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CME / ABIM MOC

Treatment Approaches in Early-Stage Bladder Cancer

  • Authors: Neal Shore, MD, FACS; Matthew D. Galsky, MD, FASCO; Stephen B. Williams, MD, MBA, MS, FACS
  • CME / ABIM MOC Released: 11/8/2022
  • Valid for credit through: 11/8/2023
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Target Audience and Goal Statement

This activity is intended for urologists, oncologists, surgeons, and other healthcare professionals who care for people with bladder cancer.

The goal of this activity is for learners to be better able to understand and recognize the latest treatment approaches for patients with or without radical cystectomy in early-stage bladder cancer.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Epidemiology of early-stage bladder cancer
    • Treatment approaches for patients who undergo radical cystectomy
    • Emerging therapeutic opportunities for patients who do not undergo radical cystectomy
  • Demonstrate greater confidence in their ability to
    • Use therapeutic options to improve the outcomes for patients with early-stage bladder cancer


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Faculty

  • Neal Shore, MD, FACS

    US Chief Medical Officer of Surgery and Oncology
    GenesisCare USA
    Director, Carolina Urologic Research Center
    Myrtle Beach, South Carolina

    Disclosures

    Neal Shore, MD, FACS, has the following relevant financial relationships:
    Consultant or advisor for: AbbVie; Alessa; Arquer; Astellas; AstraZeneca; Bayer; Bristol Myers Squibb; Clarity; Cold Genesys; Dendreon; Ferring; Foundation Medicine; ImmunityBio Incyte; Invitae; Janssen; Lantheus; Lilly; Merck; Minomic; Myovant; Myriad; NGM Biopharmaceuticals; Nonagen Bioscience; Novartis; Pfizer; Photocure; Promaxo; Protara Therapeutics; Sanofi; Sesen Bio; Telix Pharmaceuticals; Tolmar; Vaxiion Therapeutics
    Speaker or member of speakers bureau for: Astellas; Bayer; Janssen; Pfizer
    Research funding from: AbbVie; Alessa; Arquer; Astellas; AstraZeneca; Bayer; Bristol Myers Squibb; Clarity; Cold Genesys; Dendreon; Ferring; Foundation Medicine; ImmunityBio Incyte; Invitae; Janssen; Lantheus; Lilly; Merck; Minomic; Myovant; Myriad; NGM Biopharmaceuticals; Nonagen Bioscience; Novartis; Photocure; Pfizer; Promaxo; Protara Therapeutics; Sanofi; Sesen Bio; Telix Pharmaceuticals; Tolmar; Vaxiion Therapeutics
    Contracted researcher for: AbbVie; Alessa; Arquer; Astellas; AstraZeneca; Bayer; Bristol Myers Squibb; Clarity; Cold Genesys; Dendreon; Ferring; Foundation Medicine; ImmunityBio Incyte; Invitae; Janssen; Lantheus; Lilly; Merck; Minomic; Myovant; Myriad; NGM Biopharmaceuticals; Nonagen Bioscience; Novartis; Pfizer; Photocure; Promaxo; Protara Therapeutics; Sanofi; Sesen Bio; Telix Pharmaceuticals; Tolmar; Vaxiion Therapeutics
    Stock options from: Alessa; Photocure, Promaxo

  • Matthew D. Galsky, MD, FASCO

    Professor of Medicine
    Icahn School of Medicine at Mount Sinai
    Director, Genitourinary Medical Oncology Program
    Associate Director, Translational Research
    Tisch Cancer Institute
    New York, New York

    Disclosures

    Matthew D. Galsky, MD, FASCO, has the following relevant financial relationships:
    Consultant or advisor for: Alligator; AstraZeneca; Basilea; Bristol Myers Squibb; Curis; Dragonfly; EMD Serono; Fujifilm; Genentech; GlaxoSmithKline; Janssen; Merck; Numab; Pfizer; Rappta Therapeutics; Seagen Inc.; Silverback; UroGen
    Contracted researcher for: Astra Zeneca; Bristol Myers Squibb; Dendreon; Genentech; Merck; Novartis

  • Stephen B. Williams, MD, MBA, MS, FACS

    Associate Chief Medical Officer, UTMB Clear Lake
    Medical Director for High-Value Care, UTMB Health System
    Professor (Tenured)
    Chief, Division of Urology
    The Robert Earl Cone Professorship in Urology
    Director of Urologic Oncology and Director of Urologic Research
    Co-Director, Surgical Outcomes Research Program
    The University of Texas Medical Branch
    Galveston, Texas

    Disclosures

    Stephen B. Williams, MD, MBA, MS, FACS, has no relevant financial relationships.

Editor

  • Davecia Ragoonath-Cameron, MS

    Medical Education Director, Medscape, LLC

    Disclosures

    Davecia Ragoonath-Cameron, MS, has no relevant financial relationships.

Compliance Reviewer

  • Lisa Simani, APRN, MS, ACNP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Lisa Simani, APRN, MS, ACNP, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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CME / ABIM MOC

Treatment Approaches in Early-Stage Bladder Cancer

Authors: Neal Shore, MD, FACS; Matthew D. Galsky, MD, FASCO; Stephen B. Williams, MD, MBA, MS, FACSFaculty and Disclosures

CME / ABIM MOC Released: 11/8/2022

Valid for credit through: 11/8/2023

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Activity Transcript

Chapter 1

Neal Shore, MD, FACS: Hi everyone. I'm Dr Neal Shore. I'm the US Chief Medical Officer Urology and Surgical Oncology at GenesisCare. I'm the director of Carolina Urologic Research Center in Myrtle Beach. Welcome to the series, Treatment Approaches in Early-Stage Bladder Cancer. I'm going to present the first chapter in their series, A Review of Early-Stage Bladder Cancer.

This demographic is a really important one. You see bladder cancer is the fourth most common malignancy in the US. 81,000 cases diagnosed annually. There're more men than there are women, but it does affect both genders. 90% of all cases are what we describe as local regional. 10% can be metastatic. And this is an important cancer, because it really ends up in involving a lot of healthcare resources. It's a potentially curable disease early on. We do see heterogeneity much like we see in many other cancers and so that heterogeneity can affect the risk of recurrence.

It can affect the risk of progression. And we look at a lot of the typical factors that can affect our decision making, patients' comorbidities, their other health issues. A patient, fortunately that has localized disease, has a high five-year survival as you see over here. But that drops significantly when you see patients with muscle invasive disease and with metastatic disease. So at the end of the day, we are constantly looking for novel therapeutics, novel biomarkers to help us improve upon this. What are the risk factors? We've known for many, many years, tobacco inhalation. Everyone typically says tobacco and lung cancer, but bladder cancer's the number 2. And then [00:02:00] you see the list here of industrial exposures. Certain parts of the country, if you're exposed to this dyes, textiles, rubber, petrochemicals, aromatic amines, the list goes on. Medication such as cyclophosphamide, these are important and part of the family history, the sociological history, the epidemiologic history for recognizing a risk of bladder cancer.

Now we talk about muscle invasive and here I'm going to focus now on non-muscle invasive and there are all these different grades of the disease or what we call the staging. And 75% of patients fall into NMIBC. And these are patients who have Ta. Ta can be low grade to high grade. If it goes through the basement membrane or the lamina propria, it's T1. Into the muscle, it's T2. The depth into the muscle defines T2, T3, T4, and you see the different layers of the bladder. CIS at the very top, very important because it has a sort of a different appearance. We describe it as this red velvety appearance, but it has this sort of a sinister ability and a higher likelihood to lead to muscle invasive disease over time.

A high risk of progression is really when we get through that T1 or the basement membrane or lamina propria. And this really starts to set the clock for our patients to develop progression. And progression, once it gets through the lamina propria into muscle, it has a much higher likelihood of getting outside the wall of the bladder and then it's metastatic. And then the clock starts to tick much faster in terms of the likelihood of survival. So you see these five-year probabilities and they range based on stage. For our NMIBC patients, it's all about treatments to prevent recurrence and prevent progression. There are many different guidelines to look at. The National Comprehensive Cancer Network has a really nice one here. And you see with a bladder biopsy or a transurethral resection of bladder tumor showing NMIBC, which would be Ta low-grade high grade, CIS or T1.

We always strive for complete resection, the low-grade high-grade bifurcation. And then the importance, if you were T1, of repeating it, to make sure that you've re removed all microscopic disease. And then at the very table on the bottom, one sees the low-risk intermediate and high-risk classifications. It's important to understand this because this has implications regarding the use of medications that we place within the bladder, specifically intravesical therapies, that can be in the form of BCG or other chemotherapies and also intravesical strategies, which are very exciting now, as we try to better understand our abilities to treat these patients. Historically, the paradigm for patients with early-stage bladder cancer, resect the tumor completely. If the patient has muscle-invasive disease, there's neoadjuvant therapy. If they have metastatic disease, there're systemic therapies in the form of chemotherapies and now checkpoint inhibitor therapies.

We have intravesical therapies, BCG is the gold standard when it's confined within the bladder. And multiple different types of chemotherapies ranging from mitomycin, docetaxel, gemcitabine, and there are others and a whole list of really advancements in our clinical trial landscape. So as I said earlier, here's the NMIBC compartment, resection, therapies. If it goes beyond the bladder wall, from the lining, what we call the superficial lining, through the lamina propria or persistent carcinoma situ, we oftentimes will say, patients need their bladders removed. Patients can now benefit from BCG unresponsive disease. That's when they've had adequate course of BCG, pembrolizumab has been approved for patients who have BCG unresponsive carcinoma in situ. If they are platinum eligible, they meet criteria, the neoadjuvant platinum is absolutely a gold standard. Dose Dense MVAC, GemCis, these are very important. We have a burgeoning area of tri modal bladder sparing techniques, chemo, radiation, and trying to spare the bladder.

Most patients don't want their bladders removed, but at the end of the day, we want to do what's in the best interest of patients, what is anatomically achievable, surgically. And then if patients go on to have high risk features, we have adjuvant strategies and of course, multiple lines of therapy if they have metastatic disease. Here is again, a nice summary of the NCCN 2022 review of initial management for low intermediate and high-risk patients. It's not that complicated, but it's important to continue to recognize, thanks to the NCCN and other guidelines associations, AUA, ASTRO, they're constantly updating and recognizing that we see variations EAU, as well. NMIBC here, following cystectomy, did the patient receive platinum based chemotherapy neoadjuvant? If they did not, then there's consideration for adjuvant therapy with a platinum, if their platinum eligible, depending upon their stage, their depth of tissue penetration with or without lymph node involvement.

And this is very, very important to at least have that patient shared decision making conversation. Just a note, not everyone has transitional cell malignancy. There are variations. These are called variant histology. At the very bottom of the screen, the last bullet you see a list of these different variants, and this is an important area. It's a smaller, representationally 10 to 25% of cases, but we continue to do trials to better understand where these patients who have variant histology, which is oftentimes a more aggressive phenotype. And then it's important I think, that for our community based Euro pathologist to potentially consider second opinions from experts in the field to make sure we're not missing variant histology. Of course, we're always contemplating individualizing treatment plans. This is looking at the low risk, not the high risk. And the challenges, many of these patients tend to be older.

They tend to be smokers. Oftentimes they have a significant alcohol history. So individualization is quite important. I mentioned earlier, the checkpoint inhibitors, an important study, the KEYNOTE-057 led to the approval for pembrolizumab, for BCG unresponsive CIS patients. There are many other therapies that are now looking to help out in this area for the patients who don't respond well to BCG and especially in the era of a BCG shortage. Nivolumab in the phase 3, Checkmate 247 was looked at as adjuvant treatment, particularly for patients who are at high risk of recurrence and demonstrated a positive finding that you see here in terms of recurrence or death. And I think this is now, if you see the last bullet, it's now recommended as an adjuvant treatment option for patients who meet this criteria.

We have other therapies that are importantly being investigated. I mentioned this one here because it's taking advantage or exploiting the fact that FGFR is a common receptor finding in non-muscle-invasive bladder cancer patients. Additionally, this is an investigational device that can be used for FGFR patients, but even more recently, we've used this investigational device that allows for the elution of gemcitabine through this semipermeable silicone tube. I think this is very, very exciting areas. Time doesn't allow me to go through the plethora of other intravesical agents, but these are things to keep your eye on as we develop the clinical trial landscape. So with that, thank you very much for your time and really appreciate it.

Chapter 2

Matthew D. Galsky, MD, FASCO: My name is Matt Galsky. I'm a medical oncologist at the Icahn School of Medicine at Mount Sinai where I focus on bladder cancer. And today we're going to talk about therapeutic options for patients who undergo radical cystectomy.

So let's start with the case. And this is a 66-year-old man who presents with gross hematuria. He undergoes an MRI of the abdomen and pelvis, which is shown here, and you can see a bladder mass on MRI, and subsequently referred to a urologist, undergoes a cystoscopy and TURBT, which confirms muscle invasive urothelial cancer of the bladder. So what's the appropriate treatment for this patient? Well, of course we have level one evidence to support cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy. That's based on 2 randomized studies: SWOG-8710, with the result shown here, and the MRC trial. Both of those trials demonstrated that with neoadjuvant cisplatin-based chemotherapy followed by cystectomy, there's a survival benefit compared with cystectomy alone.

But this data results in a couple of voids in terms of how we best manage patients in routine clinical practice. That is that in patients who do receive neoadjuvant chemotherapy and undergo cystectomy, we know that residual cancer in the cystectomy specimen is associated with a high likelihood of metastatic recurrence, and of course that's intuitive. ] The cancer that remains in the bladder after neoadjuvant chemotherapy is probably biologically aggressive, a resistant tumor, and therefore patients are at high risk for metastatic recurrence despite receiving neoadjuvant chemotherapy. And historically, we have not had treatment options to mitigate the risk in these patients.

The other challenge with the existing neoadjuvant data regarding cisplatin-based chemotherapy is that we know that this doesn't apply to all of our patients. That is, there's a disconnect between the efficacy of treatment in large randomized clinical trials and the effectiveness of that treatment in the broader population of our patients with bladder cancer. So what if we look at this patient, and on evaluation of his laboratory test, you see that his creatinine is 1.9? Clearly in this patient, cisplatin-based chemotherapy might not be a suitable option. And we know that cisplatin-based chemotherapy can't be applied to a large subset of our patients with bladder cancer, so-called patients who are "cisplatin-ineligible." And so historically, this has been another evidence void we have not had perioperative systemic regimens to mitigate the risk of metastatic recurrence in patients who are cisplatin ineligible.

So recognizing those unmet needs, 3 large randomized clinical trials were designed to ask whether or not adjuvant immune checkpoint blockade has a role in the treatment of patients with muscle-invasive bladder cancer at high risk for metastatic recurrence. IMvigor010, CheckMate 274, and the AMBASSADOR study.

Each of these trials was designed pretty similarly with a couple of nuances. There are some nuances in terms of the control arm. CheckMate 274 is the only study that used a placebo control, the others used observation as the control arm. And the primary endpoints are slightly different from one study to another, although all involved disease-free survival as at least a co-primary endpoint.

The eligibility for these trials was almost identical and really addresses those unmet needs that I mentioned earlier. That is that patients eligible for these 3 adjuvant studies included patients who had received neoadjuvant cisplatin-based chemotherapy but had residual T2 higher disease in their cystectomy specimen, or patients who were cisplatin-ineligible, therefore didn't receive neoadjuvant cisplatin-based chemotherapy, but had residual T3 or higher disease in their cystectomy specimen.

Here are the results from IMVigor010, assessing adjuvant atezolizumab in patients at high risk for recurrence after cystectomy or nephroureterectomy. And you can see here that in the all-comer population, which was the primary endpoint of the study, adjuvant atezolizumab did not result in an improvement in disease-free survival or overall survival. When looking at the subset of patients with tumors harboring high levels of PDL1 expression, unfortunately there was no benefit in terms of that endpoint either. Interestingly, and an analysis of this study focused on patients with detectable CT DNA on cycle one day one of treatment did show a benefit with adjuvant atezolizumab. This is an exploratory analysis, but really suggesting a paradigm shift in how we might select patients for adjuvant treatments in the future.

CheckMate 274, the results were different. CheckMate 274 met both co-primary endpoints. There was an improvement in disease-free survival in the all-comer population, and there was an improvement in disease-free survival in the subset of patients with tumors harboring high levels of PDL1 expression. And this has since become a treatment standard approved by the FDA.

So we have 2 randomized studies with different outcomes. We don't have results from the AMBASSADOR study yet. Why different outcomes from these 2 trials, which were pretty similarly designed? We don't know the answer for sure. There are some hand waving reasons. One used PD1 blockade, the other used PDL1 blockade. There could be a difference in biomarker performance. We've seen that with PDL1 testing across different data sets. Could be different patient characteristics. Of course, with 2 independent phase 3 studies, there's bound to be some differences in terms of sites of enrollment and patient characteristics. And of course there's this design element in terms of using a control arm of placebo vs observation. And that could have some impact in an adjuvant clinical trial.

So we don't know the answer for sure regarding the difference, but we do have level one evidence now suggesting a benefit with adjuvant immune checkpoint blockade, adjuvant nivolumab, in patients with T2 or higher disease after prior neoadjuvant chemotherapy or T3 or higher disease with no prior neoadjuvant chemotherapy but in patients who are cisplatin-ineligible. CT DNA testing might ultimately change this treatment paradigm and allow more refined patient selection, but we really need prospective validation of that data. Thanks for your attention.

Chapter 3

Stephen B. Williams, MD, MBA, MS, FACS: Hello, my name is Dr Steven Williams and today I'll be speaking regarding therapeutic options for patients who do not undergo radical cystectomy. Bladder cancer has various stages of disease, and today I'll be specifically discussing bladder preservation options as it is focused both on muscle invasive bladder cancer. And then we will discuss non-muscle invasive bladder cancer. And the rationale for this is that we need to move the needle. Here is our radical cystectomy survival calculator, and as you could see, there's little improvement in survival with our current conventional treatment options.

And immunotherapy is certainly on the rise. However, as one could see from this diagram here as well as the following phase 2 studies exploring neoadjuvant immunotherapies, we really haven't improved our T0 rates, which hover around 30% to 40%. And there are optimal treatments for muscle invasive bladder cancer, which include eradication of tumor in the bladder, preservation of normal urinary function, preservation of normal sexual function, and then minimal other adverse effects, as well as also focusing on long-term survival benefits.

But why a patient may not undergo radical cystectomy. And what other treatments are there for muscle invasive bladder cancer? Well, 50% of muscle invasive bladder cancer patients do not undergo any definitive therapy, as we have shown about 19% only undergo radical cystectomy for stage 2 disease. In addition, there's morbidity, mortality, psychologic quality of life, as well as also access to care concerns. Moreover, there's lack of randomization or comparisons, and there has been a prior spare trial which is evaluated select bladder preservation against radical cystectomy.

However, these data need to be used cautiously as also to retrospective comparisons, different populations have been previously reported. Importantly, the debate continues and quality of life is one aspect of which trimodal therapy has been illustrated in this study resulted in estimated mean quality of life greater than that for radical cystectomy. But whether that's clinically significant remains to be determined.

And important in this recent study here, there's conflicting data in regard to radical cystectomy versus trimodal therapy. And in this study, which is a propensity score match study from high-volume Centers of Excellence comparing trimodal versus radical cystectomy, you could see trimodal therapy has 78% five-year survival versus 73% for radical cystectomy. However, this was not significant.

In so much as the NCCN guidelines now recommend trimodal therapy as a category one recommendation alongside radical cystectomy of neoadjuvant chemotherapy. However, what's critical is patient selection. These are smaller tumors, less than five centimeters in size. Clinical stage 2, 3, no CIS, no hydronephrosis, and no lymphadenopathy.

And in this slide, looking at alternative cystectomy and trimodal therapy. As one could see here, there needs to be a meticulous follow up and regimens that are used to reap the rewards and oncologic benefits of using trimodal therapy. And chemotherapy itself, it's previously demonstrated, particularly with landmark study showing the clear benefit to concurrent chemotherapy with radiotherapy.

However, trimodal therapy also has some concerns regarding late toxicity. As one could see here, toxicity remains stable over a prolonged period of time. And then as I previously mentioned, the post-randomized trial comparing radiotherapy versus radiotherapy with concurrent chemotherapy. And local regional disease-free survivals is shown here, shows a clear benefit to chemoradiotherapy vs radiotherapy alone.

However, suitable for a large number of elderly patients who are offered no curative therapy, that remains to be determined. But trimodal therapy has garnished increased support in particularly this population. The RETAIN trial is also looking at the histologic components as well is also underlying biological nuances to tailor which patients may benefit best. And these data show here overall survival benefits patients alive greater than 90%. And in addition, also looking at the particular correlation between DDR gene alterations and recurrence are clearly illustrated here and further ongoing exciting work is being explored. So trimodal therapy, a summary, there's greater than a thousand patients that are treating a prospective series are on trials and consistent five-year disease-free survival 60% and 80% of survivors preserve their bladder, and 75% have normal bladder function.

But, we need to over cover our biases, particularly as urologists in a multidisciplinary setting in treating this disease. And need to consider and discuss with select patients and moreover needs to be performed in a multidisciplinary setting. However, bladder-sparing options extend beyond trimodal therapy. We need to think beyond this as well and embrace change, have shared decision making, and really think bladder sparing and organ preservation as our goal.

Moreover, as I mentioned, this is a Category one recommendation at NCCN in the United States, but trimodal therapies appear much older in frailer than our UK counterparts. And we need to inform and transform, have urologists also a part of these collaborative initiatives. So there is a paradigm shift, delivery systems have entered the room and there are very solutions here across a bladder cancer spectrum, muscle invasive and non-muscle invasive. And I wanted to discuss more in detail the terrace or TAR-200 delivery system, which is a drug delivery system using osmotic engine to deliver gemcitabine intravascularly.

And in this phase 2 study here, SunRISe-4 are comparing TAR-200 plus cetrelimab vs cetrelimab alone in patients with muscle invasive bladder cancer and neoadjuvant treatment. And in a SunRISe-2 study, this is TAR-200 plus cetrelimab vs chemoradiotherapy, looking at a little over 274 sites comparing the oncologic efficacy in patients with muscle invasive bladder cancer with primary endpoint bleeding a bladder intact event-free survival.

And what this is commonly known is inserting the TAR-200 device, which is a pretzel inserted every 3 weeks up to 18 weeks with 18-week being a cutoff for assessment of oncologic efficacy, but also ongoing. There's 274 sites that are involved. The study started in December of 2020 and is expected each primary completion in 2026.

So if a patient is decided to undergo bladder sparing, we have patient careful selection, multimodal maximal transurethral resection of bladder tumor to rule out carcinoma in situ and then have concomitant chemotherapy in close oncologic surveillance was salvage cystectomy if needed. But also what's critical is this bladder cancer in general needs to be performed in a multidisciplinary clinic setting with medical oncology, radiation oncology surgery, and then also to ongoing clinical research to enroll patients on clinical trials.

So shifting our attention to bladder and responsive non-muscle invasive bladder cancer, there's various definitions that have been noted to denote BCG-unresponsive disease and there's different mechanisms in place. And now we have quite a number of different delivery systems to focus our attention on. And then lastly, as KEYNOTE-057, a phase 2 trial pembrolizumab and BCG-unresponsive high-risk patients of those patients themselves, we show a medium follow-up of a little over 2 years and show particularly promising early disease-free survival and particularly having complete response at 3 months. So Tomorrowland no more and bladder preservation for bladder cancer remains at the forefront will continue to remain. Thank you very much for your time.

This transcript has been edited for style and clarity.

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