The Impact of a Neoadjuvant Chemotherapy Treatment Prior to Radical Nephroureterectomy for Patients with High-Grade Upper Tract Urothelial Carcinoma - Jonathan Coleman & Wesley Yip

March 8, 2023

Wesley Yip and Jonathan Coleman join Sam Chang in a conversation discussing the impact of neoadjuvant chemotherapy prior to radical nephroureterectomy and its possible benefit on patients with high-grade upper tract urothelial carcinoma. Upper tract urothelial carcinoma is rare but deadly, with 5-year cancer-specific mortality rates of 21-59%. High-grade disease defines a high-risk population, and patients with high-grade disease have a significantly worse prognosis. To improve outcomes, advancements have been made with perioperative chemotherapy. Wesley Yip, Jonathan Coleman and colleagues evaluated neoadjuvant chemotherapy a multicenter prospective single-arm phase II study for high-risk urothelial carcinoma, defined by biopsy and/or imaging with positive selective cytology. The primary endpoint was pathologic response rate as defined by less than ypT2N0 disease. The study enrolled 58 patients. The primary endpoint was met and chemotherapy was well tolerated with minimal delay to surgery.


Jonathan Coleman, M.D, Professor, Department of Surgery and Urology, Memorial Sloan Kettering Cancer Center, New York, NY

Wesley Yip, M.D, Urologic Oncology Fellow, Memorial Sloan Kettering Cancer Center, New York, NY

Sam S. Chang, M.D., M.B.A. Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center

Read the Full Video Transcript

Sam Chang: Hello everyone, my name is Sam Chang, I'm a urologist in Nashville, Tennessee, and I'm actually coming from rainy San Diego, California. But I needed to wake up early because I had the opportunity to speak to two superstars. We have today, Jonathan Coleman, who is an attending surgeon at Memorial Sloan Kettering Cancer Center. He's a professor at the Weill Cornell University Medical Center as well. We're also joined by Wesley Yip, who is a graduating fellow at Memorial Sloan Kettering. We have been following data that both Dr. Yip and Dr. Coleman have presented in abstract form and in meeting forms and in different plenary sessions at some of the most prominent meetings, looking at the impact of a neoadjuvant chemotherapy treatment prior to radical nephroureterectomy and the possible beneficial impact it has. It's just been recently published, and so I think we'll start off with you, Dr. Yip, in terms of presentation of some of the data.

Wesley Yip: Thank you so much. Good morning. My name is Wesley Yip. I'm a current fellow of Memorial Sloan Kettering, and today I'll be discussing the results of our phase II clinical trial of neoadjuvant gemcitabine and cisplatin in upper tract urothelial carcinoma.

Upper tract urothelial carcinoma is rare but deadly, with SEER data demonstrating 5-year cancer specific mortality rates for T2 to T4 disease of 21-59%. High-grade disease, though, irrespective of stage, defines a high-risk population. And so, as seen in data from our institution, patients with high-grade disease have a significantly worse prognosis. To try to improve outcomes, several advancements have been made with perioperative chemotherapy.

From the POUT trial, we know that adjuvant chemotherapy is effective with an improvement in disease-free survival. We also know that cisplatin eligibility declines significantly from a neoadjuvant to the adjuvant setting. After nephroureterectomy, only 15% of patients remain eligible for adjuvant chemotherapy, so we designed a trial to evaluate neoadjuvant chemotherapy for upper upper tract disease. This was a multicenter prospective single-arm phase II study. The key eligibility criteria were high-risk upper tract urothelial carcinoma as defined by high-grade biopsy and/or imaging with positive selective cytology.

We use a split dose gemcitabine and cisplatin regimen over a 12-week course, and this is followed by extirpative surgery with a standardized templated lymph node dissection. Postoperative follow-up was on a standard protocol. This is Simon's Minimax two-stage design, so it'll be promising with a greater than 60% pathologic response rate and unacceptable of less than 40%. The accrual goal was 54 patients, which would be promising with at least 28 responders. The primary endpoint was pathologic response rate as defined by less than ypT2N0 disease. We had 58 who were enrolled, 58 underwent neoadjuvant chemotherapy, and 57 who underwent surgery and were evaluable for the primary endpoint. The patient characteristics are shown here and representative of an upper tract population. 89% of patients received at least three complete cycles of chemotherapy, and 18 of 24 who are listed as receiving three cycles here actually received three-and-a-half cycles. All patients were able to proceed to surgery and grade 3 or higher toxicities were primarily hematologic in nature.

Now, the pathologic response rate was 63%, and so the primary endpoint of the study was met. The complete response rate, or T0, was 19%. No patients progressed prior to surgery. The 2 and 5-year progression-free survival was 89% and 72%, while the 2 and 5-year overall survival was 93% and 79%, with a median follow up of 3.1 years among survivors. Now, when stratified by pathologic response, we found that patients with less than pT2 disease, it significantly improved progression-free and overall survival.

We also evaluated radiographic response by a predefined criteria for complete, partial, and no radiographic response. The top patient is an example of a radiographic partial response whose final pathology is T1 disease, and the bottom patient is an example of a radiographic complete response, with complete resolution of the right renal pelvis filling defect. This patient's pathology was T0, and of note, they also had an ERCC2 mutation. Once stratified by radiographic response, there was no significant difference in progression-free survival. But we did find that patients with partial or complete radiographic response did have better overall survival.

And so, in conclusion, this is the first fully accrued prospective clinical trial evaluating neoadjuvant chemotherapy prior to surgery for upper tract urothelial carcinoma. The primary endpoint was met and chemotherapy was well tolerated with minimal delay to surgery. So, this is a standard of care option for high grade upper tract disease. There are many people to thank, but especially the patients and their families.

Sam Chang: Well, first of all, congratulations to both of you and all the authors for having this accepted, getting it together, finishing the trial, getting it published in JCO. It's really something that, clearly, they've been a group that have been, I don't want to say biased, but have definitely thought, "Wow, gosh, neoadjuvant, I think, is the way to go with this disease and with other diseases."

Let's start off with some questions, probably first to Jonathan. When looking at this trial, as you guys were going through the data, tell me why you choose, and it might be just statistics in terms of that greater than 60% response to was positive and less than 40% percent would be negative, how did you come up with those percentages?

Jonathan Coleman: That's a great question. When doing trial design for a study such as this, we're trying to find an endpoint that's considered a meaningful impact for our patients. Trying to design that in upper tract disease is somewhat challenging because we're very limited in terms of our ability to clinically stage patients in the neoadjuvant setting before surgery. So we relied on nomogram based data, or at least prior published studies looking at trying to predict for patients with high-stage disease, and that was based primarily on grade, obviously, so grade was the primary driver. And then stage was driven to some degree by radiographic findings in terms of evidence of hydronephrosis or obstruction, evidence of invasion, which predict for higher stage disease.

And so, the actual endpoint of 60% versus 40%, so a 20% absolute difference between the two outcomes, was selected based on data, or at least clinical trials, that were developed in bladder cancer. Dean Bajorin was the medical oncologist who was supervising the design of this trial, and so a pathologic endpoint of pT2 or less than pT2 disease is considered a meaningful endpoint in bladder cancer. So, we've predicted for high-risk patients, those who would have pT2 disease at a high rate, and we look for an endpoint consistent with bladder cancer trials.

Sam Chang: Along those lines, do you have a rough estimate, Jonathan, because the data, to me, are overwhelming, that, yes, there's a significant, not only pathologic, but you showed slides of the radiographic response. How many do you think or estimated of these patients enrolled clearly were T2 before receiving it? Just a rough idea based on, like you were saying, radiographic or obstructive. Did you have clinical stage as a parameter that you guys tracked?

Jonathan Coleman: Well, as I said, the criteria that we selected were all meant to predict for greater than T2, so that was based on prior data. In terms of going through the trial to try and figure out how many met those criteria, they essentially all met that criteria.

Sam Chang: Right. With a high grade, all being, basically, high grade.

Jonathan Coleman: As being at high risk, right. High risk for T2 or greater. In terms of trying to actually estimate that, I think it's very hard for us to tell.

Sam Chang: Right. The last bullet, Wes, on the slide says, now this represents an option for our patients with upper tract disease, and clearly it's with the indications and the caveats of, "Hey, this is definitely a person that we're more concerned with, high-grade disease, et cetera." So how are you all balancing at Memorial or how, just as importantly, you will balance on whether or not to give patients a neoadjuvant course versus an adjuvant course?

Wesley Yip: I think a big consideration will be the patient factors of whether or not they'll tolerate it better before or after. One of the biggest considerations of their renal function and how that might be affected after nephroureterectomy. That's one of the biggest things so far.

Sam Chang: Along those lines, in terms of the true denominator, we have evolving definitions of platinum eligible. So in your next iteration, and that's really the key question is, Jonathan, where are we going to go next with this? Are we going to expand and do larger trials? Are we going to allow Carbo as a possible agent in addition to the Cis? Where do you all think next you'll go in terms of the research and studies?

Jonathan Coleman: Yeah, it's a great question. Just to follow up on the Gem-Carbo versus Gem-Cis question, I think we have two lines of evidence that suggests that cisplatin is really the key driver for these outcomes here. One is from this trial, the other is from the POUT data. The POUT trial used combination of either Gem-Cis in platinum eligible patients or Gem-Carbo. And in their analysis or sub-analysis after the trial completed, they found that the Gem Carbo, or carboplatinum, was less effective at these patients. Also, in the ECOG-ACRIN trial, which Vitaly Margulis led, they had a difficult time accruing to their Carbo-platinum arm of that study. I think for reasons because many of the medical oncologists who were treating patients really felt that it was ineffective chemotherapy.

So, I think as far as going forward, though, with further trials, I think trying to do a randomized prospective trial in this space with this regimen is going to be a bit of a challenge. The ECOG-ACRIN trial was an MVAC trial. This was a Gem-Cis based trial. SI think there are still questions about which regimen is better tolerated or which one would be appropriate, although it seems that both trials in the neoadjuvant setting had similar pT0 rates, ours having a 19% rate, I think theirs having a 13% rate. I think the key here is going to be cisplatinum as the current standard of care for the adjuvant settings, similar to what we do for bladder cancer.

But as far as going forward, and we're looking in the future, I think it's going to be looking at aspects of platinum sensitivity. Wes mentioned ERCC2 mutations being a predictor for platinum sensitivity. We also know that there are predictors for checkpoint inhibitor sensitivity, including MSI-high status and tumor mutational burden status. That data is being driven by work that's being done in the space for lynch-related cancers. So I think there's going to be some stratification for patients in terms of whether they should be enrolled in platinum-based chemotherapy regimens, neoadjuvantly, or potentially checkpoint inhibitor-based therapies, neoadjuvantly based on aspects such as MSI-high status and tumor mutation burden, potentially, and then other biomarkers that we'll have to better predict for a higher stage disease to better substratify our patients upfront.

Sam Chang: I think those points really emphasize our move to precision oncology in attempting to give us individualized treatment that are more likely to be effective. So I think those last points raised by Dr. Coleman in terms of being able to have improved disease characteristics that predict not only outcomes to therapy, but also when we can limit therapy, when we can actually tone it down where you may not need, necessarily, systemic therapy. Along those lines in response, the work we have with liquid biomarkers, with circulating tumor cells, all those such things, I think make it incredibly promising.

I'm going to end with the fact that we will hopefully hear soon from leaders in the upper tract space. As I do think, Jonathan, I think there, the AUA is putting together some guidelines for upper tract disease. Is that correct?

Jonathan Coleman: Yeah, I know there's a new guideline that's being developed for upper tract urothelial carcinoma by the AUA that's going to be very strongly evidence-based. There's a lot of literature out there in upper tract disease that provides good background data to be able to create standardized guidelines. I think that will better risk stratify patients upfront, standardize our approaches to evaluation patients initially, and also standardize our approach to management and settings such as this.

Sam Chang: Fantastic. I think we've all been looking forward from the AUA for guidance and direction in terms of the valuation and treatment and follow up for these patients, so we look forward to that. Thanks to both Jonathan and Wes, very much. Good luck, Wes, as you move on to your next career stage. Thanks again for spending some time with us, for both of you guys.

Jonathan Coleman: Thanks so much, Sam, it was a pleasure.

Wesley Yip: Thank you so much.

Jonathan Coleman: Thanks, Wes, great job.