Prospective Multicentric Evaluation of a Bladder Preservation Strategy

Phase 2

Terminated

• Conditions: Urothelial Carcinoma
• Interventions: Drug: optimal TURB

• Registration Number: NCT01093066
• Lead Sponsor: Centre Hospitalier Universitaire de Saint Etienne

Brief Summary

Radical cystectomy is the treatment of choice for bladder infiltrative urothelium carcinoma. But the removal of the bladder reservoir has a major impact of the Quality of life. Neoadjuvant chemotherapy has been shown to be associated with an absolute 5% survival benefit. Two monocentric studies suggest that this neoadjuvant chemotherapy could be used in combination with an optimal transurethral bladder resection, in a strategy of bladder preservation, provided a complete response being obtained (about 50% in every trial using neoadjuvant MVAC protocol before a radical cystectomy). In those both studies with patients T2 to T4, the 5 years overall survival is above 65%, with more than 40% bladder preservation rate at 5 years.

The feasibility and the efficacy of such an attitude in a multicentric trail using the most active regimen (in term of complete response in metastatic patients) is unknown. The chosen regimen is therefore the intensified MVAC which allows, with the use of G-CSF, to double the dose-intensity of Adriamycin and Cisplatinum, and to decrease by 30% the methotrexate and vinblastine dose-intensity.

The efficacy and safety confirmation of such an approach could lead to consider it in patients motivated to retain a functional bladder.

Detailed Description

Every patient having signed the inform consent will have the following steps Maximal and optimal TURB using a standardized procedure. The TURB will always try to be optically complete.

Neoadjuvant chemotherapy for 3 months with the intensified MVAC (6 cycles administered every 2 weeks): METHOREXATE: 30 mg/m2 D1 - VINBLASTINE: 3 mg/m2 D2 - ADRIAMYCINE 30 mg/m2 D2 - CISPLATINE 70 mg/m2 D2. + G-CSF: 5 µg/kg from D4 to D10 New maximal standardized TURB at the end of the chemotherapy. In case of a lesion localized at the bladder dome, and if a maximal TURB appears to be unsafe, a partial cystectomy without lymph node dissection will be performed.

If a complete response is obtained (no tumor cells in the bladder muscle on the last TURB), a surveillance will be proposed without any further treatment.

Otherwise (tumor cells in the bladder muscle at the second TURB), a radical cystectomy will be done.

If the balder is spared, the follow up will be as follow: clinical examination, CT, bladder endoscopy and urinary cytology every 6 months. The possible non muscle infiltrative bladder relapses will be treated according

Study Timeline

• Study First Submitted: 2010-03-24
• Study First Submitted QC: 2010-03-24
• Study First Posted: 2010-03-25
• Study Start: 2010-09-21
• Primary Completion: 2020-12-31
• Study Completion: 2020-12-31
• Status Verified: 2021-12
• Last Update Submitted: 2021-12-10
• Last Update Posted: 2021-12-30

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 77

Inclusion Criteria

• T2 clinical stage (no palpable mass under anesthesia after TURB) Absence of diffuse Cis (Cis on random bladder biopsies) Patients above 18, and below 70 years of age PS status ≤ 2 No previous treatment for a bladder muscle infiltrative carcinoma. Previous endovesical instillations for non muscle infiltrative lesions (pTa, pT1, Cis) are allowed.

No metastases on tauraco-abdomina-pelvic CT scan (no node > 1 cm) and bone scan.

Normal biological values: neutrophils > 1,5.109 /l, platelets > 100. 109 /l, Alkaline Phosphatases < 2 x N, bilirubin < 1,5 N, Transaminases < 1,5 x N, Creatinine clearance ≥ 60 ml/min Signed inform consent Patient belonging to a social security system.

Exclusion Criteria

All other histology than urothelial carcinoma:

• primitive adenocarcinoma
• epidermoid carcinoma
• little cells carcinoma In situ diffuse carcinoma associated with urothelial carcinoma muscular infiltrating Tumor stade > T2, T3 or T4 or pT4a (prostatitis) Serious cardiac, pulmonary, hepatitic, renal, digestive or neurological pathology which is non equilibrating or potential aggravating risk by treatment Cancer history or other actual cancer (except skin cancer) not remission or with an end of treatment inferior to 2 years Participation to another clinical trial in a delay inferior to 30 days

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
surgical resection and chemotherapy	optimal TURB	Maximal and optimal TURB using a standardized procedure. The TURB will always try to be optically complete. Neoadjuvant chemotherapy for 3 months with the intensified MVAC (6 cycles administered every 2 weeks): METHOREXATE: 30 mg/m2 D1 - VINBLASTINE: 3 mg/m2 D2 - ADRIAMYCINE 30 mg/m2 D2 - CISPLATINE 70 mg/m2 D2. + G-CSF: 5 µg/kg from D4 to D10 New maximal standardized TURB at the end of the chemotherapy. In case of a lesion localized at the bladder dome, and if a maximal TURB appears to be unsafe, a partial cystectomy without lymph node dissection will be performed.

Primary Outcome Measures

Name	Time	Method
the 5 years bladder preservation rate (with or without intravesical non muscle infiltrative recurrences, treated by TURB only or intravesical instillations of either BCG or mytomicin C).	5 years

Secondary Outcome Measures

Name	Time	Method
Progression free survival (either infiltrative [≥ T2] or metastatic)	5 years
proportion of complete response	6 months
Overall survival	5 years
Chemotherapy tolerance in a neoadjuvant setting using the intensified MVAC	3 months
Secondary cystectomy rate	6 months
Overall bladder preservation rate	5 years

Trial Locations

Locations (31)

Institut Bergonie; 🇫🇷 Bordeaux, France

Crlcc Francois Baclesse; 🇫🇷 Caen, France

APHM - Marseille - Hôpital de la Conception; 🇫🇷 Marseille, France

APHP - Saint-Louis; 🇫🇷 Paris, France

Polyclinique de Lisieux; 🇫🇷 Lisieux, France

Hôpitaux privés de Metz; 🇫🇷 Metz, France

Crlc Nancy; 🇫🇷 Nancy, France

Clinique AXIUM - AIX EN PROVENCE; 🇫🇷 Aix-en-Provence, France

CHU Créteil; 🇫🇷 Créteil, France

Chu Nancy; 🇫🇷 Nancy, France

ICO - SITE Gauducheau - ICL Nantes; 🇫🇷 Saint-Herblain, France

Hôpitaux du Léman - Thonon-les-Bains; 🇫🇷 Thonon-les-Bains, France

CH du Pays d'Aix-en-Provence; 🇫🇷 Aix-en-Provence, France

CHU Bordeaux; 🇫🇷 Bordeaux, France

Clinique Saint-Augustin; 🇫🇷 Bordeaux, France

CHU Caen; 🇫🇷 Caen, France

APHM - Marseille - Hôpital la Timone; 🇫🇷 Marseille, France

Chu Nantes; 🇫🇷 Nantes, France

CHU Poitiers; 🇫🇷 Poitiers, France

Chu Reims; 🇫🇷 Reims, France

Clinique Mutualiste Chirurgicale; 🇫🇷 Saint-etienne, France

Polyclinique Du Cotentin; 🇫🇷 Équeurdreville-Hainneville, France

CRLC Marseille; 🇫🇷 Marseille, France

Hôpital Européen - Marseille; 🇫🇷 Marseille, France

APHP- Hôpital Tenon; 🇫🇷 Paris, France

Institut Jean Godinot - Reims; 🇫🇷 Reims, France

ICLN; 🇫🇷 Saint-priest En Jarez, France

CHU Saint-Etienne; 🇫🇷 Saint-Étienne, France

CHI Toulon; 🇫🇷 Toulon, France

CHU Toulouse; 🇫🇷 Toulouse, France

INSTITUT CLAUDIUS REGAUD - CRLC Toulouse; 🇫🇷 Toulouse, France