Unraveling the Complexities of Treating Node Positive Bladder Cancer Presentation - Monika Joshi

August 22, 2023

At the 2023 Bladder Cancer Advocacy Network (BCAN) Think Tank Monika Joshi delivers an enlightening talk on the subject of node-positive non-metastatic bladder cancer, a new area that only started to be defined in 2017. She covers the emphasis on the recent classification of this type of bladder cancer, the EA8185 cooperative group study, and the challenges and considerations regarding lymph node identification and biopsying. Dr. Joshi highlights various studies, such as IMPART results, Big 10 Concurrent Durvalumab and Radiation Therapy, and a retrospective analysis from the United Kingdom. The talk culminates with the introduction of a phase two study on bladder-sparing chemoradiation with durvalumab and a heartening patient experience named Beverly, who shares her successful journey through chemotherapy, radiation, and immunotherapy treatments. The talk underscores the feasibility of multimodality treatment with bladder preservation and the need for further validation in prospective trials.


Monika Joshi, MD, MRCP, Professor of Medicine, Endowed Professorship in Cancer Clinical Care, Division of Hematology-Oncology, Penn State Cancer Institute, State College, PA

Read the Full Video Transcript

Monika Joshi: I'm going to talk about node positive bladder cancer. So these are my disclosures. I hope to touch upon a little bit about the introduction to node positive non-metastatic bladder cancer because this is such a new space. And then we'll talk about EA8185, which is the cooperative group study, focusing on node positive non-metastatic patients. And then I wanted to share a patient experience and hopefully bridge and make the talk interesting so you all can think and suggest what the next steps should be.

So to this group, I don't need to define what lymph node staging for bladder cancer is, but what I want to emphasize is how new this space is. It only started sometime in 2017 when it was reclassified. And it's important to remember, because I think this is an entirely new area as opposed to muscle invasive space, node negative muscle invasive space, that has been looked into for chemoRT or bladder preservation for decades. And we're so glad that we have Parminder's study moving forward and hopefully giving us a new standard of care in the future.

What we really should also think about is how do we define a lymph node? More and more we've been doing studies and just boxing ourselves into the RECIST criteria is perhaps not very smart and not very feasible for our bladder cancer patients. What we also think is reality is different. Being a perfectionist, we want a biopsy to prove it's positive, but when we are sitting in the clinic, perhaps it's not possible because the node is somewhere that it's not approachable or perhaps the patient doesn't want it. So there's several factors that play a role in why biopsying all nodes is not going to be possible. So we really need something, better imaging, better modality to pick these patients, and that's what we should also be thinking as our next step in our next study.

IMPART results, I think you saw Parminder present that. I'm going to just twist it a little bit. This actually established the feasibility of chemoRT node positive. You can again see a small sample size. So this is not a very common population to have. More and more we are doing studies. We are realizing that the node positive group is perhaps less common than what we thought, and maybe because we just don't have the modality to pick it up. But what's important to note is there was no difference between N0 versus N1. So again, these patients do well and it was feasible to deliver definitive radiation therapy.

This was our study, the Big 10 Concurrent Durvalumab and Radiation Therapy Followed by Adjuvant Durvalumab. These were patients who were locally advanced, not eligible for cisplatin. We actually have published the results in the Journal of Immunotherapy for Cancer, and then you can look at it. It has not just clinical, but a lot of data for even correlative and lots that we have not published that we are still wrapping our head around. What DUART did show, this was concurrent durvalumab and radiation followed by adjuvant, so this was one of the initial studies that looked into adjuvant immunotherapy for a year. And we focus just for this talk on what we do realize, that node positive patients had similar median PFS and OS when compared to the node negative. And one year overall PFS was 71.5%, whereas the overall survival was 83.8% for the total population. We also picked up some that patients who had high tumor mutation burden, more than 10, did better than those who didn't.

This was a very recent paper that you all must have read, published in JCO, retrospective analysis coming from the United Kingdom 2012 to 2021, 287 patients, node positive, non-metastatic. They were focusing on patients who received radical treatment, whether radiation, definitive radiation with or without chemosensitive agent or receiving palliative. And the numbers are shown here. The outcome was better for patients who received radical treatment when compared to receiving palliative treatment. What was also interesting was the choice of radical treatment, whether you actually opt for surgery or radiation therapy showed no difference in OS. So again, this is something that we can actually offer to patients and perhaps spare them some of the side effects from the surgery.

This is our EA8185. So again, it's a phase two study of bladder sparing chemoradiation with durvalumab in clinical stage three node positive. As best I can tell you, this is the only prospective study. All of the data that is currently present mostly is retrospective or they are from a small cohort in other prospective studies, but not the majority. So when we were designing this study, we actually designed very similar to the study I showed you, the retrospective one, but because you were learning more about the space, I think when it went through the taskforce into your steering committee and where is cooperative groups, I think we wanted to make it really neat and clean and we later realized perhaps that wasn't the best way to do it. We have to keep it simple, so we made a lot of changes. So it's any N1-3 node could be biopsy positive, radiologically suspicious. We've kind of kept the room open. We've also removed the requirement for neoadjuvant chemotherapy.

While you heard a lot from Parminder, it's still questionable, but it wasn't really favored by the patients. They didn't want to wait that long before they get the definitive treatment. So we removed that option, and the patients would be divided randomized to chemoRT plus or minus durvalumab, and those who would receive a response would go on in the experimental arm to adjuvant durvalumab. So the primary endpoint is complete response. So again, the study's open, we want to enroll in it because if this doesn't work, then what's next? I think, again, it's a new space so more ideas should come into how to push this study.

We have improved the design. We looked into, had various meetings, and then we realized it's a much rarer clinical scenario, and that unfortunately has not changed. And we have relaxed the mandate for the neoadjuvant chemotherapy. We have simplified the node positive definition. Impact due to Covid, as I'm speaking, I am myself positive, but the fact that you guys are all sitting there says it is probably improving, and studies open through all the cooperative groups. And again, simple is better. That's what we've learned. So we'll keep that in mind.

I wanted to share lastly, a patient experience. This was a patient in 2017 when this stage was coming out. We had the DUART open. She was very interested in going, and we realized initially she was thought to be T1, and when she went for surgery, they found some nodules. There was suspicion for local spread, but on hindsight, perhaps she was T4 node positive only, and she got her treatment. I'm going to let her speak and tell you the story to see how patients feel about this approach.

Beverly, could you share with us?

Beverly: Certainly. I came to Hershey in 2017 and I had third stage bladder cancer. It was determined that I wasn't able to have my bladder removed. However, I did have to have nephrostomy tubes in both of my kidneys in order to take the urine out. So I had bags on either side of my legs. After that, I was given the options of chemotherapy, radiation, and immunotherapy. And I can tell you, I was so pleased. I was so pleased. So I first had chemo and I had tiredness, sometimes extreme tiredness. I had loss of appetite. I didn't have nausea because when I got my chemo treatments, they always gave me nausea medication. I did end up with neuropathy in my feet, but I've found that exercising really helps with the flexibility of my feet and my balance. So then I was on to radiation, which 33 treatments, they took five to seven minutes. My husband would just drop me off, go to the parking lot and wait, and I had no effects from that.

And then it was to immunotherapy. Immunotherapy, I had several treatments. I didn't do quite as well. I had some diarrhea, some blood value issues. And then 18 months passed and I had my nephrostomy tubes taken out, and my doctor put stents in my ureters, which the ureters go from the kidneys to the bladder, and mine had been crushed. So he put the stents in and I had this full functioning bladder. It was like a miracle. I couldn't believe it. And I go every six months or a year for follow-ups. I just started five years in remission. I am so, so grateful to God and to my doctors for where I am today. I feel so healthy. I feel like I have never really been sick, which is just amazing, because it was a journey. But one thing I will say, my doctors always listened to me. They always listened to me. I could come up with some of the strangest questions and-

Monika Joshi: I had to cut it short. I think she spoke a lot about our center and Dr. Kegg and myself, and I wanted to spare that to you guys. But I think the bottom line is that you could hear how much this combination, the chemoRT and immunotherapy, I do believe that immunotherapy did give her a good response.

So with that, we'll go up to the summary. So multimodality treatment with bladder preservation in node positive non-metastatic bladder cancer is feasible. And I do think that it needs to be validated in prospective trials. Perhaps we need to have a single arm, perhaps we need to have additional arms with different combinations that could show. With that, I think I'll end and thank you.