Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial

Background: Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs. Methods: We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2–T4 pN0–N3 M0 or pTany N1–3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m²) or carboplatin (area under the curve [AUC]4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m²) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants. Findings: Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30–0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0–47·5). 3-year event-free estimates were 71% (95% CI 61–78) and 46% (36–56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported. Interpretation: Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population. Funding: Cancer Research UK

Role of α-blockers in the treatment of stent-related symptoms: A prospective randomized control study

Objective To properly use the Ureteric Symptom Score Questionnaire (USSQ) to evaluate, in a randomized control study, the effect of 2 different α-blockers in improving symptoms and quality of life in patients with indwelling ureteral stents. Methods After institutional review board approval, 150 consecutive patients with a double-J ureteral stent inserted after extracorporeal shockwave lithotripsy (ESWL) or ureteroscopic stone treatment were randomly assigned to receive tamsulosin 0.4 mg, alfuzosin 10 mg, or placebo. The validated USSQ was completed 1 and 4 weeks after stent insertion and 4 weeks after stent removal. The Kruskal-Wallis test for independent samples for non-normally distributed ordinal variables, chi-square to compare proportions or differences, and 1-way analysis of variance (ANOVA) for independent samples to compare for differences in case of continuous variables were used for statistical analysis of the results. Results Patients receiving α-blockers expressed an overall statistically significant lower urinary (P &lt;.001), pain (P &lt;.001 with stent in situ), and general health index (P &lt;.002) scores. Sexual life and quality of life were also positively influenced. Quality of work was not influenced. No patients had to discontinue medication because of side effects or underwent stent removal before the due date. There was no difference in various outcomes between the 2 α-blockers. Conclusion Stent-related morbidity is a reality in the majority of patients. Simple medication, such as α-blockers, reduce stent-related symptoms and the negative impact on quality of life. It seems that stent-related symptom improvement is independent to the type of α-blocker

Tamsulosin, solifenacin, and their combination for the treatment of stent-related symptoms: A randomized controlled study

Purpose: To properly use the Ureteric Symptom Score Questionnaire (USSQ) to evaluate, in a randomized control study, the effect of tamsulosin, solifenacin, and their combination in improving symptoms and quality of life in patients with indwelling ureteral stents. Materials and Methods: After institutional review board approval, 260 patients with a ureteral stent were randomly assigned to receive tamsulosin 0.4 mg, solifenacin 5 mg, or placebo and further randomized to receive their combination. The validated USSQ was completed 1 and 4 weeks after stent insertion and 4 weeks after stent removal. Kruskal-Wallis test, chi-squared test (or Fisher&apos;s exact test), one-way analysis of variance, and T-test (or Wilcoxon rank-sum test if not normal data) were used for statistical analysis. The results were considered significant at p &lt; 0.05. Results: Patients receiving tamsulosin or solifenacin expressed significantly lower urinary (p &lt; 0.001), pain (p &lt; 0.001 with stent in situ), and general health index (p = 0.002 in first and p &lt; 0.001 in fourth week with stent in situ) scores. Sexual life and quality of work were also positively influenced. Patients on combination therapy expressed lower urinary (p &lt; 0.001) and pain (p &lt; 0.001) scores in the fourth week with stent in situ and work performance in the first week and with stent in situ (p = 0.001) and after stent removal (p = 0.005). No patients had to discontinue medication due to side effects. Conclusions: Stent-related morbidity is a reality in the majority of patients. Simple medication, such as tamsulosin and solifenacin alone or in combination, improves stent-related symptoms and has a positive impact on quality of life. © Mary Ann Liebert, Inc. 2017