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Neoadjuvant Chemotherapy for Upper Tract Urothelial Carcinoma
Dr. Haffizulla: So, I'd love to talk about neoadjuvant chemotherapy for upper tract urothelial carcinoma. How common is this?
Dr. Grivas: That's a very good question and timely question because now we're starting to have data from prospective clinical trials in the upper tract urothelial cancer field. And over the years, we used to extrapolate data from bladder cancer to upper tract urothelial carcinoma because of the histologic similarity between the two diseases. However, I think we all recognize the need to have data dedicated in the upper tract urothelial cancer and now we start to accumulate data. However, the data and the evidence with neoadjuvant chemotherapy in upper tract urothelial cancer is not definitive yet and is not as clear as opposed to bladder cancer, muscle-invasive disease, whereas cisplatin-based neoadjuvant chemotherapy has level 1 evidence demonstrated by clinical trials.
In upper tract disease, we have data from MD Anderson, Arlene Siefker-Radtke, did a study in the past that included upper tract urothelial cancer patients and Dr. Plimack, Dr. Jean Hoffman-Censits have also studied this disease. And it seems like cumulatively that the pathologic complete response rate in upper tract urothelial cancer, numerically, seems lower to what we tend to see in muscle-invasive bladder cancers, about 15% pathologic complete response rate, and this number, specifically 14%, was actually noted in a recent clinical trial with an ECOG-ACRIN 8141 trial that Dr. Hoffman-Censits presented at the AUA meeting in 2018, and this 14% looks numerically lower than the 30-35% pathologic complete response rate we see in bladder cancer. So, the question is does that reflect different biology of disease or suboptimal endoscopic resection with upper tract disease versus more complete TURBT that sometimes you can see in bladder cancer. It's hard to say that, but I think we definitely need larger piece of evidence.
We recently published a study with my colleague, Dr. Nima Almassi, and we looked retrospectively at data in database work, National Cancer Database, for example, is a great example of retrospective studies that we can look at, and we saw significant pathologic downstaging in patients who received neoadjuvant chemotherapy compared to those who did not receive neoadjuvant chemotherapy, so we definitely saw this pathologic downstaging in those patients in the retrospective study. Of course, there are selection and confounding factors there, but I think it's at least indirectly showing that neoadjuvant chemotherapy has activity at least in the local disease setting with this pathologic downstaging.
The question is whether this translates to longer survival. And right now, we're designing studies with upper tract disease patients looking prospectively at, you know, those systemic treatment modalities. We're discussing whether chemotherapy, immunotherapy, combination thereof might be a good option for those patients and we have to answer those questions in prospective clinical trial.
To add some context in this fashion, there is data from from a nicely conducted phase III clinical trial called POUT, presented by Dr. Alison Birtle at ASCO 2018, 1 year ago, that showed disease-free survival, significant benefit, with adjuvant chemotherapy most patients had received gemcitabine and cisplatin in that study compared to observation, so definitely high level 1 evidence to give adjuvant cisplatin-based chemotherapy. That particular trial, the POUT trial, included patients with pT2, pT3, or pT4 stage or node-positive disease after nephroureterectomy, and I think, establishing the standard of care in patients who never received neoadjuvant chemotherapy before.
But the question remains, number one, is neoadjuvant better than adjuvant therapy and we don't know that yet. My practice is if someone is a good fit, is eligible for cisplatin, before nephroureterectomy, I tend to offer neoadjuvant cisplatin-based chemotherapy in the neoadjuvant setting. If they are not good candidate for cisplatin, either a clinical trial or nephroureterectomy is a reasonable option. And the last question regards the role of carboplatin in the adjuvant setting. In the POUT trial, there were 94 patients who actually received carboplatin instead of cisplatin with gemcitabine and if you look at the forest plot, you know, this confidence interval crossed one, to me, that tells me that the role of carboplatin in this adjuvant setting in upper tract disease is not clear.
The author of the study, Dr. Birtle, did an interaction test and saw that disease-free survival benefit was regardless of the chemotherapy regimen in either regimen; however, we haven't seen the published paper yet and I think the role of carboplatin is still unclear in this adjuvant setting. And we do not use carboplatin neoadjuvantly or adjuvantly in bladder cancer, so it still remains a question and hopefully, more data will come in the future, but definitely a very interesting topic and definitely a field for clinical trial evaluation and urgent need to get more data.
Dr. Haffizulla: Excellent. I do want you to touch a little more on improving surgical outcomes by using this neoadjuvant chemotherapy. Can you comment on the evidence that show in favor of this or not in favor of this?
Dr. Grivas: It's a good question and, you know, going back to this retrospective study we did with Dr. Almassi, we showed significant pathologic downstaging with neoadjuvant chemotherapy and that may enable, you know, easier surgery for the urologic oncologist because it's a smaller tumor to deal with. I think the quality of the surgery matters a lot and I think having a complete surgery with negative margins and also paying attention to the urethral cuff in the bladder is important. I think it's very critical to have as better quality of surgery in a tertiary center and experienced surgeon as possible. And so far, I think neoadjuvant chemotherapy, even in bladder cancer, does not appear to negatively impact the quality of surgery or outcomes after surgery or complication rates. So I still think that neoadjuvant chemotherapy has a role in definitely bladder cancer, level 1 evidence, but I tend to use it in properly cisplatin-fit patients in the neoadjuvant setting in upper tract disease. And it's easier because patients have two kidneys before the nephroureterectomy, so it's easier to be fit for cisplatin in that setting.
Dr. Haffizulla: So, that last description, would that be your key findings to disseminate to the clinician audience about when to use neoadjuvant chemotherapy in this setting?
Dr. Grivas: I think, you know, if you definitely have a patient in your clinic and you have high-risk disease, you have trouble with optimal staging of upper tract urothelial cancer. The exact stage is not clear. Is it a Ta, T1, T2 because the mass layer might not be available in the biopsy there in the upper tract setting. So you have a high-risk tumor and you know, you have concern, you know, that this is, you know, probably invasive disease based on endoscopic evaluation, biopsy, or 3D imaging. I think in either of those scenarios, if a high-risk patient with urothelial cancer comes to me and they are fit for cisplatin, I tend to offer neoadjuvant cisplatin-based chemotherapy and of course, you know, if someone comes to me after nephroureterectomy without prior neoadjuvant chemotherapy, in that setting the options include adjuvant-based chemotherapy, ideally cisplatin based. Again, in the options of neoadjuvant, the role of carboplatin is questionable, and of course, you have clinical trials now with adjuvant checkpoint inhibitors versus observation in that setting, but it's not an option for patients in the adjuvant setting, either with or without neoadjuvant chemotherapy.
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