Neoadjuvant Chemotherapy Versus Radical Nephroureterectomy in Upper Tract Urothelial Carcinoma

Drs. Michael Whalen and Vincent Xu of George Washington School of Medicine and Health Sciences discuss their recent analysis of neoadjuvant chemotherapy (NAC) utilization for upper tract urothelial carcinoma and the differences between radical nephroureterectomy and NAC as perioperative treatments. They examine the underutilization of NAC and how various aspects – such as patient distance from treatment facilities – play a role in this issue.

Watch part two of this interview: Dissecting the Potential of Neoadjuvant Chemotherapy as a Standard of Care for UTUC

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What are the differences between RNU and NAC as perioperative treatments? What are the benefits of NAC over RNU and its potential negative effects on renal function?

Dr. Whalen:
So I’m joined today by Vincent Xu, who’s one of the medical students at GW School of Medicine Health Sciences that helped with this project. It was the first author, so I may have him weigh in as well. His NAC is neoadjuvant chemotherapy, which is standard of care of the approach, the multimodal approach to urothelial cancer, whether it be arising in the bladder, the ureters, or the renal pelvis. So upper tract urothelial carcinoma versus lower tract urothelial carcinoma. And when studied in the bladder, about a 5 to 10% survival advantage for giving neoadjuvant chemotherapy prior to planned, radical cystectomy, which is surgical removal of the bladder for muscle invasive bladder cancer.

The data for neoadjuvant therapy in the upper tract urothelial carcinoma setting. There’s phase two evidence looking at benefits here for high risk patients, but it’s basically … the chemotherapy before surgery is part of a planned multimodal approach in an effort to downstage disease, basically make tumors shrink and reduce the possibility that there’s micrometastatic disease in regional lymph nodes or systemically. Cancer can spread either through the lymphatic system or hematogenously to distant organs like the liver or the lungs, the bones. So the theory here is that giving chemotherapy before the surgery allows treatment of these micrometastatic deposits for high risk patients.

Surgery requires a healing phase, right? The body’s resources are funneled toward healing after surgery, and usually patients will need anywhere between six weeks to 12 weeks to heal from an operation. So if a patient is high risk, meaning they have aggressive cancer or cancer that started to spread outside the organ of origin into nearby tissues, that basically three month period of having to heal from the surgery is also a period of time where they’re not, we’re not doing anything to treat the potential micrometastatic disease. So the rationale here is that giving medicine first neutralizes that micrometastatic disease, patients recover and then can safely get through their surgery. Radical nephroureterectomy or RNU is not perioperative. That’s the operation. It’s a radical nephroureterectomy, which is removal of the kidney and the ureter in a cup of the bladder to fully remove cancer basically in the upper urinary tract.

Can you describe the design and results of your study?

Dr. Xu:
So for our study, we use the national cancer database, which is a large national database of … it encompasses around 70% of all cancer diagnoses in the United States. And for our study, we queried it from 2004 to 2019 for all patients that were diagnosed with high grade, any stage upper tract urinary cancer or UTC that were also treated with RNU. And then we looked at stratified those patients based on whether they received neoadjuvant chemotherapy before or if they didn’t receive any before their RNU and then we looked at a few different outcomes. One was the overall survival between patients who did and did not receive NAC as well as the pathologic response rates, whether it be pathologic response or complete pathologic response. And then we also looked at different variables that were associated with increased or decreased risk … increased or decreased odds of receiving neoadjuvant chemo.

And this was all done with multivariate logistic models for the models that predicted the receipt of neoadjuvant chemo or we used Kaplan-Meier and Cox’s proportional hazards model for the survival. And our results showed that from … in this 15 year period of … we had around six and a half thousand patients, only around 200 of them received neoadjuvant chemo, just showing how … and of those patients, the majority of them were in the more recent years of that data set, showing that the growth and adoption of neoadjuvant chemo grew over time, but still is suboptimal. And the patients that were most likely to receive neoadjuvant chemo were patients that lived closer to their treatment facilities, patients that had higher clinical T-stages, as well as had positive clinical no status as well as if they were treated at an academic facility. And then in terms of the pathologic response rates, we had around a 34% pathologic response rate and 5.3 complete response rate, which is lower than the pathologic response rates reported in some of the trials that had come out already.

And additionally, when looking at … in multi-variable analysis, we found that neoadjuvant chemo still significantly increased the likelihood of achieving pathologic response rate, whether it be complete or not complete.

Are there any studies underway to resolve the issue of lack of patient access to NAC? Can community practices play a hand in finding a solution?

Dr. Xu:
There’s a lot of research in the space with urothelial bladder cancer, probably primarily because it’s a much more common diagnosis, and the establishment of neoadjuvant chemo came before in that space and there’s a lot of studies showing very similar findings where patients who were treated at academic facilities are more likely to get it, and patients in more rural settings are less likely.

So there’s definitely a big push towards increasing regionalization of care for patients so that we can get better access to patients who are well suited for neoadjuvant chemo. In the space of upper tract cancer or UTUC, there’s significantly less research. The whole rationale that we wanted to pursue in this study was because there weren’t many publications up until the point that looked into socioeconomic factors that influenced the receipt of neoadjuvant chemo. So definitely there’s a growing void of research that needs to be done in terms of what can be better done to make sure that access is equitable between patients no matter what treatment facility they have access to and the region of the country they live in.

Dr. Whalen:
One thing that’s interesting and notable, I guess, about neoadjuvant chemotherapy is that there are some patients who are not good candidates for it. For example, if they have baseline poor renal function because one of the components of the chemotherapy, which is cisplatin, can be nephrotoxic or damaging to the kidneys. So if patients don’t have a suitable baseline kidney function, then they’re not good candidates. One thing that the national cancer database does not publish is patient comorbidities, like other medical conditions that they may have that actually may exclude them from being eligible to safely receive neoadjuvant chemotherapy. Other things would be baseline hearing loss or peripheral neuropathy. So because there’s no comorbidities in the NCDB, we can’t tell … you can only look sort of on a population level in general, how many patients are kind of known to have these things. It’s been reported previously that about 50% of patients, when they’re diagnosed with upper intraepithelial carcinoma may not be candidates for neoadjuvant chemo already. And then after you remove a kidney, someone’s overall kidney function will continue to decline because you’ve removed basically half of their nephrons.

So in that setting, only about 20% of people after surgery will actually be candidates to get the most effective chemotherapy regimens. There was something called the POUT trial that showed that giving carboplatin instead of cisplatin still did have a benefit in the adjuvant setting, meaning after surgery. But that’s one thing too with neoadjuvant, with all that, if for patients that we think are going to benefit, meaning those who have locally advanced disease or no positive disease or large tumors or high grade tumors, that giving the chemotherapy first, as I said before, not only helps with the micrometastatic disease, but also is in the window of opportunity when you can give it. Because after surgery, once you remove the kidney and do radical nephroureterectomy, a lot of patients will no longer be candidates to get the cisplatin because of that decline in kidney function that happens after surgery.

With regard to how this intersects with your question about rural areas and access, depending on different regions of the country, I suppose, or maybe more rural areas, things like other comorbidities like hypertension, diabetes, or even obesity, tend to be concentrated in more rural areas. And so it might not only be an issue with access of these community centers that are delivering care, that they sort of don’t know about this. Although in the modern era, most people are plugged into society guidelines and things, but also that maybe people have more comorbidities in these rural areas in addition to the other potential barriers like patients having to travel three or four hours for care and other things like that. So we can’t necessarily comment on the true reason for maybe the lower incidence of use in the rural areas, but it likely is multifactorial.