The management of patients with upper tract urothelial carcinoma is challenging due to the lack of high-level evidence, which results from the disease’s overall rarity. The standard of care treatment for patients with high-risk disease (high-grade or invasive) is radical nephroureterectomy, with some advocating for the added use of neoadjuvant or adjuvant platinum-based chemotherapy (Leow et al. Eur Urol 2014, Seisen et al. JCO 2017). The added benefit of platinum-based chemotherapy in patients with locally-invasive UTUC has been mostly extrapolated from the muscle-invasive bladder cancer literature and supported by several retrospective and population-based reports. Alison Birtle and colleagues reported the results of the first randomized clinical trial in the field assessing the added benefit of adjuvant platinum-based chemotherapy administration after radical nephroureterectomy (ASCO-GU18, EAU 2018).
First of all, the authors have to be warmly congratulated for doing what many considered undoable in the field of this rare disease. The POUT trial, a multicenter academic UK effort, enrolled 262 patients with locally advanced and/or node-positive UTUC (pT2-T4; N0-3; M0) between 2012 and 2017. The patients were randomized (1:1) to 4 cycles of adjuvant gemcitabine (1 000 mg/m2 at D1 and D8 every 3 weeks) + platin (cisplatin 70 mg/m2 or carboplatin in case of GFR 30-49ml/min) or surveillance following RNU. Patients with a GFR < 30 and those with incompletely resected macroscopic disease where excluded from the trial. Follow-up consisted in cross-sectional imaging and cystoscopy every 6 months for the first two years, then annually for a total of 5 years. The primary endpoint for the trial was disease-free survival (DFS), with recurrence-free survival (RFS), overall survival (OS), toxicity and quality of life (QoL) being secondary endpoints.
The trial was expected to recruit 338 patients in order to detect a 15% improvement in 3-year DFS; however, the safety monitoring committee stopped the trial early due to significant improvement in observed DFS. Thus, the intention to treat analysis was conducted on 262 patients with 131 patients in the chemotherapy arm and 131 in the surveillance one. The majority of patients enrolled had pT3 disease (30% pT2, 65% pT3) and were node negative following lymph node dissection (91%). Noteworthy, of the patients receiving adjuvant chemotherapy, 66% were treated with Gem-Cis, and 68% successfully completed the 4-planed chemotherapy cycles. Approximately 50% of patients undergoing chemotherapy developed a grade 3 or greater adverse event with only one patient suffering a death related to an upper GI bleed.
The POUT trial met its primary endpoint: a significant improvement in DFS (HR 0.49 [CI 0.31-0.76], p=0.001) was observed at a median follow-up of 17.3 months. Following adjustment for nodal involvement the difference was more pronounced with an HR 0.47 [CI 0.30-0.74), p=0.001). On univariable analyses, positive margins and receipt of gem-carboplatin were not associated with a an improved DSF following chemotherapy, which may be related to the short follow-up and to the low sample size, but still questioning the potential benefit of a non-cisplatin (ie.; carboplatin) regimen. On secondary end-points, adjuvant chemotherapy was also associated with an improvement in RFS (HR 0.49 (0.30-0.78), p=0.02). A difference in the OS curves favoring the adjuvant chemotherapy arm, but the difference remained non-significant likely due to the short follow-up.
In summary, the POUT trial provides an exciting and convincing first level I evidence on the benefit adjuvant chemotherapy administration after RNU in patients with locally-invasive or node-positive UTUC. The unanswered questions are the potential benefit of non-cisplatin-based chemotherapy regimens (thus questioning the even more strong rationale for neoadjuvant chemotherapy in the setting of UTUC where the radical surgery inevitably affects renal function) (Xylinas et al. BJUI 2012), the consistency of the benefit among subgroups (pN0/pN+/pNx, positive margins,…) and the benefit of adjuvant chemotherapy over chemotherapy at the time of relapse (Sternberg et al. Lancet Oncol 2015). The latter is of importance, as in muscle-invasive bladder cancer, adjuvant chemotherapy failed to demonstrate a significant improvement in overall survival compared to delayed chemotherapy at the time of relapse (EORTC trial 30994), although lack of power, as a result of low accrual, might have impacted the outcomes (Sternberg et al. Lancet Oncol 2015). Finally, the immunotherapy revolution that is ongoing in UC will likely impact the management of patients with UTUC. To date, clinical trials are ongoing in the adjuvant setting of UC that are including UTUC patients to receive either atezolizumab (NCT02450331) or nivolumab (NCT02632409), whereas no studies of preoperative immunotherapy are available to date. The opportunity to address clinical trials in the selected UTUC population is rationale, now feasible (thanks to Institute of Cancer Research, United Kingdom), and is supported by different underlying biology in UTUC compared to UC originating from the bladder. Such differences may be mirrored by the mechanisms of response and resistance development to immune checkpoint inhibitor therapy.