associated with any surgical procedure. Speak with your physician about these risks to find out if minimally invasive surgery is right for you.