Transcript of What is Metastatic Bladder Cancer? with Dr. Arlene Siefker-Radtke

December 12, 2023

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Voice over:

This is Bladder Cancer Matters, the podcast for bladder cancer patients, caregivers, advocates, and medical and research professionals. It’s brought to you by the Bladder Cancer Advocacy Network, otherwise known as BCAN. BCAN works to increase public awareness about bladder cancer, advances bladder cancer research, and provides educational and support services for bladder cancer patients and their loved ones. To learn more, please visit bcan.org.

Rick Bangs:

Hi, I’m Rick Bangs, the host of Bladder Cancer Matters, a podcast for, by and about the bladder cancer community. I’m also a survivor of muscle invasive bladder cancer, the proud owner of a 2006 model year neobladder and a patient advocate supporting cancer research of the Bladder Cancer Advocacy Network, or as many call it BCAN, producers of this podcast. I’m pleased to welcome today’s guest, Dr. Arlene Siefker-Radtke.

Dr. Siefker-Radtke is a medical oncologist and is a professor in the department of Genitourinary Medical Oncology Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, where she has been exclusively focused on the treatment of urothelial cancer for over 20 years. Dr. Siefker-Radtke earned her medical degree from the Johns Hopkins University School of Medicine. An active researcher, Dr. Siefker-Radtke Has published over 150 journal articles, abstracts, editorials, and book chapters. She focuses on developing effective therapies for the treatment of urothelial cancer and other rare tumors of the bladder and upper tract. She is well-known for her novel clinical trial designs, development of novel agents and targets, including immunotherapy, fibroblast growth factor receptor inhibitors, development of neoadjuvant chemotherapy and expertise in treating even the rarest tumors of the bladder. Dr. Siefker-Radtke is actively involved in the oncology research programs at NCCN, the National Comprehensive Cancer Network. She currently serves as a member and Value Pathways Task Force member of the NCCN Bladder Penile Cancers Panel, and she’s on the NIH Bladder Cancer Task Force.

Dr. Siefker-Radtke, thanks for joining our podcast today.

Dr. Arlene Siefker-Radtke:

Oh, thank you so much for the kind introduction, Rick, and please do call me Arlene.

Rick Bangs:

Okay, thanks Arlene. All right, so at this year’s think tank, the BCAN Think Tank, you were part of the terrific panel and it discussed a specific topic that I think is going to be interesting for our listeners. And the topic was defining treatment lines in metastatic urothelial cancer, choosing the right targets in combinations of the right type. So we’re going to focus today on metastatic urothelial cancer. I thought we should start with some basics. So what is metastatic cancer?

Dr. Arlene Siefker-Radtke:

Metastatic cancer is considered the highest stage of cancer. You may hear it referred to as either metastatic or stage four disease. This is typically cancer that has spread to other areas, which could include lymph nodes, especially multiple or bulky lymph nodes. It could include other sites such as lung metastases or liver or bone metastases, which are some of the most frequent sites that this cancer does indeed spread to. When we do here it is a metastatic cancer, unfortunately, that means it’s less likely to be curable, but it is still treatable. And the goal of treatment in this setting is to try to shrink that tumor and control it, help control a person’s symptoms with the goal toward extending that individual’s life.

Rick Bangs:

Okay. And so how does a metastatic cancer differ from what’s referred to as an advanced cancer?

Dr. Arlene Siefker-Radtke:

So an advanced cancer, that is one of those vague terms that I always require clarification because different institutions identify advanced cancer differently. For some places they call an advanced cancer a tumor that is still potentially curable but might be extending beyond the wall of the bladder or at be at a high risk of recurrence with surgery alone. So we’ll often hear the term locally advanced in that setting. But there’s others who use the term advanced cancer to describe tumors that are already metastatic. So when I hear the term advanced, I often ask for more clarification. It’s not a formal medical definition, so what does that person’s individually view as an advanced cancer?

Rick Bangs:

This is really helpful. It helps clear up some of my own personal confusion. So glad to hear that it’s not consistent across institutions. I always wondered.

Dr. Arlene Siefker-Radtke:

Yeah. You’re right to wonder. It’s not a well-defined medical term. It’s more a personal term of preference or how that physician or their institution might view a malignancy.

Rick Bangs:

Got it. And are the risks consistent for all metastatic diagnoses?

Dr. Arlene Siefker-Radtke:

Well, the risks are indeed different. There are some tumors that, say they involve lymph nodes in the pelvis and these can even be multifocal lymph nodes that would meet the definition of stage four disease due to their multiplicity or size. And while that’s stage four most commonly incurable, we do have patients where we give aggressive chemotherapy where we get those lymph nodes into a complete remission and then we can do surgery which is removal of the bladder and a bunch of the lymph nodes nearby, resulting in the potential for cure in the range of 30 to 40%. At MD Anderson, we consider this surgical consolidation because these are patients who were typically not involved in neoadjuvant trials because they require a response to treatment to be considered surgically resectable.

There’s other disease sites that have a worse prognosis. Lymph node only disease has always had a better prognosis compared to those who have cancer that has spread to the lung. And if we look at historical data, cancers that have spread from the bladder or the urothelium to the liver or to the bone have typically had the worst prognosis overall. And they may respond differently to different treatments. Where lymph node only disease responds better to immunotherapy, but patients whose disease has spread to the liver may not have as much benefit from an immune checkpoint inhibitor alone.

Rick Bangs:

So are the lymph nodes a jumping off point for the liver or the lungs or the brain, or can it actually be skipped and just go from the bladder to the liver to the lungs? How does that work?

Dr. Arlene Siefker-Radtke:

Sure. Well, most commonly we see the tumor starting in the bladder and then we see it spreading to local lymph nodes starting in the pelvis. They then move up from the pelvis into the abdominal cavity along the arteries by the kidneys, and then they can go into lymph nodes in the chest or even in the left neck or clavicle areas. But we also see patients who don’t have tumor in the lymph nodes and rather they have metastatic disease. So we suspect that these different tumors or how they may spread, if they go through the lymph nodes, it’s probably through a lymphatic distribution and they eventually can jump from the lymph nodes to entering the bloodstream and spreading to different organs via the bloodstream. And those who don’t have any lymph nodes but have metastases to lungs and liver or bone, often had that early spread or invasion into blood vessels in the tumor that allowed them to spread via the blood system.

Rick Bangs:

Okay, thanks. That’s always confused me. So that’s really helpful. So what factors are more likely to result in my having a metastatic bladder cancer diagnosis?

Dr. Arlene Siefker-Radtke:

So metastatic tumors are typically defined by CT scans where we see evidence of tumor spread. And each patient’s tumor, every person’s tumor is different. We see some tumors that are very low grade, low stage, spend a long time in the bladder and may never spread to other areas. These are typically superficial tumors managed by urology treated with local resections. But when we start seeing high grade disease in the bladder, those are tumors that are starting to gain that more aggressive potential where they can start invading the lymphatics and go into lymph nodes or invading the blood vessels of the tumor in the bladder and spread to the lung, liver, bone or other organs.

As far as why do some tumors spread in different ways, we don’t yet fully know why some prefer to go the lymphatic route and some prefer to spread via the bloodstream.

Rick Bangs:

And why is metastatic so difficult to treat?

Dr. Arlene Siefker-Radtke:

Well, once the tumor has spread to multiple areas, there’s a high likelihood that their seeds of tumor in other areas of the body as well. I often tell patients, this is like having a dandelion in your lawn. When you see one dandelion, you’re more likely going to see additional dandelions over time. And that’s why we need systemic treatments, treatments that go throughout the whole body, throughout the bloodstream to potentially kill off not only the tumors that we can see on the CT scans, but also kill off those microscopic seeds of tumor in other locations, the ones that are too small to be seen.

Rick Bangs:

Okay. And I think we had some exciting news this past weekend, and so I wanted to ask you about treatment options because I think your answer might be a little bit different today than it would’ve been a week or two ago unless you were privy to some of the information that was shared at ESMO.

Dr. Arlene Siefker-Radtke:

Oh, absolutely, Rick, it’s such an exciting time for the treatment of urothelial cancer and bladder tumors in general. If we look at what’s been done in the past, it was really focused on cisplatin versus carboplatin based chemotherapy with life expectancies that were around one year. Then we had the addition of immune checkpoint inhibitors, which resulted in extension of life for more people living longer. And then a few of these rare patients, probably less than 5%, who had these durable responses that lasted many, many years and some of whom have not relapsed.

We’ve had the recent development of these targeted strategies, antibody drug conjugates, which bring chemotherapy more directly to the cancer, which results in decreased side effects for the patient because we’re getting more of that chemotherapy to the tumor tissue rather than having it go to other organs in the body that don’t have cancer. And by targeting the cancer more directly, we’re seeing effective responses that are also extending a patient’s life.

Now, what’s been so exciting this past weekend, it’s like combining peanut butter and chocolate. We had immune checkpoint inhibitors, that’s our peanut butter. We’ve seen these lovely respondents and then we’ve got the chocolate, the new antibody drug conjugates. And we combine them together in the frontline setting. And what we saw was a significant improvement in overall survival by giving this combination together.

I mentioned when we started, when I started in this field, the average life expectancy was around one year. One year. We needed to do better than that. With this combination of enfortumab vedotin plus pembrolizumab, so that targeted chemotherapy with a medicine that stimulates the immune system to fight cancer. They presented data suggesting that average life expectancy is now 31 months, over two and a half years. And what an average means, that average means half live less than that, and the other half live longer than that. So we are now seeing people with bladder cancer who are living even longer than they ever did in the past in patients who have been with me and seeing me in my clinic for many years. So it really, really was exciting data just seeing how long people are now living with their incurable bladder tumors.

Rick Bangs:

Wow. This has just been an incredibly long wait to get to this point, but it’s so exciting that we’re here. So in case people are listening and they want, they’re in this kind of state, would they be able to get this combination today? There’s still research being done, so would I be able to get this combination today?

Dr. Arlene Siefker-Radtke:

Well, you are able to get this in the United States, the FDA granted accelerated approval to this combination of enfortumab vedotin with pembrolizumab in patients who are not eligible for cisplatin based chemotherapy. So you can certainly get it now. The biggest question is should we give it even in patients who are eligible for cisplatin? And I would argue the current data suggests we should. We are seeing this prolongation of life even in patients who could have received more aggressive chemotherapy. And this combination has a toxicity profile or side effect profile that appears easier for patients, where patients are able to tolerate more doses for longer. So I think in the United States, we are able to have access to these therapies. Other countries are a little further behind and they’ll be waiting for further evaluation and publication of the data and then for review by their own bureaucracies to determine whether they can receive this in their local countries.

Rick Bangs:

But we’re getting more effective treatment with less side effects, and that is a combination we’re always striving for.

Dr. Arlene Siefker-Radtke:

Absolutely being able to treat more patients with more effective therapy and not cause side effects, I think that’s an oncologist’s dream. And I would argue if we get really good at this and there’s no side effects, they’ll start giving this at Walmart and I’ll be out of a job. But that’s okay. It would be a wonderful thing to have happen. We’re not there yet. There’s still side effects with treatment, but we are able to now treat more patients than we were able to treat before.

Rick Bangs:

Excellent. Excellent. All right. But still more research to come, so we’ll be listening for that, but this is really exciting news.

So for the person who does not receive treatment for whatever reason, what would their typical journey be as a metastatic bladder cancer survivor?

Dr. Arlene Siefker-Radtke:

So when we look at the average bladder cancer patient, this is typically a cancer of the geriatric patient population where the average age is in the 70s. These are individuals who unfortunately through living life have developed comorbid medical conditions. These are other medical issues that might be even contributing to the development of bladder cancer. Oftentimes smoking, it’s one of the biggest risk factors for bladder cancer, which can contribute to heart disease, emphysema, and contribute to diabetes, which also impacts kidney function and causes nerve damage.

So, we are seeing a lot of patients who are older patients, are geriatric patients, and ones who can’t tolerate the most aggressive treatments, which is why it’s so important to give and develop treatments that everybody can handle. Before we had some of these novel agents, it was estimated that less than half of patients with metastatic bladder cancer were eligible for standard of care chemotherapy with cisplatin, and they would often receive carboplatin, but there are patients who cannot tolerate carboplatin either.

So for patients who truly are unable to tolerate chemotherapy, the typical journey was that we would give them single agent immunotherapy, a medicine to stimulate their immune system to fight cancer. And we saw response rates in about 20 to 25% of patients, meaning one out of four patients who received this treatment would have their tumor shrink and it would result in an average life expectancy of around one year.

Rick Bangs:

So we have a number of people who can’t get chemo, and then we have a number of people within the group that can get chemo that are going to have side effects that are just not going to be acceptable. And we have an alternative, which may work for a number 25 or whatever percent, some portion. So by the time we start with the population it’s going to be a very small group here that actually can benefit. Right?

Dr. Arlene Siefker-Radtke:

Well, when we look at response rates and who’s benefiting from therapy in the era of cisplatin and carboplatin, we had a lot of unmet need. We had a lot of patients who just couldn’t tolerate that treatment, especially in the community. At academic centers where I work, I do tend to see healthier patients who are able to make the trip and have enough energy or reserve where they want to try novel agents or get advice from experts who see this disease routinely.

With the development of enfortumab vedotin with pembrolizumab and the ability to give this in patients who cannot tolerate cisplatin, what I’m seeing is that more patients who were considered ineligible for treatment are now able to receive a potentially effective treatment. And the response rates with this enfortumab vedotin and pembrolizumab are quite high. In fact, 6 to 8 people out of 10 will have some reduction in the size of their tumor as a result of treatment. So as we build better treatments that have an improved safety profile and are more tolerable, will be able to treat more patients effectively and help control those symptoms or delay those symptoms and help patients live longer.

Rick Bangs:

Okay. So let’s talk a little bit about the side effects. If I’m getting standard chemotherapy, what might my side effects look like and what would they look like if I’m getting enfortumab vedotin and pembrolizumab?

Dr. Arlene Siefker-Radtke:

One of the big differences between these two treatments are the low blood counts. When we treat with typical chemotherapy, it does suppress the cells associated with the immune system. It kills off neutrophils and lymphocytes. These are the immune cells that help fight infection. So when we talk about side effects from standard chemotherapy, one of the most common ones was low blood counts, needs for transfusion and actual infections. You may hear your doctor talk about neutropenic fever, which is when your blood counts are low when you develop a fever or infection. These have frequently required hospitalization with intravenous antibiotics, allowing the patient time for their blood counts to recover and for them to fight off an infection.

So one big difference is that enfortumab vedotin with pembrolizumab does not impact the immune cells like chemotherapy does. It can for some. No treatment’s perfect, there are side effects. But on average, very few people are developing these fevers or neutropenic fevers requiring admission to the hospital with enfortumab vedotin plus pembrolizumab.

Now we do see side effects though that are more associated with the enfortumab vedotin and pembrolizumab. The two most common ones are that patients can have neuropathy or nerve damage. This usually starts as numbness and tingling in the fingers and toes and it can extend up into the hands through the feet and into the shins impacting a person’s ability to walk. When we have too much neuropathy, we can’t feel the floor effectively, and it results in a higher risk for falling and fractures of the hip. So neuropathy is one of the side effects that we’re seeing more commonly with enfortumab vedotin plus pembrolizumab.

Another side effect is a skin rash, which is probably due to the drug going to some of the skin cells and causing death in some of the skin layers. An additional toxicity is the autoimmune effects from pembrolizumab. So pembrolizumab is a medication that stimulates your immune system to fight cancer. But sometimes the immune system gets turned on too much and it starts attacking vital organs and we’ll see patients needing thyroid hormone replacement, probably about 15 out of 100 patients will need that. About 10% of patients will have their immune systems target a vital organ. Usually we can cool it off by giving steroids or other medications, but there is still a risk of death from treatment. And the risk of death from immunotherapy is typically less than 3%, which has been similar to the risk of death from systemic chemotherapy.

Rick Bangs:

If I have neuropathy, can you give me something to help with the neuropathy?

Dr. Arlene Siefker-Radtke:

Unfortunately, there’s no effective treatment that helps the neuropathy heal faster. So when we see neuropathy, it’s important to tell your doctors you are experiencing it. The best strategy is to reduce the dose of the enfortumab because by reducing the dose earlier, patients are able to stay on treatment longer. So being able to reduce the dose does help people stay on treatment.

If someone has neuropathy, there are medications we can give to help with the symptom. But these medications, they alter our perception of the neuropathy. So they don’t actually heal the nerves, they just make it less aggravating. We don’t feel or experience the neuropathy as much. And some of those medications include gabapentin. It really does take time though, and for a lot of patients who develop neuropathy from treatment, if they take a break from their treatment, the neuropathy will improve over time.

Rick Bangs:

So you mentioned earlier that for most metastatic bladder cancer patients, they would not do a radical cystectomy. So could you quickly kind of summarize why that is? What’s the thought process?

Dr. Arlene Siefker-Radtke:

Once your cancer has spread elsewhere it’s like the horse is out of the barn. So doing something to try to fix the gate doesn’t help. It doesn’t extend a person’s life. The cancer seeds have already spread to other areas. So putting someone through a major procedure and removing their bladder so they now have to use an ostomy, which is the most common surgical strategy. If it doesn’t save lives or extend a person’s life, I don’t think we’re justified in doing that to someone.

Rick Bangs:

Yeah. It makes sense. Okay. So now I want to talk about two terms that are sometimes confused and they are different. So let’s talk first about palliative care. So when should a patient seek out palliative care?

Dr. Arlene Siefker-Radtke:

I think it has been very important to help control symptoms even while patients are receiving active treatment. And this is a skillset that many medical oncologists have acquired over time, giving medications to help with constipation, to help with neuropathy, to help control pain. This is all important to helping people feel well so they can continue on effective treatment. A lot of programs have also developed palliative care programs or supportive strategies. These are often working with pain doctors who can help control pain when some of the easier pain medications that we can give are no longer working. In those instances we’ll often send someone to supportive care to help improve their pain management or help improve management of constipation or other symptoms.

But unfortunately, there is another step in palliative care. This is when treatment is no longer effective. Unfortunately, this cancer over time becomes resistant to the best treatment strategies that we have available. And when this cancer becomes resistant to treatment, then continuing therapy typically causes more harm than good. It gives the patient side effects without any benefit, without any improvement of symptoms, and without that extension of life. In that setting we typically move to a purely palliative or hospice based strategy where we focus on keeping them comfortable, trying to get them closer to their loved ones since their time may be short so they can spend whatever quality time they have remaining with their family and friends.

Rick Bangs:

Important discussion for a patient to be involved in here or the family making those decisions on goals and when to move into palliative care or hospice, particularly in this setting. Thanks for helping us with that.

So when would a second opinion make sense for me as a metastatic bladder cancer patient?

Dr. Arlene Siefker-Radtke:

Well, I think second opinions always make sense. This type of cancer is more rare. A lot of medical oncologists in the community may only be treating a few patients each year. So whenever a person feels they want to explore other options or just ensure they’re receiving the correct or the best upfront therapy, it is very reasonable to ask for that second opinion. It provides reassurance to the family, even if they are on the most effective treatment, that they are doing the right thing and they’re getting the best treatment available for them.

We also have a lot of novel agents and novel strategies being studied on clinical trials, and it’s through persons participating in these trials that we are building these more effective treatment strategies resulting in drug approvals, allowing us to then offer these treatments to everyone, not just those on a clinical trial. So we always appreciate clinical trial involvement. It’s the patients who participated in trials in the past that have gotten us to this point today where we are seeing improved treatments with less toxicity that are also helping patients live longer.

Rick Bangs:

So I think you and I are on the same page. Second opinions always make sense. Clinical trials always make sense. Not just in the metastatic situation, but also across the spectrum. So it’s always a good idea to ask about clinical trials or second opinions.

So what questions should patients ask when they’re presented with options in the metastatic context?

Dr. Arlene Siefker-Radtke:

So when a person sees their oncologist I think the first question to ask is, is this curable or is this not curable? That way you know the goals of treatment. It’s also personal choice. I’ve had some patients who did not wish to know because they still wanted that hope. I personally think having appropriate hope, knowing what to plan for, what’s going to happen down the road can be very helpful. And then when you are seeing your medical oncologist asking what are the side effects of treatment? Are they able to tolerate those side effects? Even though we talk about treating the average patient, no patient is truly average. We all have things that have happened to us throughout our lifetime and we need to take that into account as we build the best treatment strategy for a particular patient.

Other questions they should ask their oncologist is, are they going to do any tests on the tumor, especially for mutations? This is important because we do have approved treatments such as with erdafitinib, which is a pill that targets an FGF mutation that’s found on 15 to 20% of tumors of the bladder, and up to 35% of tumors involving the renal, pelvis and ureter. Knowing this mutation is present helps you plan for incorporating this additional strategy, erdafitinib, which has been associated with extension in life.

Rick Bangs:

And we wouldn’t have been having this conversation a few years ago, so this is late breaking in the last few years, which is incredible. All right. Any final thoughts on this particular context and diagnosis?

Dr. Arlene Siefker-Radtke:

Well, what I can say about bladder cancer is even when it’s incurable, there’s more hope today than there ever was in the past. Patients are living longer. We’re seeing responses that have the potential for durability and people who are now living not just one year, but many years. With some, it’s still a small number, but some whose disease doesn’t relapse over time. At the moment, we can’t predict who those will be. But I think it does provide that hope and that reason for trying these novel agents and novel strategies to see if you can achieve that great response and then have that potential for durability. One of those responses that may last, not just one year, but many years.

Rick Bangs:

So we’ve come a long way. We’ve still got a long way to go, but we certainly come a long way.

Dr. Arlene Siefker-Radtke:

We have come a long way.

Rick Bangs:

Yep. Yep. So asking these kinds of questions is really important. So Arlene, I want to thank you for sharing your perspective on navigating this very challenging diagnosis of metastatic bladder cancer.

Dr. Arlene Siefker-Radtke:

It’s certainly my pleasure, Rick. I think everyone deserves to get effective treatment, and I’m so thrilled that we’re now seeing more effective strategies that can be used for even more patients with this deadly cancer.

Rick Bangs:

Amen to that.

If you’d more information on bladder cancer, please visit the BCAN website, www.bcan.org. Just a reminder, if you’d more information about bladder cancer, you can contact the Bladder Cancer Advocacy Network at 1-888-901-2226. That’s all the time we have today. Be sure to like, comment and subscribe to this podcast so we have your feedback. Thank you for listening, and we’ll be back soon with another interesting episode of Bladder Cancer Matters. Thanks again, Arlene.

Dr. Arlene Siefker-Radtke:

Oh, it’s my pleasure, Rick.

Voice over:

Thank you for listening to Bladder Cancer Matters, a podcast by the Bladder Cancer Advocacy Network, or BCAN. BCAN works to increase public awareness about bladder cancer, advanced bladder cancer research, and provide educational and support services for bladder cancer patients. For more information about this podcast and additional information about bladder cancer, please visit bcan.org.