A Phase III Randomised Trial of Peri-Operative Chemotherapy Versus sUrveillance in Upper Tract Urothelial Cancer (POUT)

Study Overview
=================
Brief Summary
-----------------
POUT is a multi-centred randomised controlled phase III trial. 345 patients who have undergone nephro-ureterectomy, are surgically staged pT2-pT4, N0-3 or are pT1 and node positive, and who are fit for adjuvant chemotherapy, will be randomised to four cycles of adjuvant platinum based chemotherapy (experimental group) or surveillance (control group). Participants will be followed up according to routine practice. 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

Official Title
-----------------
A Phase III Randomised Trial of Peri-Operative Chemotherapy Versus sUrveillance in Upper Tract Urothelial Cancer

Conditions
-----------------
Transitional Cell Carcinoma of Ureter

Intervention / Treatment
-----------------
* Drug: Chemotherapy
* Other: Surveillance


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent ≥18 years of age Post radical nephro-ureterectomy for upper tract tumour with predominant TCC component - squamoid differentiation or mixed TCC/SCC is permitted. Histologically confirmed TCC staged pT2-pT4 pN0-3 M0 or pTany N1-3 M0 (providing all grossly abnormal nodes are resected). Patients with microscopically positive margins on pathology may be entered (providing all grossly abnormal disease was resected). Satisfactory haematological profile (ANC> 1.5 x 109/L, platelet count ≥ 100 x 109/L) and liver function tests (bilirubin < 1.5 x ULN, AST and Alkaline phosphatase < 2.5 x ULN), Glomerular filtration rate ≥30 mls/min. Fit and willing to receive adjuvant chemotherapy with first cycle to be commenced within 90 days of radical nephro-ureterectomy if allocated WHO performance status 0-1. Available for long-term follow-up Exclusion Criteria: Evidence of distant metastases Pure adenocarcinoma, squamous cell carcinoma or small cell or other variant histology Un-resected macroscopic nodal disease Concurrent muscle invasive bladder cancer (patients with concurrent Non-muscle invasive bladder cancer (NMIBC) will be eligible) GFR <30 ml/minute. NB Gemcitabine-carboplatin can only be given for patients with suboptimal renal function for cisplatin i.e. for GFR 30-49ml/min. Patients with poor performance status or co-morbidities that would make them unfit for chemotherapy are ineligible for the trial Significant co-morbid conditions that would interfere with administration of protocol treatment Pregnancy; lactating women or women of childbearing potential unwilling or unable to use adequate non-hormonal contraception (male patients should also use contraception if sexually active); Previous malignancy in the last 5 years except for previous NMIBC, adequately controlled non melanoma skin tumours, CIS of cervix or LCIS of breast or localised prostate cancer in patients who have a life expectancy of over 5 years upon trial entry.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Surveillance<br>Patients allocated to surveillance will be seen at 4, 7, 10 and 13 weeks post randomisation - equivalent to the end of cycle in patients receiving chemotherapy - in order to collect details of early treatment failure in this group and comparative data relating to toxicity and quality of life. Patients on surveillance will then be followed up for signs of recurrence at the same intervals as those who received chemotherapy | Other: Surveillance<br>* Patients will be closely monitored for early signs of recurrence, for which they will receive treatment as decided in discussion between the clinician and patient. This may include chemotherapy.<br>|
| Experimental: Chemotherapy<br>Patients allocated adjuvant chemotherapy will receive 4 x 21 day cycles of gemcitabine-cisplatin. Patients who have a sub-optimal renal function (GFR 30-49ml/min) will receive carboplatin instead of cisplatin. | Drug: Chemotherapy<br> <br> * Other names: Carboplatin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival (DFS) | To determine whether adjuvant combination chemotherapy improves the disease-free survival for patients with resected histologically confirmed muscle invasive (pT2-T4, N0-3) or node positive upper tract TCC. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Whether adjuvant platinum-based chemotherapy improves overall survival in this patient group | Patients followed-up for 5 years | 
| Metastasis free survival | To determine whether adjuvant platinum-based chemotherapy improves metastasis free survival in this patient group. | Patients are followed up for 5 years | 
| Incidence of bladder second primary tumours | Whether adjuvant platinum-based chemotherapy reduces incidence of second primary urothelial cancers | Patients are followed up for 5 years | 
| Incidence of contralateral primary tumours | To determine whether adjuvant platinum-based chemotherapy reduces incidence of contralateral primary urothelial cancers. | Patients are followed up for 5 years | 
| Acute and late toxicity | To assess the toxicity of chemotherapy in this patient group. | Patients are followed up for 5 years | 
| Quality of life (QoL) | To assess the relative quality of life in patients undergoing adjuvant chemotherapy or surveillance in this patient group. | Patients' QoL will be assessed over 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Adjuvant chemotherapy, Surveillance, Nephro-ureterectomy