Dr. Matthew Galsky:
Welcome to The ASCO Post Roundtable Series on Immunotherapy Approaches in Muscle-Invasive Bladder Cancer. I'm Dr. Matthew Galsky from the Icahn School of Medicine at Mount Sinai. Joining me today are two of my colleagues, Dr. Sridhar and Dr. Tripathi. Please go ahead and introduce yourselves.
Dr. Srikala Sridhar:
Hi, I am Dr. Srikala Sridhar. I'm a medical oncologist at the Princess Margaret Cancer Center and a professor at the University of Toronto. Thank you for having me.
Dr. Abhishek Tripathi:
Hi, everyone. I'm Abhishek Tripathi. I'm a genitourinary medical oncologist and a clinical investigator at the City of Hope Comprehensive Cancer Center in Los Angeles.
Dr. Matthew Galsky:
Thank you for joining us today. Today we'll be discussing the role of immunotherapy in bladder cancer with three patient case studies. Our first installment will focus on neoadjuvant therapy for a patient with muscle-invasive bladder cancer with squamous differentiation.
This is a 65-year-old man with a history of hypertension, type 2 diabetes. He presents with gross hematuria. A CT scan of the abdomen and pelvis is obtained by his primary care physician and that shows a bladder mass. And there's a solitary enlarged pelvic lymph node, measures about 1 cm in size. There's also mild right-sided hydronephrosis. He has some blood work done and that's notable for a creatinine clearance of 65. His urinalysis shows red blood cells and his labs are otherwise unremarkable.
So, Dr. Sridhar, what would you do next for this patient?
Dr. Srikala Sridhar:
Yeah. I mean, I think that it's really important to think about the whole patient. And I review, of course, the CT of the chest, abdomen, and pelvis, just make sure that there's no distant disease. We know that these patients may be at risk for other malignancies, like for example, lung cancer, so I want to rule out any other primaries.
I don't tend to use any other staging. We, of course, did a study looking at the use of PET scans. I think it's variable, but it didn't really show that much of a significant change in management. So I would keep with the CT of the chest, abdomen, and pelvis as my upfront imaging modality and I would start with that.
Dr. Matthew Galsky:
Thank you. So he's referred to a urologist. He has an office cystoscopy, which confirms a bladder tumor so he's taken to the operating room. Has a cystoscopy under anesthesia with a transurethral resection of bladder tumor, and his pathology shows muscle-invasive bladder cancer. But there's 55% squamous differentiation.
So, Dr. Tripathi, when you get a pathology report back and you see variant histologies, what starts to run through your mind in terms of next steps?
Dr. Abhishek Tripathi:
Absolutely. So variant histology presents a unique challenge in certain situations. It can be seen in a significant subset of patients, up to 20% of patients to varying degrees. The first thing I look for is there a presence of pure variant histology or is it a component of urothelial with other variant histologies.
And then if we can get a sense of what the percentage of the variant histology is, is it predominantly variant vs mostly urothelial with a small component of variant. Those are some important things.
And lastly, I always look out for presence of any kind of small cell or neuroendocrine carcinoma, which can be also seen in these patients just because the systemic therapy options and the overall aggressiveness of the disease changes based on that. But like in our patient, the squamous differentiation is noted frequently in conjunction with urothelial carcinoma and it's important to keep in mind while planning the treatments.
Dr. Matthew Galsky:
Thank you. I'll summarize, this patient is a 65-year-old man. He has a history of hypertension and diabetes. He has a creatinine clearance of 65. He has a bladder tumor on scan with some hydronephrosis, and a 1-cm pelvic lymph node, and a TURBT specimen showing urothelial cancer with squamous differentiation involving into the muscle, muscularis propria that is.
So, Dr. Sridhar, contemporary management for a patient with clinically localized muscle-invasive bladder cancer with a pelvic lymph node that's enlarged.
Dr. Srikala Sridhar:
Yeah, so a couple really important points here. First off, in a patient with muscle-invasive bladder cancer, my standard of care is cisplatin-based combination chemotherapy. There's level 1 evidence for this, improvement in overall survival. We can of course discuss which regimen is the best regimen, and there's been a lot of debate about that.
In my practice, I tend to use gemcitabine and cisplatin, but dose-dense MVAC is another very reasonable systemic regimen. The goal of systemic therapy, of course, is to go after the local disease, shrink the tumor within the bladder, perhaps a nodal disease. But also perhaps most importantly, to go after the micrometastatic disease, and in doing so reduce the risk of distant metastases and disease progression.
Currently, those are the regimens that have been used in the neoadjuvant setting. We do try wherever possible to give neoadjuvant chemotherapy even down to a lower creatinine clearance. I know you were very involved in your criteria to outline cisplatin usage in this setting, but I think we have better supportive care mechanisms and maybe we're a little bit better at giving cisplatin than we were a few years ago. And so we even do things like splitting the dose of cisplatin. That's a very well-tolerated approach, gemcitabine/cisplatin on day 1, gemcitabine/cisplatin on day 8. My patients find it super easy, and it does allow me to get the neoadjuvant chemotherapy into the patient.
So that's the first step for me in a patient like this.
Dr. Matthew Galsky:
Dr. Tripathi, anything that you're thinking about in terms of this borderline-enlarged pelvic lymph node on scan. Do you do any other testing? Do you do a biopsy in this setting?
Dr. Abhishek Tripathi:
Absolutely. Not necessarily a biopsy in every patient. Perhaps in situations where we are thinking about a bladder-sparing modality, we might do a biopsy. Or if a lymph node is far up enough in the retroperitoneum that it may actually change the definitive local therapy in terms of consolidation vs cystectomy. In those cases, we might consider a biopsy.
We are concerned for lymph node and metastases and the systemic therapy should be able to target that as well. So the goal will be to have neoadjuvant systemic therapy, but keep an eye on those lymph nodes as a sign of progression of response while the patients are on the systemic therapy.
I would just like to add that we try to assess how the kidney function was prior to the diagnosis on a long-term basis, because sometimes these patients can have long-term issues, as diabetes and other comorbidities, that can impact the kidney function, vs a more immediate drop in the renal function, which could be due to hydronephrosis, which is probably a little bit easier to manage with percutaneous nephrostomy tubes and stents and so forth.
So we work closely with our multidisciplinary team of urologists and interventional radiologists to help optimize the renal function prior to starting systemic therapy.
Dr. Matthew Galsky:
And thank you. That was going to be my next question about this patient with unilateral hydro on the side of the tumor and a creatinine clearance of 65. To administer cisplatin-based chemotherapy, do you put in a, quote/unquote, "prophylactic nephrostomy tube," or do you start treatment and monitor the creatinine and see what happens?
Dr. Srikala Sridhar:
I think that we are seeing a growing specialty of onco-nephrology that we involve quite frequently in managing these patients.
In this current patient with a creatinine clearance of 65, I wouldn't necessarily put in a nephrostomy tube at this point. My hope would be that the chemotherapy will go after the disease, and sometimes you actually see an improvement in the hydronephrosis because of tumor response. And so I'd probably start with that and hope that I would get a response without necessarily having to put in a tube into this patient.
Dr. Matthew Galsky:
We have a patient with N1 disease, clinical N1 disease on imaging squamous differentiation. A lot of these factors historically have been exclusion criteria for our traditional neoadjuvant randomized clinical trials. Historically, patients with clinical node-positive disease were enrolled on metastatic studies rather than on neoadjuvant studies. Similarly, patients with greater than 50% variant histologies have often been excluded from our trials.
Well, any exception to this or a contemporary exception is the NIAGARA study of course. So NIAGARA enrolled patients with clinically localized muscle-invasive bladder cancer, but N1 disease was allowed. Patients could have any degree of variant histology, as long as there was urothelial cancer. And patients were randomized to gemcitabine/cisplatin/durvalumab in the neoadjuvant setting with continuing durvalumab in the adjuvant setting, vs neoadjuvant gemcitabine/cisplatin followed by cystectomy with no planned adjuvant treatment.
So in the context of this patient, how do you think about integrating immune checkpoint blockade? Dr. Sridhar?
Dr. Srikala Sridhar:
Sure. Yeah. I think that the NIAGARA study was a really, really important study, and I'll tell you why. I think it's because of the fact that it included a fairly broad patient population. It allowed patients with a creatinine clearance of 40 to 60, which is really quite unusual for these neoadjuvant studies which have held a very strict creatinine clearance. And it allowed this use of split-dose cisplatin, which again is a really, really important point. As I mentioned earlier, we use a lot of split-dose in routine practice.
And so this made the study very sort of generalizable, I would say. And it also included node-positive disease and variant histology, so all these components of the patient population would allow us to take this regimen into our clinic quite easily. And we always have to keep in mind of course, that patients on trials tended to be a little bit better than the routine population. So the fact that this trial aims to get a patient population that's a little bit closer to what we see in practice, is a really critical point.
The second thing about the NIAGARA study, which I think is really important, is it gets the patients to the medical oncologist early and upfront. And that's really critical because we know that that referral often will lead to increased uptake of neoadjuvant chemotherapy. And of course, we've been trying to get uptake of neoadjuvant chemotherapy up for years and years. And so I think the fact that this trial gets patients referred to medical oncology early to make that decision around neoadjuvant is super important.
So those are two aspects of the NIAGARA trial that I really liked and I think is really important as it applies to our practice today.
Dr. Matthew Galsky:
Thank you. Dr. Tripathi, we're talking about cystectomy for this patient after neoadjuvant therapy. What other options are there in terms of definitive local therapy?
Dr. Abhishek Tripathi:
Yeah, so post-neoadjuvant therapy, I think we have the standard-of-care option would be to perform radical cystectomy. But for patients who are electing to have a bladder-preservation approach, we could use a trimodal therapy. Although the data in perhaps node-positive disease is not as extensive, but that could be considered in patients with clinical node-negative disease who have responded otherwise well. That usually includes concurrent chemotherapy, concurrent radiation, and maximal transurethral resection of the bladder tumor.
And that perhaps needs to be a little bit better studied in the context of combined immune checkpoint inhibition and perioperative systemic therapy. I don't think we have the definitive answer in terms of that their immunotherapy adds to their trimodality regimen yet. There are a few trials that are looking at that context. For example, the SWOG 1806 trial has completed accrual and is looking at the addition of atezolizumab with chemotherapy and radiation. And similar trials that are being designed through the SWOG mechanism from a bladder preservation approach after neoadjuvant therapy. So lots to come in that disease space.
Dr. Matthew Galsky:
Thank you.
Let's talk about some takeaways from this case. So perioperative durvalumab demonstrated an improvement in event-free survival and overall survival in the NIAGARA study. Eligibility for NIAGARA included patients with any degree of variant histology, as long as there was urothelial cancer present. And eligibility also included patients with clinical N1 disease similar to the case that we outlined.
This brings us to the end of this case. Please see the other segments for further discussions about the latest research in bladder cancer or visit ascopost.com. Thank you.
