Abstract
Objectives: To evaluate the benefit of neoadjuvant chemotherapy (NAC) for patients with high-risk upper tract urothelial carcinoma (UTUC) using a large, well-curated multi-institutional database. Patients and Methods: This study was a multi-institutional retrospective analysis conducted by the UTUC Collaborative Network (UCAN), combining data from 2276 patients with UTUC who underwent radical nephroureterectomy at seven high-volume tertiary care centres in the United States. The UCAN data were analysed to evaluate the impact of response to NAC on survival outcomes in patients with UTUC. Results: A total of 378 patients in the UCAN database underwent NAC. On final surgical pathology, 101 patients (26.8%) had ≤ypT1N0 disease and were defined as NAC treatment responders. Patients who responded to NAC had significantly longer overall survival (OS) and progression-free survival (PFS) compared to non-responders. At 5 years post-surgery, 81.5% of responders were alive compared to 59.8% of non-responders. The median OS and PFS times among non-responders were 7.0 years (95% confidence interval [CI] 5.6–9.7) and 6.0 years (95% CI 4.6–9.3) respectively, while the median OS and PFS were not reached among responders. Limitations of this study include its retrospective design, heterogeneity in chemotherapy regimens, and the absence of clearly defined patient selection criteria for treatment. Conclusion: These data suggest that NAC can play a pivotal role in the treatment of well-selected UTUC patients who respond positively. Non-responders had clearly inferior outcomes. More work is needed to find predictors of response which can improve patient selection.
| Original language | English |
|---|---|
| Pages (from-to) | 994-999 |
| Number of pages | 6 |
| Journal | BJU International |
| Volume | 135 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2025 |
Bibliographical note
Publisher Copyright:© 2025 BJU International.
Funding
Alice Yu: No conflicts exist. Patrick J. Hensley: No conflicts exist. Heather L. Huelster: No conflicts exist. Austin Martin: No conflicts exist. Aaron Potrezke: No conflicts exist. Jonathan Pham: No conflicts exist. Jay D. Raman: No conflicts exist. Maximilian Pallauf declares support from the Paracelsus Medical University Research and Innovation Fund (2022-FIRE-004-Pallauf). Nirmish Singla: No conflicts exist. Andrew Katims: No conflicts exist. Jonathan Coleman: No conflicts exist. Vitaly Margulis: No conflicts exist. Surena F. Matin declares support from the Eleanor and Scott Petty Fund for Research on UTUC, and the Monteleone Family Foundation for Research in Kidney and Bladder Cancer. Philippe E. Spiess: No conflicts exist. This is one of the larger studies to date assessing pathological response to NAC and survival patterns among responders, and it provides an important contribution to the scarce literature in this space [4–7]. We found a significant difference in survival between responders and non-responders. Furthermore, these favourable outcomes were sustained over time as the median PFS was not reached in this cohort. This is consistent with findings from previously published prospective trials further affirming that there is a role for NAC in the treatment of UTUC. Additionally, this demonstrates that a positive response to NAC is an important marker for survival outcomes. This information is crucial for counselling patients after surgery and could guide further research about indications for adjuvant therapy. We acknowledge that this study has limitations due to its retrospective design. We noted that pathological downstaging to ypT1 or less was 17.3% in patients with confirmed AJCC stage ≥2 at diagnosis, which is relatively low compared to previously published trials [1,2]. We hypothesise that the response rates were poor due to the variability in both chemotherapy regimens and the number of treatment cycles administered, as we would expect with real-world data. Notably, approximately 30% of our patient population did not receive cisplatin-based chemotherapy, which may be a contributing factor. We also acknowledge that, in this cohort, a notable portion of patients who underwent NAC presented with clinical stages Tis, Ta, or T1, N0, which conventionally would not trigger the utilisation of NAC. It is important to note that these patients were treated prior to the publication of contemporary phase II trials, which have helped define the ideal candidate for NAC. We also attribute this observation to the complexities involved in accurately staging UTUC. It is plausible that, in these instances, physicians may have suspected more advanced disease stages, prompting the administration of NAC, but such nuances were not fully captured within our retrospective database. This bias needs to be considered when interpreting these data. Furthermore, almost all patients with AJCC stage ≤1 had high-volume or high-grade disease. One can make the argument that ypT1 disease may have been classified as cT1 to begin with, which explains the better survival outcome. To address this, we performed a sub-analysis excluding patients with AJCC stage ≤1 and the overall results and observed trends remained consistent. We know that there is a role for adjuvant chemotherapy in patients with advanced UTUC [8–10]. As the POUT trial demonstrated, administration of gemcitabine-platinum chemotherapy within 90 days of radical nephroureterectomy significantly improves PFS. However, it is crucial to recognise that not all patients are candidates for this treatment, often due to factors such as renal function deterioration, postoperative complications, and extended post-surgery recovery periods. This suggests that it might be preferable to administer chemotherapy in the neoadjuvant setting. Our study, one of the most extensive published to date, provides additional evidence indicating that, among patients who do respond positively to NAC, there are dramatically superior PFS, CSS and OS outcomes. These findings strongly suggest that NAC could play a pivotal role in the treatment of well-selected patients, particularly those at risk of renal function deterioration after surgery. While we acknowledge the positive outcomes in responders vs non-responders, there is a clear need for further investigations to establish predictors of response to improve the precision of NAC administration, ensuring its targeted application for patients who are most likely to derive substantial benefits [11]. Utilising data garnered from a multi-institutional collaboration (UCAN), this study constitutes one of the larger studies investigating the role of NAC in UTUC that have been published to date. These results further underscore the potential benefits of NAC for patients presenting with high-risk disease upon diagnosis, as previously demonstrated by smaller randomised controlled trials. Respondents exhibited markedly better PFS and OS compared to non-responders, and these data have clinical utility for patient counselling and prognostic assessment. Alice Yu: No conflicts exist. Patrick J. Hensley: No conflicts exist. Heather L. Huelster: No conflicts exist. Austin Martin: No conflicts exist. Aaron Potrezke: No conflicts exist. Jonathan Pham: No conflicts exist. Jay D. Raman: No conflicts exist. Maximilian Pallauf declares support from the Paracelsus Medical University Research and Innovation Fund (2022-FIRE-004-Pallauf). Nirmish Singla: No conflicts exist. Andrew Katims: No conflicts exist. Jonathan Coleman: No conflicts exist. Vitaly Margulis: No conflicts exist. Surena F. Matin declares support from the Eleanor and Scott Petty Fund for Research on UTUC, and the Monteleone Family Foundation for Research in Kidney and Bladder Cancer. Philippe E. Spiess: No conflicts exist. Alice Yu: No conflicts exist. Patrick J. Hensley: No conflicts exist. Heather L. Huelster: No conflicts exist. Austin Martin: No conflicts exist. Aaron Potrezke: No conflicts exist. Jonathan Pham: No conflicts exist. Jay D. Raman: No conflicts exist. Maximilian Pallauf declares support from the Paracelsus Medical University Research and Innovation Fund (2022‐FIRE‐004‐Pallauf). Nirmish Singla: No conflicts exist. Andrew Katims: No conflicts exist. Jonathan Coleman: No conflicts exist. Vitaly Margulis: No conflicts exist. Surena F. Matin declares support from the Eleanor and Scott Petty Fund for Research on UTUC, and the Monteleone Family Foundation for Research in Kidney and Bladder Cancer. Philippe E. Spiess: No conflicts exist.
| Funders | Funder number |
|---|---|
| Eleanor and Scott Petty Fund for Research on UTUC | |
| Norman Arts Council | |
| Paracelsus Medical University Research and Innovation Fund | |
| UCAN | |
| Paracelsus Medizinische Privatuniversität | 2022‐FIRE‐004‐Pallauf |
| Paracelsus Medizinische Privatuniversität | |
| Eleanor and Scott Petty Fund for Research on UTUC | 1,2 |
Keywords
- carcinoma
- chemotherapy
- neoadjuvant
- nephroureterectomy
- urothelial
ASJC Scopus subject areas
- Urology
Fingerprint
Dive into the research topics of 'Response to neoadjuvant chemotherapy leads to better survival outcomes in upper tract urothelial carcinoma'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver