Feasibility of Neo-adjuvant Versus Adjuvant Chemotherapy in Upper Tract Urothelial Carcinoma

Study Overview
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Brief Summary
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The aim of this study is to explore feasibility of Upper Tract Urothelial Carcinoma (UTUC) treatments based in real world data in various European countries. The study will allow to gain insight in the true proportion of patients that fit to receive complete cisplatin-based neo-adjuvant or adjuvant chemotherapy, and the proportion and clinical outcome of patients with poor prognostic factors (PS and renal function) who receive only standard treatment (Radical nephroureterectomy (RNU)). This comparison will be made using a uniform diagnostic and treatment protocol.

Detailed Description
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There are no definitive treatment recommendations for patients diagnosed with UTUC. Radical nephroureterectomy (RNU) has been considered the gold standard treatment for UTUC. However due to the high recurrence rates reported, patients are often offered perioperative chemotherapy provided that they have a good renal function and performance status. With regard to the choice of chemotherapy treatment, there are also no clear recommendations since there are no data from randomized studies. If perioperative chemotherapy is considered in daily practice, gemcitabine/cisplatin regimen is often chosen and occasionally dd-MVAC. The aim of this study is to explore feasibility of UTUC treatments based in real world data in various European countries. Patients who fulfil good prognostic factors (inclusion criteria for treatment randomization) will be allocated to neo-adjuvant (Arm B) or adjuvant (Arm C) chemotherapy (receiving 3 cycles of gemcitabine/cisplatin or dose dense Methotrexate, Vinblastine, Adriamycin, and Cisplatin (MVAC). Patients who don't fulfil criteria for treatment randomization will undergo Radical nephroureterectomy (RNU) only (Arm A). Patients will be followed up for 5 years.

Official Title
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Neo-adjuvant Versus Adjuvant Chemotherapy in Upper Tract Urothelial Carcinoma: A Feasibility Phase II Randomized Clinical Trial (URANUS)

Conditions
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Upper Tract Urothelial Carcinoma

Intervention / Treatment
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* Procedure: RNU
* Drug: Gemcitabine/Cisplatin
* Drug: M-VAC Protocol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age > 18 years Histological and radiological defined UTUC: Histologically-confirmed diagnosis of predominantly urothelial carcinoma of the upper urinary tract Patients with UTUC cT2-pT4 cN0-N1 M0 (TNM classification) Women with negative serum pregnancy test within 14 days of first dose of study treatment and agreement to use effective contraception Patients without bladder cancer or with concomitant non muscle invasive bladder cancer Adequate organ system function defined as follows: Hematologic: Absolute neutrophil count (ANC) 1.5 X 109/L; Haemoglobin 5.6 mmol/L (9.02g/dL); Platelets 100 X 109/L; Prothrombin time (PT) or international normalized ratio (INR)b 1.2 X ULN; Activated partial thromboplastin time (aPTT)1.2 X Upper limit of normal (ULN). Hepatic: Total bilirubin 1.5 X ULN; Alanine amino transferase (ALT) and Aspartate aminotransferase (AST) 2.5 X ULN. Renal: GRF <or> 55 ml/min: Electrolytes: potassium and calcium: within normal limits. CT scan of the chest, abdomen and pelvis and Bone scan without evidence of distant metastasis Exclusion Criteria: Histology of pure adenocarcinoma, pure squamous cell carcinoma, sarcomatoid or predominant small cell carcinoma. History of cardiovascular conditions within the past 6 months. Incidentally found asymptomatic pulmonary embolism (PE) or recent deep vein thrombosis (DVT) is not an exclusion criteria but requires anticoagulation treatment. Any major contraindication to a surgical procedure. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures. Active infection contraindicating chemotherapy Other active neoplasms. Patients with in situ cervical carcinoma, non-melanoma skin cancer or prostate cancer T1 Gleason <7, Prostate specific antigen (PSA) <10. Patients with past medical history of cancer can be included if diagnosed at least 4 years ago. Concomitant muscle invasive bladder cancer Patients who have been or still are on methotrexate treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: M-VAC protocol plus RNU<br>Patients who fulfil inclusion criteria for cisplatinum-based chemotherapy (renal function: GRF > or = 55 ml/min) receiving 3 cycles of MVAC every 2 weeks (Methotrexate (30 mg /m²) , Vinblastine (3 mg /m²) , Adriamycin (30 mg /m²) , and Cisplatin (70 mg /m²) before surgery | Procedure: RNU<br>* Radical surgical removal by open or laparoscopic access<br>* Other names: Radical nephro-ureterectomy;Drug: M-VAC Protocol<br>* Methotrexate (30 mg /m²) and Vinblastine 3 (mg /m²) day 1; Adriamycin 30 mg /m² and Cisplatin 70 mg /m² in day2<br>* Other names: DD MVAC;|
| Other: RNU plus M-VAC protocol<br>Patients who fulfil inclusion criteria for cisplatinum-based chemotherapy (renal function: GRF > or = 55 ml/min) receiving 3 cycles of MVAC every 2 weeks (Methotrexate (30 mg /m²) , Vinblastine (3 mg /m²) , Adriamycin (30 mg /m²) , and Cisplatin (70 mg /m²) after surgery | Procedure: RNU<br>* Radical surgical removal by open or laparoscopic access<br>* Other names: Radical nephro-ureterectomy;Drug: M-VAC Protocol<br>* Methotrexate (30 mg /m²) and Vinblastine 3 (mg /m²) day 1; Adriamycin 30 mg /m² and Cisplatin 70 mg /m² in day2<br>* Other names: DD MVAC;|
| Other: Radical nephro-ureterectomy (RNU)<br>Patients who dont fulfil inclusion criteria for chemotherapy treatment randomization (poor renal function: Glomerular Filtration Rate (GFR) <55 ml/min or unfit for cisplatin-based chemotherapy) | Procedure: RNU<br>* Radical surgical removal by open or laparoscopic access<br>* Other names: Radical nephro-ureterectomy;|
| Other: Gemcitabine/Cisplatin plus RNU<br>Patients who fulfil inclusion criteria for cisplatinum-based chemotherapy (renal function: GRF > or = 55 ml/min) receiving 3 cycles of Gemcitabine (1000 mg/m2) + Cisplatin (70 mg/m2) every 3 weeks before surgery | Procedure: RNU<br>* Radical surgical removal by open or laparoscopic access<br>* Other names: Radical nephro-ureterectomy;Drug: Gemcitabine/Cisplatin<br>* Gemcitabine (1000 mg/m²) day 1 and 8 and Cisplatin (70 mg/m²) day 1<br>* Other names: Gemcitabine plus Cisplatin;|
| Other: RNU plus Gemcitabine/Cisplatin<br>Patients who fulfil inclusion criteria for cisplatinum-based chemotherapy (renal function: GRF > or = 55 ml/min) receiving 3 cycles of Gemcitabine (1000 mg/m2) + Cisplatin (70 mg/m2) every 3 weeks after surgery | Procedure: RNU<br>* Radical surgical removal by open or laparoscopic access<br>* Other names: Radical nephro-ureterectomy;Drug: Gemcitabine/Cisplatin<br>* Gemcitabine (1000 mg/m²) day 1 and 8 and Cisplatin (70 mg/m²) day 1<br>* Other names: Gemcitabine plus Cisplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of UTUC patients randomized to neo- or adjuvant chemotherapy that is actually able to start and finalize three courses of planned chemotherapy | Percentage of patients randomised to adjuvant or neo-adjuvant treatment | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival (DFS) | time from randomisation to local recurrence or distant metastasis | 1-2 years | 
| Overall Survival (OS) | time from randomisation to death for any cause different from urothelial carcinoma | 1-2 years | 
| Cancer-Specific Survival (CSS) | time from randomisation to death from urothelial carcinoma | 1-2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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UTUC, Upper Tract Urothelial Carcinoma, Neoadjuvant chemotherapy, Adjuvant chemotherapy, Radical nephroureterectomy