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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center, and it's a pleasure to welcome to the forum, and to our audience, once again, someone who really needs no introduction, a dear friend, and an expert in all things oncology. Here today to talk to us about bladder cancer, Professor Neal Shore, who is Medical Director, Chief Medical Officer of GenesisCare, and also the Director of the Carolina Urologic Research Center, is joining us today. Neal, always a pleasure to have you here. Today, we're going to talk about how we can understand the nuances of risk stratification of patients with non-muscle invasive bladder cancer and how you apply the guidelines, especially the AUA guidelines, to a patient when he or she is sitting in front of you in the clinic. So, with that background in mind, if you could take us through what you use, the clinical parameters, the clinical factors, to make that distinction between low, intermediate, and high risk for our patient.

Neal Shore: Well, thanks very much, Ashish, and it's really a great pleasure to be here with you. And kudos to you for the enormous amount of work you've done in guidelines, both in the US and internationally, and particularly the great work you're doing with the IBCG and combining that with forums at AUA, ASCO GU, and EAU. So, it's a pleasure to be here with you. We've made great strides, thanks to your efforts and others. AUA guidelines, as you're suggesting, their great work led by our good friend and colleague, Sam Chang. We have made great strides in stratifying our patients with non-muscle invasive bladder cancer, just kind of moving away from the definition of just using superficial.

And within NMIBC, where we see 60, 70,000 patients a year diagnosed in the US, about 75% are going to be NMIBC. And how we stratify them as low risk, intermediate risk, high risk is very important because it impacts treatment decision-making, particularly the number of cystoscopies we do, the aggressiveness of our TURBTs, the appropriateness for using adjuvant post-TURBT chemotherapy, and, very importantly, the use of induction courses of therapy, particularly BCG, which we can talk a little bit more about, which I've pretty much relegated just to my high-risk patients now, in keeping with the recommendations of the IBCG. And that's because of the BCG shortage.

So, risk stratifying, in all areas of malignancy, becomes important because, as we both recognize, it helps us better invoke the really important notion around patient-physician shared decision-making, helping patients recognize that, "Yes, you have a cancer diagnosis emanating from the bladder," but so, for example, if you're low risk and you have one or two very small non-aggressive non-muscle invasive lesions, these can oftentimes be easily managed with just simple biopsy fulguration or occasionally resection. And then, the rigor of following these patients with regular cystoscopy becomes markedly decreased. And I think that's where, just from a sort of treetop view, we can start to cut down on the cost of care. And in bladder cancer, we're always fond of saying it's one of, if not the most, expensive cancer that we treat. And a lot of it has to do with the intensity of the cystoscopies and the repeated biopsies.

If we go from low risk to high risk, and the high risk encompasses those patients who have papillary disease but are high grade, based upon the WHO 2004 classification, which said we really should be training our pathologists to say you're either low grade or high grade. And I think that was a really important advance. Still, occasionally see some pathologists who haven't adapted to that educational initiative. So, the high risk are the papillary high grade or the TaG3. Also included in that are the patients with carcinoma in situ. And also included in that are patients with lamina propria basement membrane invasion, but not yet into muscle. That's the T1. The intermediates are those that fall in between, for simplicity purposes, low grade, low risk, high grade, high risk. And I really like, frankly, the work that IBCG has done and said you're intermediate risk if you're multifocal or recurrent certainly within a year, you fall into that, or any tumor greater than three centimeters.

We're learning a lot about how we address the intermediate risk folks. Because of the BCG shortage in the US, I really like the guidance from IBCG, which is saying, "Prioritize your BCG for your high-risk patients." And for your intermediate risk patients, certainly, there's good evidence to suggest that when you do your TURBT, they should get post-administration intravesical chemotherapy, gemcitabine is perfectly reasonable, very cost-effective. And then, there's a decision about induction and a year of maintenance with intravesical chemotherapy for our intermediate risk folks. This is how I approach it for the high risk, the TaG3, the CIS, the NMIBC, who are BCG naive, I try to prioritize them to get an induction course of BCG. I'm old school. I totally follow the LAM study, with maintenance starting at three months and then, every six months after that, try to get them out to three years.

Like most, I'm pretty fortunate if I can get them out to two years. So that's that. Now, within the high risk, I think you were asking too, Ashish, and if I'm short on BCG, I totally prioritize the T1s at the top of the list, then CIS and TaG3. Now keep in mind, of course, a standard of care for some of these high-risk patients, especially the T1s, especially the ones with really very diffuse multifocal CIS and maybe arguably those who have poor bladder function, radical cystectomy is a standard of care for those patients.

And so, the concern about the high risk as opposed to the low risk and, even to some extent, the intermediate risk is we always talk about recurrence in the low risk and the intermediate. Recurrence is a challenge for the high risk, but it's progression. When progression rears its ugly head and you start getting penetration beyond the lamina propria basement membrane, anything with lymphovascular invasion into the muscle, that's when the biology is really worrisome. That's where we worry about metastatic disease. And then, of course, our inability to cure patients with local control options, whether it's aggressive TURBT and bladder sparing versus radical cystectomy.

Ashish Kamat: I love the way you sort of simplified that, and to be honest with you, you went through like 50 pages of guidelines in five minutes and very succinctly. And I really like that. I like the fact that you emphasized that the risk classification and stratification of patients is based on progression. Because non-muscle invasive bladder cancers will recur, but if the low grade, low risk patients recur, it's not a threat, like you said. They don't progress to metastatic disease; they're not at risk of losing their bladder. And the high risk patients are the ones that are at risk of progression. In those, you want to intensify the treatment. You mentioned a little bit about de-intensification of treatment in the low risk patients. Could you elaborate a little bit on your surveillance strategy for the low risk, compared to the high risk, patients?

Neal Shore: Yeah, I appreciate that question, and in the arc of my career, it's been really enjoyable to say to a patient who has one or two small very unaggressive, we use all sorts of non-scientific terms, like ditzel or something that's just, I'm not going to call them PUNLMP, although PUNLMP for sure, if you get a PUNLMP, those patients, for sure, I will just check a urine on them, in three to four, six months, as long as that's negative. And I'll just maybe survey them in a year and then, stop if they're negative. The low grades, I am very comfortable just checking a urine on them, of course, if they have gross hematuria, instructing them to come back sooner, but surveying them on a yearly basis. Because we know that there's such great meta-analyses suggesting that the risk of progression in that patient population, you can never say zero, but it's close to zero. It's certainly under 1%.

And so, many of the patients, as long as you know that they're going to at least come back for a check of urine, the whole biomarker issue is somewhat controversial. But I really enjoy telling a patient, and my experience has been, in those patients with low-risk disease, "We don't have to do cystoscopy. We don't have to instrument you. You're going to be okay." I find that actually a very enjoyable conversation to have. I appreciate that, for urologists, we think about the cystoscope as our version of the cardiologist's stethoscope, but it's still intervention, it's still instrumentation. And so, I enjoy that level of de-intensification for the low-risk patients.

Ashish Kamat: And you mentioned, for the low-risk patients, you would do perioperative chemo. You also mentioned, for the high-risk patients, you use BCG, and you use the classic six-plus-three protocol. For the intermediate-risk patients, you did allude a little bit to the fact that we recommend, now in the US, to hold off on BCG. Do you have a preferred chemotherapy regimen for that intermediate-risk group? Do you like gem? Mito? What do you use?

Neal Shore: Yeah, I've moved away from mito. Used it back in the day because of the small but real percentage of granulomatous-type calcifications, the small but real risk of penetration, at least especially immediately post a TURBT for that immediate adjuvant therapy, the chemical peritonitis that can occur. I like gem-doce when I can. Certainly, I'll use monotherapy gemcitabine. I think there's great data on that. For my more intermediate-risk patients, the ones who are more concerning to me, I really like the gem-doce regimen. It's a little bit more cumbersome in clinic because you have to give it sequentially. It does take up some time in the clinic. I have nurses who are very comfortable doing the mixing. We have a hood that we use. We have safety precautions. We were able to dose it in a way that we find it from an economic standpoint acceptable, but I tend to prefer that. But I also understand why many would just use gemcitabine as monotherapy as well.

Ashish Kamat: And just again, in closing, because I know you've done a lot of work on this, we recognize, all of us really, that BCG is the best immunotherapy for cancer period, right? The proven track record, the efficacy, more than 75, 80%. But many folks face this issue of BCG short supply, and you've done a lot of work to try and help people understand how they can do split dosing, use it in their clinic. So, in brief and in closing, if you could share some of these nuggets with our audience, that'd be great.

Neal Shore: Yeah, when the BCG shortage was really hitting us hard, and we got some great work from colleagues, like Jonathan Rubenstein, who does a lot of great work on proper coding and helping us, over the years, as a representative of urology for the AUA and in the community. There is a separate J-code that you could now use, that, in addition to bringing in two or three patients, when you crack a vial of BCG, which it's not expensive, but it's a precious commodity sometimes, because of where you are in the shortage spectrum. And so, if you can bring in two patients concomitantly or even occasionally three, you can split the dose, and there's an appropriate J-code to use, so that you're comfortably billing for it, and you're not having to lump one person with the administrative cost. So, that's a very nice, ethical, rational way for getting more patients to get the treatment.

Patients are much smarter these days because of internet accessibility. Great organizations, such as BCAN, the Bladder Cancer Advocacy Network, make people want to know if their physician says, "Look, I can't get treatment. Where do I go? And what about split dosing?" There are nice seminars on that. But I will just, in my closing add, Ashish, say I'm super excited about some of the great clinical trial work that you're leading, and I'm honored to be part of various programs where we're looking at new things in BCG naive, as well as in BCG unresponsive patients. And bladder cancer, as opposed to seven, eight years ago when we didn't really have a lot of things, we have so many things right now. There's this really amazing embarrassment of riches. I think at AUA 2024 in San Antonio, you're going to see some exceptional presentations. We have two approved therapies now in BCG unresponsive in the last few years that we never had before for NMIBC patients, particularly with CIS. So, it's a great era right now for our colleagues to be really aware of all the great advances that have happened in bladder cancer, particularly in NMIBC.

Ashish Kamat: Yeah, no, absolutely. I think our patients were overdue for us as a community to make these advances. And again, kudos to you and your group because you guys do a phenomenal job with accruing patients to these clinical trials and really are the leaders in how clinical trials can be done. In fact, I'm hoping we can do a separate session with you on that topic at some point here on UroToday. But I do want to thank you for taking the time and thank UroToday for allowing us to do this. And stay safe and stay well.