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Ongoing Clinical Trials Aim to Avoid Cystectomies for Select Patients With Bladder Cancer

Danielle Ternyila
Published Online:8:03 PM, Mon June 10, 2019
Paul L. Crispen, MD
Paul L. Crispen, MD
A major focus in bladder cancer lately has been bladder preservation,  as avoiding cystectomies can improve the quality of life (QoL) for patients with bladder cancer. However, cystectomies have historically been the only curative option for many patients despite the morbidity of this procedure.

The University of Florida is focused on investigating potential alternatives to cystectomy. For example, patients are being offered clinical trials of neoadjuvant chemotherapy prior to cystectomy at the university. Physicians are looking toward neoadjuvant chemotherapy as an opportunity to reduce the need for cystectomies.

One such trial out of the Alliance Cooperative Group that is enrolling at the university looks to preserve more bladders by using standard-of-care gemcitabine (Gemzar) and cisplatin in patients with documented DNA damage repair (DDR) mutations—which may represent a positive predictive biomarker for patients that are likely to respond to cisplatin-based chemotherapy. If there is no evidence of the cancer following chemotherapy, patients do not need to undergo cystectomy.

“For patients, that is a huge win,” said Paul L. Crispen, MD. “Because although that cystectomy can be a life-saving procedure, it’s also a very morbid procedure that we try to avoid as often as we can.”

Other data show that patients whose tumors have PD-L1 expression or high tumor mutational burden (TMB) have been associated with an increased complete response (CR) rate after neoadjuvant chemotherapy. For those who are ineligible for chemotherapy, neoadjuvant immunotherapy may also provide patients the opportunity to avoid cystectomy as well.

In an interview with Targeted Oncology, Cripsen, an assistant professor of urology at the University of Florida Health, discussed several ongoing trials for patients with bladder cancer focused on the importance of bladder preservation. He also highlighted a clinical trial currently enrolling at the University of Florida Health for patients with upper tract disease.

TARGETED ONCOLOGY: What is a recent development in the bladder cancer field that you are working on at the University of Florida that you think is particularly important for improved patient care?

Crispen: Our big push at the University of Florida right now is to focus on bladder preservation therapy in 3 distinct patient populations. One is the BCG-refractory stage I population. We currently offer those patients clinical trials before going on to cystectomy. Another is increasing our selection of patients undergoing trimodal therapy for stage II and III bladder cancer. The third is participating in trials evaluating ways to predict CR rates in patients receiving neoadjuvant chemotherapy prior to cystectomy in the hopes of avoiding cystectomy with predicting CR rates.

TARGETED ONCOLOGY: What are some other recent updates that you’ve seen across the field?

Crispen: The data that I see as being the most significant now in the care of advanced bladder cancer is the work on predicting response to systemic therapy, whether it be chemotherapy or immunotherapy. We see emerging data from different trials to show that patients with specific mutations or TMB may help us select which patients who [could] benefit from a specific type of systemic therapy.

One example of this is the presence of DDR mutations, or DNA damage response mutations, in bladder cancer and the responsiveness to chemotherapy. With the preliminary data that have been documented, there are now some very exciting trials that are open evaluating the concept of treating patients with chemotherapy and if they clinically have a complete response, maybe not removing their bladder or maybe not undergoing a radical cystectomy in the case of patients receiving neoadjuvant chemotherapy. 

One such trial evaluating this is a trial out of the Alliance Cooperative Group, of which we are participating. This trial has just opened in the last several months. Thankfully, that trial at the University of Florida is recruiting very well so far. In this trial, patients all go on the standard-of-care chemotherapy of gemcitabine and cisplatin. In patients who have documented DDR mutations in their tumor, those patients then go on through the trial and have the option of having a repeat transurethral resection of the bladder tumor. If there is no evidence of cancer, they can have their bladder remain in place and not undergo cystectomy. For patients, that is a huge win. Because although that cystectomy can be a life-saving procedure, it’s also a very morbid procedure that we try to avoid as often as we can.

With some of the other data that’s currently being released, we’re also seeing some possible ways to predict this and improve response with immunotherapy. Patients who express PD-L1 in their tumors or patients who have high TMB also have been showing an increased CR rate to neoadjuvant chemotherapy. For patients who may be ineligible for chemotherapy, they may be able to get neoadjuvant immunotherapy, and this may also provide a way to select patients who may be able to maintain their bladder for a longer period of time.

I think that the most important thing in this space is to focus on patients receiving neoadjuvant chemotherapy because neoadjuvant immunotherapy is not currently approved in this patient population.

TARGETED ONCOLOGY: Going forward, how do you see the field evolving based on these trials that are ongoing now?

Crispen: I’m very hopeful that moving forward, we will not only get improved care and improved CR rates in these patients, but we will also be able to do it in a manner in which we preserve more bladders and avoid cystectomies in a greater number of patients. Not only are we increasing the CR rate, but, in doing so, we are also going to be able to improve the QoL for these patients.

TARGETED ONCOLOGY: What are some of the enduring challenges in the field?

Crispen: We’ve been talking mostly in terms of bladder cancer and focusing on advanced disease. We need to gain a lot of ground in the treatment of BCG-refractory stage I bladder cancer. It’s good to see that there is currently a lot of work being done within this group of patients and trying to get newer agents evaluated and approved in this patient population with stage I disease who would otherwise be recommended for cystectomy to preserve their bladders as long as possible for these additional therapies being made available. 

TARGETED ONCOLOGY: What other trials do you have ongoing at your institution that you would like to highlight?

Crispen: Right now, we have one investigator-initiated trial at the University of Florida looking at urothelial carcinoma. This is a study involving patients with upper tract disease—cancers involving the renal pelvis or the ureter—looking at the timing of adjuvant chemotherapy administration, the intravesical chemotherapy mitomycin (Mitomycin-C), in preventing recurrences after their nephroureterectomy. 

TARGETED ONCOLOGY: Could you discuss the rationale for this trial?

Crispen: We know patients who have clinically localized urothelial carcinoma of the kidney and ureter. The most common site of recurrence is in the bladder, so these patients will have up to a 30% chance of developing a bladder cancer after their nephroureterectomy, even if they have never had bladder cancer before. The theory is that this is from the seeding of the cancer from the ureter during the surgery. Previous trials have shown that if you give patients intravesical chemotherapy, mainly mitomycin, after the surgery, that it can decrease the recurrence rate in the bladder significantly.

We’ve had some experiences here at the University of Florida where we had different surgeons instilling mitomycin at different times. About half the patients were getting the instillation in the operating room during the surgery, and the other half were getting it on the first postoperative day. 

This started off as a retrospective study, so we decided to go back and look at our results to see if there was a difference in the rate of bladder tumor recurrences in those 2 populations. What we noticed was that patients who got the mitomycin C in the operating room had a significantly reduced risk of having a tumor recurrence. Our hypothesis right now is that the timing of giving the mitomycin may help to further decrease the recurrence rate in the bladder postoperatively.

This trial is currently enrolling, and it opened up in November [2018].

[We did find out recently from a poll] looking at when patients get mitomycin during the perioperative period. So far, and this is very unofficial, about 20% to 30% of [physicians] don’t give it at all—which is a little bit surprising to me—and then another 20% give it in the operating room as we’re doing here, and then the rest give it either on postoperative day 1 or sometime before the catheter is removed. One of the shocking things about that is the fact that still a significant amount of urologists don’t give it at all, and then the other thing is it’s very variable when they give it, and none of that is supported by any data. We’re hoping to answer that question to see if that can make a difference.

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