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Report as closed All reports will be confirmed by our staff. Permanently Closed. Permanently Closing Soon. The trial is registered with ClinicalTrials. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of participants. Between June 19, , and Nov 8, , we enrolled participants from 57 of 71 open study sites.
One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. No treatment-related deaths were reported. 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.
At the inception of this study, systemic treatment had no proven role for locally advanced UTUC. UTUC shares several clinicopathological features with muscle-invasive urothelial transitional cell carcinoma of the bladder.
Robust survival improvements are seen with platinum-based chemotherapy in patients with urothelial bladder cancer, in both the neoadjuvant and metastatic settings. Before this study, findings of a literature review available online in Audenet et al, showed that no level 1 randomised trial evidence was available assessing the efficacy of systemic chemotherapy for locally advanced upper tract urothelial carcinoma UTUC.
The paucity of research is partly because of the rarity of the disease. Undersized or retrospective studies had not shown a convincing survival benefit for chemotherapy. Guidelines from the European Association of Urology, therefore, recommended nephroureterectomy followed by surveillance as the standard of care.
Most urothelial carcinomas in both UTUC and bladder cancer originate in the transitional epithelium transitional cell carcinoma. It is logical, therefore, to consider data from trials of systemic bladder cancer treatment for signals to indicate whether chemotherapy could be efficacious in UTUC.
Therefore, a comparable trial in UTUC was justified, particularly in view of the inferior stage-for-stage outcomes in UTUC when compared with bladder urothelial carcinoma. Challenges of obtaining definitive histology and accurate staging for UTUC before nephroureterectomy risk either undertreatment or overtreatment with neoadjuvant therapy. The POUT trial was, therefore, designed as a phase 3 randomised trial of adjuvant platinum-based chemotherapy, intended to provide, for the first time, robust evidence regarding its efficacy in UTUC.
To the best of our knowledge, our study is the largest randomised controlled clinical trial done exclusively in patients with UTUC worldwide. We have shown that giving adjuvant platinum-based chemotherapy within 90 days after nephroureterectomy reduces subsequent rates of disease recurrence. Our data, therefore, suggest that adjuvant platinum-based chemotherapy should be recommended as a new standard of care after nephroureterectomy for all patients with locally advanced UTUC in whom there are no definitive contraindications to chemotherapy.
Because of the strength of evidence showing survival gain, neoadjuvant chemotherapy is the accepted standard of care for muscle-invasive bladder cancer. Although a neoadjuvant approach is attractive for patients with UTUC, particularly when the loss of renal function associated with nephrectomy is considered, the unreliability of preoperative UTUC staging and histopathology would probably result in overtreatment for some patients and undertreatment for others.
Thus, for many patients with muscle-invasive UTUC, surgery alone is considered the standard approach. Patient-reported outcome data for this rare population are also absent, with most available published work at the outset of this trial focusing on short-term outcomes after nephroureterectomy and no data obtained within the context of randomised controlled trials. We aimed to prospectively assess in a randomised controlled trial the POUT trial the effect of adjuvant platinum-based chemotherapy on disease-free survival, overall survival, safety, and quality of life after radical nephroureterectomy in patients with locally advanced UTUC.
An intervention was included to understand and then support recruitment to the trial. Formal extended lymph-node dissection was not mandated. Participants with lymph-node involvement identified on preoperative imaging or during surgery had all grossly abnormal nodes resected. Postoperative imaging was mandated for these patients before randomisation; those with residual lymphadenopathy as ascertained by the local investigator were excluded.
Participants were recruited by their clinical care teams and provided written informed consent before enrolment. The trial management group was overseen by independent data monitoring and trial steering committees appendix p The full study protocol is available in the appendix pp 13— Balancing factors were planned platinum agent cisplatin vs carboplatin , preoperative radiologically or pathologically assessed nodal involvement N0 vs N1 vs N2 vs N3 , status of microscopic surgical margins positive vs negative , and treating centre.
Participants were randomly allocated either surveillance or chemotherapy. Treatment allocation was not masked. Participants allocated chemotherapy received four day cycles of platinum-based combination chemotherapy, to begin within 14 days after randomisation.
Protocol-specified recommendations were for chemotherapy to begin within 90 days of nephroureterectomy, for gemcitabine to be given as a min intravenous infusion in mL normal saline, cisplatin as a 4-h intravenous infusion in 1 L saline, and carboplatin as a 1-h intravenous infusion. Use of generic agents was allowed; no recommended manufacturer was specified. Hydration and infusion rates were in accordance with local practice. The protocol-recommended calculation of GFR was by the Cockcroft and Gault method; however, use of the Wright formula or estimation by radioisotope clearance were also permitted.
Participating sites prespecified their intended assessment method before activation and were requested to use the same GFR assessment method for a participant throughout the study. Patients otherwise unsuitable to receive cisplatin were not permitted to join the trial to minimise the potential confounding effects of frailty and comorbidity.
All participants receiving chemotherapy had haematology and serum biochemistry assessments and their GFR was estimated and body surface area calculated before every cycle of chemotherapy. Participants allocated surveillance underwent adverse event assessment every 3 weeks after randomisation to mirror the assessment schedule of participants allocated chemotherapy.
Participants in both study groups were followed up at 3, 6, 9, and 12 months, then every 6 months to 36 months from randomisation, regardless of whether chemotherapy was complete, and annually thereafter. Assessment of disease recurrence included either plain film radiography or cross-sectional imaging CT of the thorax plus CT of the abdomen and pelvis at 3, 6, 9 thorax only , 12, 18, 24, 30 thorax only , and 36 months, then annually to 60 months.
Cystoscopy was done every 6 months to 24 months, then annually to 60 months to detect recurrence in the lower urinary tract. Follow-up assessments were done in accordance with standard practice in the UK at the time. Assessment of adverse events was done at every follow-up visit to 24 months.
Participants in both study groups who had disease recurrence were permitted to receive any appropriate further treatment as clinically indicated, including platinum—gemcitabine chemotherapy. Participants in an optional patient-reported quality-of-life substudy were asked to complete on paper the European Organisation for Research and Treatment of Cancer EORTC quality-of-life of cancer patients questionnaire QLQ-C30 and the EuroQol five dimensions five levels questionnaire EQ-5D-5L at baseline and before cycle three week 7 and at 3 months, then at 6, 12, and 24 months post randomisation.
The primary endpoint was disease-free survival according to local assessment and was defined as time from randomisation to either first recurrence in the tumour bed, first metastasis, or death from any cause.
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. Published by Elsevier Ltd. Quality of life QoL [ Time Frame: Patients' QoL will be assessed over 2 years ] To assess the relative quality of life in patients undergoing adjuvant chemotherapy or surveillance in this patient group.
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Search for terms. Save this study. Warning You have reached the maximum number of saved studies Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Last Update Posted : May 4, Study Description. Primary endpoint: Disease-free survival DFS Secondary endpoints: Overall Survival Metastasis free survival Incidence of bladder second primary tumours Incidence of contralateral primary tumours Acute and late toxicity Treatment compliance Quality of life.
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