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 with me today, we have Dr. Vignesh Packiam, who is an assistant professor at the University of Iowa Healthcare System in the Department of Urology. Dr. Packiam has been involved with and has led several of the studies that were done with intravesical, gemcitabine, and docetaxel at the university and has recently been the senior author in a publication that has gotten a lot of interest and deservedly so in which a study was done where they compared sequential intravesical gem/doce versus BCG in patients with high-risk, non-muscle invasive bladder cancer. So Vignesh, thank you for joining us today and I'll let you take it from here.

Vignesh Packiam: Thank you, I appreciate that introduction and also appreciate very much the opportunity to speak about our study. So first, to introduce a few points, the cohort that we studied was high-risk non-muscle invasive bladder cancer per AUA criteria, and the AUA and other bladder cancer guidelines all recommend a six-week induction course of BCG for these patients. There are many substrains of BCG, but we currently only have one strain of BCG approved in the United States and that's available at this time, which is BCG TICE. The BCG shortage is a major problem and one that all urologists are familiar with. It has been going on since 2012 and has waxed and waned over time with a relatively severe shortage around 2019 and seemingly again right now. So what are we to do during the shortage? Multiple guidelines recommend adjuvant intravesical chemotherapy as an alternative option, single agent chemotherapy, particularly mitomycin C, has been compared extensively to BCG, but several meta-analyses have shown BCG to be superior to these regimens for both efficacy and side effects. So we are lacking a true viable alternative.

How did sequential intravesical gemcitabine and docetaxel or gem/doce come about? Mike O'Donnell, who is known as an innovator for non-muscle invasive bladder cancer, and I'll also say an incredible mentor to me, he initially combined gemcitabine and mitomycin as a combination regimen for BCG refractory non-muscle invasive bladder cancer, which showed promising results. But in 2009, there was actually a mitomycin shortage, so that regimen was altered to gem/doce and the gem/doce regimen was first published in 2015. This study showed 34% two-year recurrence-free survival, which was very promising for a heavily pretreated population, and this was replicated in multi-institutional cohorts, which included patients from MD Anderson and Johns Hopkins. So as the BCG shortage worsened, gem/doce was also used for patients with BCG naive disease. Last year, we published our series of 107 patients with AUA, high-risk BCG naive disease and found 82% two-year recurrence-free survival with no progression events or death from bladder cancer.

However, the main limitation of this study was lack of a comparator group. So that brings us to our current study that we just published in JAMA Network Open. We retrospectively assessed 312 patients with AUA high-risk non-muscle invasive bladder cancer from 2011 to 2021. There were 174 patients who received BCG. They got full dose BCG for induction if that was available. Maintenance was given for one year as per the phase II BCG interferon trial at three, nine, and 15 months. There were 138 patients who received gem/doce, which consisted of one gram gemcitabine instilled for 90 minutes. After that, the catheter was unclamped and 37.5 milligrams of docetaxel was instilled and the catheter removed. The patient was instructed to void the docetaxel after at least 90 minutes, but ideally two hours. This was done once weekly for six weeks for the induction and then monthly maintenance was given for two years.

A formal restaging procedure at three months with blue and white light cystoscopy, random bladder and prosthetic urethral biopsies, and upper tract washes was performed. There were quarterly cystoscopies for two years and then semi-annually. The primary endpoint was high-grade recurrence-free survival. The cohorts were relatively well-balanced with respect to clinical pathologic characteristics. Patients who received gem/doce were significantly older than those who received BCG and owing to the chronic BCG shortage, gem/doce became the defacto first-line regimen at our institution. So patients receiving gem/doce tended to receive it in more recent years. These are the Kaplan Meier curves of high-grade recurrence free survival for gem/doce and BCG. The two-year high-grade recurrence-free survival for BCG was 69% and for gem/doce was 81%. There was significantly longer follow up for BCG, which was 49 months compared to gem/doce, which was 23 months.

There were no significant differences in other oncologic outcomes, including progression-free survival, cancer-specific survival, or overall survival between the groups. We performed multi-variable cox regression analysis to assess for risk factors for recurrence and found that gem/doce yielded significantly superior recurrence-free survival when controlling for age, sex, treatment year, and the presence of CIS. We repeated this analysis for high-grade recurrence-free survival and found the same results with the presence of CIS also as a predictive factor. Looking at adverse events, about 50% of both groups reported them. There was 9% of the BCG cohort who was not able to complete at least five of six induction installations compared to 3% of the gem/doce cohort. The side effect profile of both groups were slightly different with more bladder spasms in the gem/doce group, probably due to increased dwell time and more presumably immunologic side effects like dysuria and arthralgia in the BCG group.

So in conclusion, these results show that gem/doce has promising efficacy and tolerability and can be considered as a first line agent for high-risk non-muscle invasive bladder cancer, especially with the ongoing BCG shortage. There are some limitations, including need for optimization of installation protocols, clarifying patient selection for gem/doce versus BCG, and most importantly, we really need prospective validation of these results. I do want to give a quick plug for the BRIDGE study, which is being led by Max Kates, and we have a variety of excellent collaborators. This is a recently activated 870 patient randomized control trial that we are very excited for. And for the listeners, please reach out to us if you have interest in joining. Thank you.

Ashish Kamat: Thank you very much, Vignesh, for that succinct presentation. If I might ask you a couple of questions. Obviously, in the BRIDGE study, which you mentioned, which clearly needs to be done, and again for the listeners, please do reach out to folks, we'll have that slide up so you can reach out to the appropriate folks, and there should also be hopefully a study in the UK along similar lines, which Wei Shen Tan is going to hopefully lead. He's currently working with me here at MD Anderson, but has done numerous multicenter studies while still in the UK and then in India, through Doctor Memorial, Professor Prakash will hopefully be taking the lead to do this trial with the help of the IBCG. But again, circling back to the design of the BRIDGE study and the SWOG protocol in general, it's BCG that's given obviously for six weeks and then as you know, three months, six months, and then every six months thereafter. Why did y'all do that part of the BCG a little differently?

Vignesh Packiam: Yeah, that's a great question. I think there's a lot of urologists that tend to give one year of maintenance BCG rather than the full three years, mostly out of concern for tolerability and studies suggesting that the recurrence-free survival isn't vastly different between three years and one year. Those are the main reasons that we have stuck to a one-year protocol here.

Ashish Kamat: But even in the first year, your schedule does not seem, or at least what you published and what you mentioned today, doesn't seem to parallel the SWOG schedule. So in other words, you skipped the six month, you did the three-month maintenance and then you skipped the six month and went straight to nine months. Was there a specific reason for that?

Vignesh Packiam: Yeah, I think a lot of that protocol was developed here due to logistics. So we basically give the maintenance at three, nine, and 15 months and do cystoscopy between each of those intervals and immediately proceeding BCG, just to have more of a standardized protocol here that's easier to follow.

Ashish Kamat: Okay, great. Great. So just a point for the listeners that, again, these results are quite remarkable and definitely eye-popping in many ways, but in order to follow sort of the purest way of thinking of things, the BCG that y'all did was not the classics SWOG protocol, the slightly modified protocol that I guess you use at the Iowa. A second question that often comes up is for folks that are planning to do gem/doce in their clinics, and again, we went through this when we started this, gosh, 10 years ago now, but I'm sure you have a lot more experience with helping centers. What are some of the tips that you would give to folks in the community that are looking to the logistics of how to do gem/doce in their clinics?

Vignesh Packiam: Yeah, that's a great question and especially with the BRIDGE trial activating, we've been helping new sites get up and running with the protocols. One thing is that it's nice to have a dedicated person doing the instillations. So here, we have APPs running our instillation clinic and we have room set aside for these instillations and it's similar providers each time that are giving it and that can help a lot with troubleshooting some of the problems that come up. I'd say about three quarters of patients are able to tolerate the medicine so that we can do the standard protocol, which is instillation of the gemcitabine in the office, draining that medication in the office, putting in the docetaxel, and then removing the catheter that will allow the patient to be in the office for one-and-a-half to two hours. But about a quarter of patients are unable to tolerate that and they need other instillation methods.

So we initially used something called split dosing where we gave a smaller volume of medication, about half the medication for 45 minutes, and then give the other half for another 45 minutes. And this allows patients to tolerate the medication if they have a smaller bladder capacity or have bladder spasms. But as you can imagine, that's a much longer office visit because they need to stay for the entire time for the docetaxel as well. More recently, we've devised another type of instillation method, which is called Gravity instillation, where we basically hook the Foley catheter up to a large drainage bag, elevate that drainage bag to gravity so that when a patient has a bladder spasm, the medication can reflux up the tubing and then when the bladder spasms complete, the medication comes back into the bladder. But again, this requires that the patients stay in the office the full three hours.

Ashish Kamat: The other thing that I found when doing gemcitabine and docetaxel is that certain patients have really severe local symptoms and that can often be attributed to the gemcitabine and then they are helped with bicarbonate, for example. Is that something you're doing routinely? Have you found that useful or are you only doing it on an as needed basis?

Vignesh Packiam: Yeah, another great question. We do give sodium bicarbonate the night prior to instillation as well as the morning of instillation 1300 milligrams each time. And that goes a long way in improving tolerability, especially for the gemcitabine.

Ashish Kamat: And is that something you would recommend to folks starting this program new to give it to everybody or just do it for patients who have symptoms?

Vignesh Packiam: Yes, absolutely. I think it goes a long way to do that for all patients.

Ashish Kamat: Great. Then another question, again, these are more practical questions, again, is for folks that are looking to do this, is one gram in 50 ml in your opinion the same as doing two grams in 100? And if it is, then could you potentially cut it down to half that and half the volume in those that have small capacity bladders? Have you looked at that?

Vignesh Packiam: Yeah, that's a good question. We do have some other protocols that use two grams of gemcitabine. Obviously, that's used very commonly for the immediate postoperative dose after TURBT. But we've found that in this setting, two grams is much more toxic and less tolerable, which is why we move towards one gram in this population.

Ashish Kamat: I think it's the volume, right? Because again, with chemotherapy, it's the concentration that's more relevant than the actual absolute amount in the bladder. And doing two grams in 100 is almost the same as one gram in 50, right? So that's why we switch to one gram in 50 as opposed to two grams many years ago. And again, most folks will use a lower quantity of gemcitabine with the same concentration because you have lower volume and patients tolerate it better. There has been some thought about if you can do that and go even lower in concentration, might that help? Just something for folks to think about. Well, Vignesh, again, excellent discussion. Any closing thoughts for the audience that you want to leave them with as we wrap up?

Vignesh Packiam: No, I think you hit a lot of major points. I think we're very excited about the BRIDGE trial. It's going to be great to have prospective validation of these results. And again, anyone that's interested in opening that study, we'd welcome you to join.

Ashish Kamat: Great, thank you again. Take care.

Vignesh Packiam: You too. Thanks.