Localized Bladder Cancer Paradigm Still Faces Obstacles

Brock O'Neil, MD

Better biomarkers are needed to identify which patients with localized bladder cancer are best to receive neoadjuvant chemotherapy, a treatment that is still not widespread in the community due to toxicity, explained Brock O’Neil, MD. “We need to push hard on [finding] the patients we know are going to benefit,” said O’Neil, an assistant professor in the Division of Urology at the University of Utah School of Medicine.

Beyond cisplatin-based chemotherapy, he added, researchers are beginning to explore immunotherapy in the neoadjuvant setting. Even more of a challenge is implementing adjuvant therapy into these patients with bladder cancer, which is largely due to poor accrual to clinical trials.

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In an interview with O’Neil during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, he shed light on the struggles with treating localized bladder cancer in both the neoadjuvant and adjuvant settings, as well as the advancements with robotic cystectomy.O’Neil: In contrast to some of the other topics [discussed at this meeting], it hasn’t changed a lot recently. The data that we are going off of are really 20 years old now, which demonstrates that neoadjuvant therapy with cisplatin-based chemotherapy should be offered to all patients undergoing cystectomy. Some of the important issues with it are that we don’t do a very good job as a profession; urologists especially are highly to blame for that. We don’t do as much neoadjuvant chemotherapy as we should be doing. It is getting better, but we still have a lot to do.

Other issues are that neoadjuvant chemotherapy isn’t tolerated by everybody, especially [by] patients with bladder cancer. We run into a lot of issues with renal insufficiency; those patients are not cisplatin candidates. The clear message that we run into in the community is that there are patients who are not qualifying for cisplatin-based chemotherapy, and they end up getting carboplatin. And, we know that is a much inferior approach.

Have biomarkers been identified?

Why has there been a challenge with widespread neoadjuvant chemotherapy?

Can you expand on the state of adjuvant therapy?

The last couple of things that we are very hopeful about is getting new markers. That will help us identify who is going to benefit from neoadjuvant chemotherapy. The benefit is relatively small to modest; that is a small survival benefit at 5 years. If we can identify patients who are less likely to benefit from that, and can move on to timely cystectomy, that would be highly beneficial.There are a number of markers that have retrospectively been identified. There are some commercially available ones, in fact, but nothing that has been prospectively validated that has established that. There are some things that are close. One is the COXEN trial that we participated in, but results aren’t back yet. We are hopeful that will give some signals on whether this is truly a predictive marker, which will help us make these decisions. It is kind of a task among some commercial entities to try and identify prospectively some markers. As a urologic oncologist, I can’t wait for that. We are very anxiously waiting that time.One is that the chemotherapy regimen is reasonably toxic. It is certainly not the worst out there, but it’s rough on patients. Second, we know that getting patients to timely cystectomy is really critical in terms of improving outcomes. There is a feeling that offering chemotherapy to a patient that is toxic has some benefit, [a] 5% survival benefit depending on your “glass half full, half empty” kind of view. It could be a lot or might not be. Then, we say, “Well, is that really what I want to give to my patient upfront or can I do it after surgery?” The trials have been challenging to do in the adjuvant setting, so we don’t know if there is a benefit there.There are several trials that were unsuccessful and failed due to lack of accrual. The big problem was that cystectomy is a very morbid procedure and all of the trials have a certain window in which the patients need to get enrolled on adjuvant therapy. There are a lot of challenges to get patients onto that after dealing with postsurgical complications. The trials [had very] poor accrual and eventually closed.

Are there any emerging techniques?

There is still a lot of feeling among urologists that we [should] identify those who are most likely to benefit from neoadjuvant therapy and do your surgery [first] in those who aren’t going to benefit. Then, select those who didn’t get neoadjuvant chemotherapy, who you’re still worried about, and then give them adjuvant chemotherapy. That is probably the direction we will move in.There is a lot of interest in robotic cystectomy right now. In general, the field is moving in that direction, especially doing intracorporeal urinary diversions. It is getting more established and people are getting more comfortable with that. There are a couple of big trials ongoing; there were results presented from the RAZOR trial that are promising and encouraging.

What they don’t do is they don’t show any significant benefits over complications. They seem to appear to be equivalent in terms of oncologic outcomes. The biggest benefits come in blood loss and maybe length of hospital stay. Then the second thing is that there is a big push for early recovery after surgery protocols. Most centers that are doing cystectomies have those, and those have shown to reduce hospital lengths of stay and may have some impact on complications. But [cystectomy] remains a very morbid procedure.

Can you share more details on the RAZOR trial?

The last thing that has a lot of interest, and is very early and is getting around, is getting wearable sensors. We could see if fitness trackers, or some kind of wearable device, will give us an idea of who is getting in trouble after surgery earlier so we can intervene before they have to be readmitted or have a major complication.This was a randomized trial comparing open cystectomy with robotic cystectomy. In some ways, [the trial] is a little bit old. During the robotic arm they did open urinary diversions and most people are moving in the direction of doing intracorporeal urinary diversions.

Is there anything else you would like to add?

The results were presented last year and suggested that patients in the robotic arm may have had a higher margin status, but the recurrence rate appeared to be the same. The update this year revisited the margin status and it seems that maybe there [were] some recording errors or something that explained that. Overall, it appears that there is an oncologic difference and there may be some benefit, at least with blood loss and length of hospital stay.The other thing with a lot of interest is neoadjuvant treatment. Immunotherapy is very much coming into play for the metastatic setting, and there is a lot of interest in trying to see if it has a role in the neoadjuvant setting. That could have a big impact either in improving that 5% benefit to something greater or potentially replacing cisplatin-based chemotherapy. That is farther off but potentially has a better side effect profile that surgeons would be more interested in and encourage their patients to do that. That is far off; they are just trying to get some phase II trials underway.