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Sam Chang: Hello, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University, and we are joined by a rising star in urothelial carcinoma evaluation, treatment, and importantly, cutting-edge combination therapies of intravesical gemcitabine and docetaxel for patients with non-muscle invasive bladder cancer.

We have Vignesh Packiam, who recently left Iowa and is now at the Rutgers Cancer Institute of New Jersey and is an associate professor well on his way, quickly I know, to full professorship. And we've been lucky enough to have him go over the landscape of non-muscle invasive bladder cancer but focus on this sequential combination chemotherapy. You've had multiple publications. You just had one in Urologic Oncology in 2023, so if we could hit some of the highlights, that'd be great. And thank you, first of all, for joining us.

Vignesh Packiam: Thank you for having me, Sam. I appreciate the introduction and the opportunity to be here. So this was our study that we published last year in Urologic Oncology, sequential intravesical gem-doce for treatment-naive and previously treated intermediate-risk non-muscle invasive bladder cancer.

So I want to give a little bit of background as to the cohort that this study focused on. We looked at patients with AUA intermediate-risk disease. And as a reminder, that's predominantly patients with most low-grade Ta tumors except those that are so favorable that they're considered low risk. And it does include some patients with very favorable high-grade disease, patients with small, unifocal, and non-recurrent tumors.

The AUA recommends for patients with intermediate-risk disease that they get either induction intravesical chemotherapy or immunotherapy, which is BCG. But unfortunately, due to ongoing BCG shortages, the SUO has recommended that intravesical chemotherapy should be prioritized for patients with intermediate-risk disease, and that's what's commonly done in practice. Mitomycin C has probably been the most extensively studied single-agent chemotherapy in this space. And in this Cochrane review, it shows that especially in patients that get maintenance BCG, mitomycin C is clearly inferior to BCG.

And in general, for mitomycin and other chemotherapies in general, the two-year recurrence-free survival seems to be somewhere around 60%. And mitomycin C, in particular, is a fairly toxic treatment that does have some side effects.

So we don't have BCG available, or we're not supposed to use it for intermediate-risk disease. Single-agent chemotherapy appears to be suboptimal. What are people doing in the real world? This was a survey by the SUO that was done in 2020, where it shows that there is a growing utilization of gem/doce in intermediate-risk disease due to its success in other disease spaces.

So I want to take a second to discuss the history of gem/doce and how it's come to this space. The regimen was first published in 2015 by my friend Ryan Steinberg, and it was developed by Mike O'Donnell initially in response to a mitomycin shortage.

Gemcitabine-mitomycin was used as a salvage regimen for patients that had BCG failure. In this publication, they showed that when it was used in the salvage setting, the two-year recurrence-free survival was 34%, which at the time, compared to what was available, was much better than alternatives.

As the BCG shortage continued, people started using this for treatment-naive high-grade disease or high-risk disease. So, this was a paper that looked at over 300 patients with AUA high-risk treatment-naive disease that were treated with either BCG or gem/doce. And this showed that the high-grade recurrence-free survival of gem/doce was superior to BCG, and other oncologic outcomes appeared fairly similar. Interestingly, while CIS was predictive of high-grade recurrence-free survival, other traditional clinical-pathologic features like age, gender, multifocality, presence of high-grade T1 disease were not predictive of response.

In our study, we really aim to focus on the intermediate-risk population. We did a retrospective review of 77 patients with AUA intermediate-risk disease treated between 2012 and 2022. The majority of patients had low-grade TA or papillary disease. There were a couple of patients with low-grade T1 disease and a few with small unifocal high-grade TA tumors that are intermediate risk by AUA criteria. Most of the patients in the cohort had recurrent disease, and about 20% had disease at initial presentation. Most patients were treatment-naive, and 33 were previously treated, mostly with BCG, but also with mitomycin C or docetaxel.

And what we found was that the overall two-year recurrence-free survival was 71%. When we stratified by receipt of prior treatment, the two-year recurrence-free survival for patients that were treatment-naive was 79%. And in those that were pretreated, it was 64%. And interestingly, when you look at patients that were intermediate risk or high risk that were treatment-naive, comparing between this study and one of our prior studies, the complete response rates are almost identical when you look at low versus high grade.

With the two-year complete response being essentially 80% in both studies. We did a Cox regression analysis for risk factors for disease recurrence within the intermediate-risk paper. And again, there were no pathologic features that were predictive of response, whether or not patients had high-grade or low-grade TA disease or if they had multifocal tumors. Failing a prior treatment did increase recurrence, which we saw in our Kaplan-Meier curves. And interestingly, maintenance was not associated with recurrence. Most patients in this study did get maintenance treatment, but I think that this does raise the question of whether or not patients with intermediate-risk disease really need maintenance or not.

When we looked at the side effects, this regimen was very well tolerated. Almost all adverse effects were grade one or two. There was a single grade three adverse event, and 96% of patients were able to complete the full induction course. So, in conclusion, our paper showed that gem/doce was efficacious and well tolerated. There is some compelling evidence that supports non-risk adapted use. It seems to work well for different grades and stages of disease. It's already increasingly utilized in other disease spaces. It's cheap, it's widely available. However, there are some limitations to this study that require further research. This was a retrospective report, and it really needs prospective validation. The mechanism of action of gem/doce is unclear. There have been many studies looking at BCG, but more work looking at gem/doce is needed, and again, the role of maintenance in the intermediate risk disease space is to be determined.

Sam Chang: That was great. This combination chemotherapy should be lauded because it really has, with Dr. O'Donnell's work and your work and the other multi-institutions that have been involved in some of your evaluations and a retrospective cohort of different patients, clearly become almost de facto a treatment choice that perhaps can be used in the naive setting as well as in the post-BCG unresponsive type setting. Let's talk a little bit about those patients who have already received a dose of gemcitabine. You talked about in this study, and you've talked previously about those that have received BCG. What about the patients that have received perioperative gemcitabine, which has become kind of the treatment choice? Have you noticed that if you use a combination there seems to be a decrease in efficacy, or do we not have enough numbers to really help tease that out?

Vignesh Packiam: Yeah, that's a great question. We did look at that in this study. The sample size of this cohort was relatively small, 77 patients, but there did not seem to be an impact on the efficacy of gem/doce, whether or not patients received their perioperative dose of gemcitabine in this study.

Sam Chang: So, at this point, with the limited data, there should not necessarily be an automatic stop, don't do it, it's not going to work. There is a possibility, a real one it seems, that there could be some efficacy with this combination, which is great to know as groups try to start integrating this combination chemotherapy. Can you tell me a little bit about the specifics regarding your dosing and how you do it? I'm a patient, I come in, this is my first combination intravesical chemotherapy. What do I actually get? What order, how long, etc.?

Vignesh Packiam: Yeah, absolutely. So, we're actually working on optimizing our patient education handouts for this because, as you know, BCG has been around forever, and there are well-researched documents for patients and for care teams for that. And I think gem/doce needs something similar. First of all, it's really important to do alkalinization as pre-treatment. So, we do 1300 milligrams of sodium bicarbonate the night prior to treatment and the morning of intravesical therapy. The reason for that is gemcitabine is very acidic. It has a pH of 2.5, so a lot of the toxicity from the regimen comes from the acidity of the gemcitabine, which the alkalinization can alleviate.

Sam Chang: This is great. I hate to interrupt, but I think many people have discussed this and have discussed alkalinization with mitomycin, the optimization, etc. But I think there's been an under-education out there regarding the use of bicarbonate before and the day of, to perhaps decrease the side effects, which I think is really important. So, I think that's a great tip. Go ahead. Sorry to interrupt.

Vignesh Packiam: No, no, that's okay. So, when the patient comes in, we put in an indwelling Foley catheter, drain the urine, and then we instill one gram of gemcitabine. The original gem/doce protocol from 2015 actually was to retain that medication for one and a half hours. We've actually moved to one hour, looking at the success of what other folks have achieved with that. So, we clamp the catheter, keep that medicine in for one hour, drain the gemcitabine, then we instill the docetaxel. That's also retained for one hour, and then you can drain that medication too. Now, if the patient's able to hold the medication and tolerate it well, at future visits, after the docetaxel is instilled, we can remove the catheter and then have them leave the office and void the medication at home.

Sam Chang: And the docetaxel dose, do you guys use 37.5 or 75?

Vignesh Packiam: We use 37.5 milligrams. As people are getting more experience using this regimen and onboarding with this regimen, pharmacies have different compounding abilities. So, our pharmacy compounds a bag of 37.5 milligrams, but typically it comes in 20 milligram vials. So, if you want to do a cheap and easy way to do it, you just mix two vials of the 20 milligram docetaxel into 40 ccs of saline, and each of those vials has two ccs, so it ends up being 40 milligrams and 40 ccs. So, that's kind of an alternative.

Sam Chang: That's great. And so, another key point is obviously working with, I mean, we have the advantages. Do you think it is definitely more difficult in those locations that don't have a pharmacy on-site? So, in future talks, we should talk about logistical setup in that situation. What do we do? How do we refer out, do we partner with infusion centers, etc., because that ability to have the pharmacy prepare those dosages ready for you to give in a close to 50 CC aliquot or close to 75 CC aliquot really makes this actually all go. So, Vignesh, where next with this research? You all have done a wonderful job in helping to establish this as a legitimate, viable, and perhaps even a better treatment alternative to what we've been using historically. What next in terms of research?

Vignesh Packiam: Yeah, I think there are two main focuses. One is we really need prospective evaluation of this, especially in the salvage setting. We have a lot of prospective clinical trials. This regimen is widely used, but there is no prospective data to support it. So, I'm very excited about the BRIDGE study that's looking at gem/doce versus BCG in high-grade treatment-naive disease. But we need similar prospective studies in the salvage setting, and I think for intermediate-risk disease as well. The other next step for this is to understand predictors of response. I think it's unlikely that we find a holy grail, one-size-fits-all treatment for non-muscle invasive bladder cancer. We can probably identify which patients are going to be treated best with this regimen versus others and be able to tailor treatments for patients.

Sam Chang: That move to precision oncology and really understanding true risk stratification and treatment alternatives for each individual is obviously the next step that really would help dictate not only escalation of treatment but de-escalation of treatment as well. That could help answer some of the questions that you just raised in your limitations, such as what's the role of maintenance? We know that chemotherapy works differently than immunotherapy, and perhaps with immunotherapy, we don't need constant exposure, whereas with chemotherapy, we may.

And so, I think that rationale in terms of understanding what are truly the predictive as well as the prognostic biomarkers for this heterogeneous group of patients is really, really essential. So, I look forward to your future research, and congratulations on your move. I know that the folks in Iowa are crying, and the folks at Rutgers are celebrating. And so, I'll join you in your celebration and I'll commiserate with the folks in Iowa. So, thank you again for spending some time with us, and I hope we get to do this again in the future as we look at the continued integration of combination chemotherapy for non-muscle invasive bladder cancer patients. So, thanks again, Vignesh.

Vignesh Packiam: I appreciate it, Sam. Thank you.