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ORIGINAL ARTICLE
Year : 2020  |  Volume : 32  |  Issue : 2  |  Page : 73-74

Lessons learned from the POUT trial: Adjuvant chemotherapy does improve the outcomes of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma


1 Center of Robotic and Endoscopic Urology, Athens Medical Center, Athens, Greece
2 Department of Urology, Bichat-Claude Bernard Hospital, Paris, France

Date of Submission21-Oct-2019
Date of Decision26-Oct-2019
Date of Acceptance29-Oct-2019
Date of Web Publication30-Nov-2020

Correspondence Address:
Evanguelos Xylinas
Department of Urology, Bichat-Claude Bernard Hospital, Paris
France
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/HUAJ.HUAJ_8_20

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  Abstract 


Introduction: The management of patients with upper tract urothelial carcinoma (UTUC) is challenging, with radical nephroureterectomy (RNU) being the gold standard of treatment for high-risk disease. The role of chemotherapy is unclear. The POUT trial is a multicenter UK effort that addresses whether adjuvant chemotherapy improves disease-free survival (DFS) in patients with locally advanced and/or node-positive UTUC. Methods: The POUT trial enrolled 262 patients with UTUC (pT2-T4, N0-3, and M0) between 2012 and 2017. The patients were randomized (1:1) to four cycles of adjuvant gemcitabine–cisplatine (gemcitabine–carboplatin if GFR 30–49 ml/s) or surveillance following RNU. The patients were followed with cross-sectional imaging and cystoscopy every 6 months for the first 2 years and then annually for 5 years. The primary end point was DFS, whereas recurrence-free survival (RFS), overall survival (OS), toxicity, and quality of life (QoL) were the secondary end points. Results: The intent-to-treat analysis was conducted in 262 patients (131 chemotherapy and 131 surveillance). Among the patients treated with chemotherapy, 66% were offered gem-cis, while 68% completed successfully the four planned chemotherapy cycles. Approximately 50% of the patients undergoing chemotherapy developed Grade 3 or greater adverse events. A significant improvement in DFS (hazard ratio [HR]: 0.49 [confidence interval (CI): 0.31–0.76], P = 0.001) was observed at a median follow-up of 17.3 months. Considering the secondary end points, adjuvant chemotherapy was also associated with an improvement in RFS (HR: 0.49 [CI: 0.30–0.78], P = 0.02). Following adjustment for nodal involvement, the difference was more pronounced with a HR: 0.47 (CI: 0.30–0.74), P = 0.001. A difference in the OS curves favoring the adjuvant chemotherapy arm was noticed, but the difference remained nonsignificant due to short follow-up. Conclusions: The POUT trial provides exciting and convincing Level I evidence on the benefit associated with adjuvant chemotherapy administration in patients with locally invasive or node-positive UTUC.

Keywords: Adjuvant, chemotherapy, nephroureterectomy, randomized, surveillance, upper tract urothelial carcinoma


How to cite this article:
Ploumidis A, Pappas A, Ouzaid I, Xylinas E. Lessons learned from the POUT trial: Adjuvant chemotherapy does improve the outcomes of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma. Hellenic Urology 2020;32:73-4

How to cite this URL:
Ploumidis A, Pappas A, Ouzaid I, Xylinas E. Lessons learned from the POUT trial: Adjuvant chemotherapy does improve the outcomes of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma. Hellenic Urology [serial online] 2020 [cited 2021 Jan 28];32:73-4. Available from: http://www.hellenicurologyjournal.com/text.asp?2020/32/2/73/301825




  Introduction Top


The management of patients with upper tract urothelial carcinoma (UTUC) 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 (RNU), with some advocating for the added use of neoadjuvant or adjuvant platinum-based chemotherapy.[1],[2] 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 et al. reported the results of the first randomized clinical trial in the field assessing the added benefit of adjuvant platinum-based chemotherapy administration (ASCO-GU18, EAU 2018).


  Materials and Methods Top


To start with, the authors have to be warmly congratulated for doing what many considered undoable in the field of this rare disease UTUC. The POUT trial, a multicenter 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 four cycles of adjuvant gemcitabine–cisplatin (gem-cis)/gem–carboplatin (GFR 30–49 ml/min) or surveillance following RNU. Patients with a GFR <30 and those with incompletely resected macroscopic disease were excluded from the trial. Patients were followed up closely with cross-sectional imaging and cystoscopy every 6 months for the first 2 years and transitioned to annual follow-up for a total of 5 years. The primary end point for the trial was disease-free survival (DFS), with recurrence-free survival (RFS), overall survival (OS), toxicity, and quality of life (QoL) being the secondary end points.

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 the observed DFS. Thus, the intent-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 and 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 four planned chemotherapy cycles. Approximately 50% of the patients undergoing chemotherapy developed a Grade 3 or greater adverse event, with only one patient suffering a death related to an upper gastrointestinal bleed.


  Results Top


The POUT trial met its primary end point: a significant improvement in DFS (hazard ratio [HR]: 0.49 [confidence interval (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 of 0.47 (CI: 0.30–0.74), P = 0.001. On univariable analyses, positive margins and receipt of gem–carboplatin were not associated with an improved DFS following chemotherapy, which may be related to the short follow-up and the low sample size, but still questioning the potential benefit of a noncisplatin (i.e., carboplatin) regimen. On secondary end points, adjuvant chemotherapy was also associated with an improvement in RFS (HR: 0.49 [CI: 0.30–0.78], P = 0.02). A difference in the OS curves favored the adjuvant chemotherapy arm, but the difference remained nonsignificant likely due to the short follow-up.


  Conclusion Top


In summary, the POUT trial provides exciting and convincing Level I evidence on the benefit associated with adjuvant chemotherapy administration in patients with locally invasive or node-positive UTUC. The unanswered questions are the potential benefit of noncisplatin-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),[3] the consistency of the benefit among subgroups (pN0/pN+, positive margins,…), and the benefit of adjuvant chemotherapy over chemotherapy at the time of relapse.[4] The latter is of importance, as in muscle-invasive bladder cancer, adjuvant chemotherapy failed to demonstrate a significant improvement in OS 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.[4] Finally, the immunotherapy revolution that is ongoing in ulcerative colitis (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, is feasible (thanks to the 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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Leow JJ, Martin-Doyle W, Fay AP, Choueiri TK, Chang SL, Bellmunt J. A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma. Eur Urol 2014;66:529-41.  Back to cited text no. 1
    
2.
Seisen T, Krasnow RE, Bellmunt J, Rouprêt M, Leow JJ, Lipsitz SR, et al. Effectiveness of adjuvant chemotherapy after radical nephroureterectomy for locally advanced and/or positive regional lymph node upper tract urothelial carcinoma. J Clin Oncol 2017;35:852-60.  Back to cited text no. 2
    
3.
Xylinas E, Rink M, Margulis V, Clozel T, Lee RK, Comploj E, et al. Impact of renal function on eligibility for chemotherapy and survival in patients who have undergone radical nephro-ureterectomy. BJU Int 2013;112:453-61.  Back to cited text no. 3
    
4.
Sternberg CN, Skoneczna I, Kerst JM, Albers P, Fossa SD, Agerbaek M, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): An intergroup, open-label, randomised phase 3 trial. Lancet Oncol 2015;16:76-86.  Back to cited text no. 4
    




 

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