Time to define an international standard of postoperative care for resected upper urinary tract transitional cell carcinoma (TCC) – opening of the peri-operative chemotherapy versus surveillance in upper tract urothelial cancer (POUT) Trial
POUT: A phase III randomised trial of Peri-Operative chemotherapy vs sUrveillance in upper Tract urothelial cancer (CR-UK/11/027)
Alison J. Birtle, Rosemere Cancer Centre, Royal Preston Hospital, Preston, Lancashire, PR2 9HT, UK. e-mail: firstname.lastname@example.org; email@example.com
European Association of Urology
muscle-invasive bladder cancer
Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer
Trial Management Group
upper urinary tract TCC.
Upper urinary tract TCC (UUT-TCC) is a rare tumour, accounting for ≈5% of all urothelial cell carcinomas, with an estimated incidence of 2–4 cases per 100 000 individuals per year . Standard treatment involves radical nephroureterectomy (RNU), often with a laparoscopic approach. Data from the BAUS Cancer Registry suggests that 48% of UUT-TCC are muscle invasive  The higher incidence of muscle-invasive disease and a high rate of local recurrence and of metastatic disease, results in a poorer survival, stage-for-stage, than for muscle-invasive bladder cancer (MIBC) . A recent analysis of 1-year recurrence-free survival for UUT-TCC in the UK was 68% for females and 74% for males : T3 ureteric tumours having a 24% 5-year overall survival.
PREVIOUS STUDIES OF ADJUVANT CHEMOTHERAPY FOR UUT-TCC
Despite suggestions that adjuvant systemic chemotherapy might improve these poor survival figures, there are limited data supporting this. All adjuvant chemotherapy studies have been hampered by low patient numbers (<50 patients) and whilst some studies have shown improvements in overall survival, others have not . Several retrospective reviews showed no survival benefit, but these used various chemotherapy regimens that would be considered sub-standard in contemporary uro-oncological practice .
Updated European Association of Urology (EAU) guidelines  state that the role of chemotherapy as adjuvant treatment in locally advanced or N+ UUT-TCC tumours remains to be proven, requiring prospective randomised trials before it can be regarded as routine practice; chemotherapy is only recommended for metastatic disease. Although a recent adjuvant chemotherapy study in MIBC (European Organisation for the Research and Treatment of Cancer – EORTC 30994) accrued 284 randomised patients, making it the largest ever trial in this setting, and therefore likely to make a major contribution to an updated meta-analysis, the trial was forced to close prematurely due to low recruitment rates. Several factors contributed to its slow accrual: the publication of data on neoadjuvant chemotherapy in MIBC during the recruitment period of the trial leading to change in the standard of care; initial exclusion of patients with a coincidental finding of prostate cancer on cystoprostatectomy specimens; and the significant recovery time required after cystectomy before patients were fit enough to receive chemotherapy. Such issues should be far less relevant for an adjuvant study in UUT-TCC, as patient recovery rate after RNU is faster than after cystectomy and no other large centre trials in this arena are currently on-going and therefore new data are unlikely to be available during the lifetime of the Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer (POUT) trial.
ADJUVANT VS NEOADJUVANT CHEMOTHERAPY
Data from studies in the neoadjuvant and palliative treatment of MIBC show that urothelial malignancies are chemo-sensitive. In bladder cancer, meta-analysis  has shown that neoadjuvant, cisplatin-based, combined chemotherapy improves both overall survival (hazard ratio [HR] 0.86, 95% CI 0.77–0.95, P = 0.003, equivalent to a 5% absolute improvement at 5 years) and in disease-free survival (HR 0.78, 95% CI 0.71–0.86, P < 0.001, equivalent to a 9% absolute improvement at 5 years). In contrast, for UUT-TCC there is only a single published study of 15 patients evaluating pathological response to neoadjuvant chemotherapy before RNU. The study was unable to address prognosis due to few patients .
Adjuvant treatment also has the benefit of definitive histology, before chemotherapy, minimising the risk of over-treatment – either of low-risk disease or from preoperative over-diagnosis of malignancy. In one UK study , 12.8% of patients, presumed on radiological and clinical grounds to have a UUT-TCC, had no tumour found in the subsequent surgical specimen. Thus, although there are strong data in favour of neoadjuvant chemotherapy in MIBC, its routine use in potentially resectable UUT-TCC is not currently deemed appropriate .
Consequently, in the UK there is no standard strategy for the perioperative management of patients with muscle-invasive or N+ UUT-TCC. A recent survey conducted by the POUT TMG found that 14 of the 36 UK centres surveyed offered chemotherapy on a ‘case by case’ basis with the remaining 22 offering surveillance alone. Despite this lack of uniform practice, all 36 UK centres surveyed strongly supported the concept of a randomised study of adjuvant chemotherapy in UUT-TCC.
The POUT trial (ISRCTN98387754) is a randomised controlled trial of adjuvant chemotherapy in UUT-TCC, due to open in April 2012 in the UK and shortly afterwards in several European countries. It provides a unique opportunity to define the standard of care, and potentially improve outcome, in this relatively poor prognosis patient group. Funded through Cancer Research UK (CR-UK/11/027) and supported by the National Cancer Research Institute (NCRI) Bladder Clinical Studies Group, National Cancer Research Network (NCRN), BAUS, British Uro-oncology Group (BUG) and the EAU Research Foundation, POUT aims to recruit 345 patients who have undergone RNU and have been pathologically staged as pT2–T4 pN0–N3, or pT1N+ with the caveat that all macroscopically visible nodes must have been resected (Fig. 1).
Given the low incidence of UUT-TCC, early identification of potential patients and the widespread engagement of urologists is vital for the success of a study of this type. The current RADICALS (radiotherapy and androgen deprivation in combination after local surgery) study  has shown the benefit to recruitment of giving patients a short information sheet, preoperatively. Other techniques to enhance accrual to a study of adjuvant chemotherapy include early postoperative identification of patients via pathology review by a site-specialist pathologist within a multi-disciplinary team, a practice which is routine in UK oncology, and trial ‘Champion’ at each recruiting centre, to ensure a robust patient pathway .
The POUT trial aims to build on the success of the UK's ODMIT-C (One Dose Mitomycin C) trial , which showed that trials in UUT-TCC can successfully complete accrual and can influence global practice. POUT represents an important opportunity for concerted international effort to provide a clear evidence base for defining the standard of care for patients after RNU. A clear definition is urgently needed in a disease that continues to be a significant cause of morbidity and mortality for patients and to present a significant clinical challenge to urologists and non-surgical oncologists alike.
FOOTNOTE/DECLARATION OF INTEREST
Enquiries and further expressions of interest regarding the POUT trial are welcomed from centres both in the UK and internationally (POUTfirstname.lastname@example.org, Alison.email@example.com).
CONFLICT OF INTEREST
Emma Hall is a named ICR grant holder for the grant from Cancer Research UK that covers research costs for the trial.