Impact of cisplatin ineligibility on receiving adjuvant therapy for UTUC

A retrospective study evaluated whether cisplatin ineligibility prevented patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy (RNU) from receiving adjuvant therapy. Results were presented at the 2022 Society of Women in Urology Annual Clinical Mentoring Conference by Kathleen Puttman, MD, PQY4 urology resident at The Ohio State University in Columbus, OH.1

Co-author Shawn Dason, MD, FRCSC, discusses the findings and takeaways of this study in a recent interview with Urology Times. He gives his perspective on the use of neoadjuvant therapy in UTUC patients compared to other therapies and advises urologists to be selective when choosing patients for this specific treatment. Dr. Dason is a urologic oncologist and an assistant professor of urology at The Ohio State University in Columbus, Ohio.

Please discuss the background of this study.

Patients with the upper tract urothelial cancer undergoing nephroureterectomy frequently have recurrent [metastatic] disease, as it's something that is a high-risk cancer. So, there's a lot of thought that adjuvant or neoadjuvant treatment with medications that can kill these [micrometastatic] cancer cells is something that that should be pursued. There are 2 big categories in how that's being approached. Neoadjuvant [therapy], or treatment before surgery, is something that is one camp of how to treat these patients and that's generally with cisplatin-based chemotherapy. And then adjuvant treatment, or treatment after surgery, is something that's another perspective. Also, there is some role in studies for carboplatin-based chemotherapy—less robust data—and, more recently, a role for immunotherapy, [which was] also [a] less focused population. To summarize, there are a few different approaches in perioperative medical chemotherapy or immunotherapy treatment, and it's unclear as to how we should consider all these different approaches.

What were some of the notable findings of this study? Were any of them surprising to you or your co-authors?

The most notable finding for us was that if you look at the overall population, only a small minority of patients met a few criteria [for losing eligibility for cisplatin chemotherapy when they truly needed it]. Those criteria were, firstly, that they were eligible for cisplatin-based chemotherapy, which is what the neoadjuvant approach would be. Secondly, after surgery, they were ineligible, suggesting that they're now no longer able to receive that potentially beneficial treatment. And thirdly, they had a tumor stage that would have qualified them, based on the POUT study,2 which is the best data we have for adjuvant treatment. Their tumor stage would have qualified them for that treatment. So, how many patients missed out on treatment by an adjuvant-only approach? When we looked at all of that, it was only about 11% of our cohort. We had about 280 patients—after exclusions, low 200s—and only about 26 patients met all of those criteria.

And so, it begs the question for us: How relevant is this in the overall context? And especially with, more recently, adjuvant nivolumab [Opdivo] being approved, how many of those patients would have had a worse eventual cancer treatment course if they then go on to adjuvant nivolumab? Now, the data is uncertain on this. We don't have comparative studies between all of these things, but it does suggest that this is a small fraction of the overall population. [For] that 11%, [what would happen] if we apply some more stringent criteria [to] mainly patients that would have only a subgroup benefit in POUT. For example, if we looked only at the patients that met certain criteria where in that adjuvant study, they clearly benefited, that number would drop further. If we kind of looked only at patients that had low PDL1 expression, that number would [also] drop further, as the PDL1 expression is thought to be a biomarker for adjuvant nivolumab benefit. And so, it's a hard question to answer, but I think the gist of our study is that perhaps this is a small population in the context of everything overall, [who] are rendered ineligible for chemo. If it is a small population, we should think about how we ultimately select or find the small population rather than catering treatment paradigms as a whole toward the small population that becomes cisplatin ineligible and, as a result, unable to receive neoadjuvant treatment.

How will these findings impact the way that you manage upper tract urothelial carcinoma in the future?

We definitely don't have a clear standard. And so, perspectives in some of these studies are helpful in shaping paradigms slightly. My own paradigm is influenced slightly to recognize that, firstly, this problem may not be as large as I once thought it was. Secondly, the potential for a lower stage disease that is PT1 or less on nephroureterectomy pathology is higher than I thought, even when I thought that the criteria that we used to suggest higher stage disease were met. As a result, in a patient that is relatively likely, at least in my estimation, to be able to receive adjuvant treatment, I think that neoadjuvant treatment would not be my favored approach. I think in a patient that, to me, is clearly going to be rendered ineligible for cisplatin-based chemotherapy but is borderline on the GFR [glomerular filtration rate] and would really benefit from it—[someone] with a kidney that is looking very healthy, and a GFR that suggests they're going to be way below that 50 cut-off after surgery—I still do think that neoadjuvant chemotherapy would be ideal in that scenario. But the findings will make me look at it more selectively than before. I think that this is partially what I hypothesized after seeing a little bit of a disconnect between the pathologic findings of nephroureterectomy specimens and what I would have predicted based on some of the criteria, like a positive cytology and/or mass and/or hydronephrosis to be PT2 or PT3, but ultimately ending up as a T1 or a TA. So that was what I was hypothesizing, but the magnitude of it in our overall series was lower than I expected. That was not a surprise, per se, but it was definitely something notable.

What is the take-home message in general for the practicing urologist?

With these kinds of cancers that are less common, they're always good, multidisciplinary cases [and] they're always good tumor board cases. I think it's good to not have a fixed perspective on whether all patients should receive treatment before surgery [or] treatment after surgery. I think that the best kind of message we could get out of this is that treatment perioperatively is likely the best way that we're going to advance survival in upper tract urothelial cancer, but the jury is probably still out [on] whether that should be before surgery, or after surgery. And if it's after surgery, whether that should be with cisplatin-based treatment, nivolumab, or even carboplatin-based treatment. So, I think we're uncertain about all of these questions. Multidisciplinary discussion is best, and a strict neoadjuvant approach for all patients that meet the criteria may be something that is over treating a reasonable degree of patients and may be a little bit lower in the scale of evidence that we have right now. That would be the general message. [We] really can't be clearly favoring one thing or another thing. I think it really brings to light the importance of careful consideration.

Is there anything else you feel our audience should know about this topic?

One big thing is this adjuvant nivolumab is an option in some of these patients. There was beneficial data, and this is now part of the [National Comprehensive Cancer Network (NCCN)] guidelines. And so, I think that any patient after nephroureterectomy [who] has pathologic features that you're concerned will recur, it's worthy of a medical oncology discussion for that consideration. That's really new [and] that really changes the perspectives on a lot of things. It really does change the new neoadjuvant/adjuvant paradigm to that if somebody is rendered ineligible for chemotherapy because of renal function, they may not be as limited in their options after surgery like they were before. And so, bringing that study, which does have limitations and may not be pursued in all patients, definitely can have some caveats, [to light is important].

Reference

1. Puttmann K, Scimeca A, Langston D, et al. How often does cisplatin ineligibility prevent patients from receiving adjuvant therapy following radical nephroureterectomy for upper tract urothelial carcinoma? Paper presented at: 2022 Society of Women in Urology Annual Clinical Mentoring Conference; February 7-9, 2022; New Orleans, Louisiana. Poster #5985.

2. Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomized controlled trial. Published online March 5, 2020. Lancet Oncol. Doi: 10.1016/S0140-6736(20)30415-3