Neoadjuvant chemotherapy for high-risk upper tract urothelial cancer

The outlook of patients with non-metastatic high-risk (HR; high-grade and/or stage ≥ cT2) upper tract urothelial carcinoma (UTUC) treated with surgery alone remains guarded. In the randomized phase III POUT trial, patients in the control arm treated with radical nephroureterectomy (RNU) alone experienced 5-year disease-free survival of approximately 45% and overall survival of 57%, establishing both the aggressive natural history of HR UTUC and the importance of perioperative systemic therapy. ¹ Although POUT demonstrated a clear survival benefit for adjuvant platinum-based chemotherapy, postoperative renal function decline after RNU frequently renders patients ineligible for cisplatin, the preferred platinum agent, thereby limiting delivery of optimal systemic therapy. In contrast, data from large retrospective cohorts indicate that neoadjuvant systemic therapy for UTUC is associated with improved oncologic outcomes compared with surgery alone and can be administered while renal function is preserved, ² establishing a compelling rationale for treatment intensification in the preoperative setting.

Against this backdrop, a recent European Urology publication reported the final long-term outcomes of neoadjuvant chemotherapy (NAC) for HR localized UTUC, based on a prospective single-arm phase II trial and an expanded institutional cohort. ³ Investigators at Memorial Sloan Kettering (MSK) evaluated three to four cycles of gemcitabine and cisplatin administered prior to RNU, with a minority of patients receiving gemcitabine–carboplatin or methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC). This trial enrolled 57 participants and now reports mature long-term outcomes, with a median follow-up of 5.4 years. There were 21 bladder cancer recurrence-free survival events, 20 disease-free survival events, reflecting recurrence or progression of upper tract disease, 11 cancer-specific survival events, and 18 overall survival events. The pathologic response rate to NAC, defined as pT ≤ 1N0 disease at RNU, was 63%, and the pathologic complete response rate was 19%.

Patients who experienced a pathologic response had substantially improved long-term outcomes. Seven-year disease-free survival was 78% in responders compared with 31% in non-responders, with a hazard ratio of 0.15. Cancer-specific survival at seven years was 90% versus 56%, and overall survival was also 90% versus 56%. Outcomes were similar between complete and partial responders, indicating that pathologic downstaging rather than complete response alone was associated with benefit. Interestingly, response to NAC did not influence bladder recurrence-free survival. Similar findings were observed in an independent cohort of 69 patients treated at MSK with a median follow-up of 2.6 years among survivors. ³ The two cohorts were highly comparable with respect to demographics, performance status, tumor characteristics, completion of NAC, and renal function. Again, response to NAC was not associated with bladder recurrence-free survival.

Several conclusions can be drawn from this report, which combines a phase II trial with an institutional clinical series. First, defining clinical HR UTUC preoperatively remains challenging; although ureteroscopic biopsy and cytology allow reasonably accurate assessment of tumor grade, particularly for high-grade disease, discordance with final pathologic findings remains.^4,5 Second, cisplatin-based NAC can be administered safely and reliably, with perioperative and 30-day grade ≥3 complication rates of 5% and 11%, respectively. Most patients were able to receive the planned treatment, with 90% completing at least three cycles and 64% completing all four cycles. Third, slightly more than 60% of patients achieved objective pathologic responses, and approximately one fifth achieved pT0 disease at RNU. Fourth, pathologic response to NAC was strongly associated with improved disease-free, cancer-specific, and overall survival.

However, even successful NAC did not prevent subsequent bladder recurrences. Patients in the phase II study did not receive a single immediate postoperative intravesical instillation of chemotherapy at the time of RNU, an intervention shown in randomized studies to reduce intravesical recurrence.^6,7 Although the phase II trial was initiated before publication of these studies, patients in the independent cohort were treated afterward, and no explanation was provided for the omission of intravesical therapy. Notably, underimplementation of immediate postoperative intravesical chemotherapy has been widely observed in clinical practice, reflecting logistical, safety, and workflow barriers, despite consistent evidence of efficacy across multiple disease settings. ⁸ Other issues not addressed include the frequency and management of contralateral UTUC, how such events were classified analytically, and whether patients who recurred in the bladder also developed recurrence in the RNU bed or progressed systemically.

Despite these limitations, conducting a phase III trial in a disease as uncommon as UTUC is inherently challenging, particularly given the persistent difficulty of accurate preoperative staging. The authors should therefore be congratulated for undertaking this effort in the absence of a contemporary control group. Their findings suggest a potential advantage to a neoadjuvant approach, presumably driven by patients who achieve a pathologic response. While NAC was well tolerated in this cohort, an important unanswered question is whether the approximately 12-week delay to definitive surgery may disadvantage the one-third of patients who did not respond. Given the limitations of disease assessment in nonmetastatic UTUC, it is unlikely that reliable methods exist to monitor response and discontinue therapy before completion of all four cycles.

Finally, these findings should be interpreted within the context of a rapidly evolving therapeutic landscape in urothelial carcinoma. Both perioperative platinum-based studies were conceived and conducted before the establishment of enfortumab vedotin plus pembrolizumab as standard first-line therapy for advanced urothelial cancers, ⁹ a shift that may have meaningfully influenced trial outcomes and contemporary benchmarks. Paradoxically, as high-level evidence is only now emerging to define the benefit of platinum-based chemotherapy in the perioperative setting, alternative neoadjuvant strategies, particularly immunotherapy and antibody–drug conjugates, which are less constrained by renal function than cisplatin, are already advancing rapidly. This evolution is now extending into HR UTUC, exemplified by the ongoing multicenter phase II trial (NCT05868265) evaluating neoadjuvant enfortumab vedotin—without pembrolizumab—prior to RNU, with pathologic complete response as the primary endpoint. ¹⁰ In parallel, molecularly targeted approaches are also being explored, including regimens incorporating FGFR inhibition, given that FGFR3 alterations are present in a significant portion of HR UTUC. ¹¹ Taken together, these developments point to a rapidly evolving and increasingly competitive treatment landscape in which the role of platinum-based NAC will need to be continually reappraised.