Effectiveness of an Immediate Postoperative Intravesical Instillation With Either Gemcitabine or Epirubicin in Patients With Urinary Bladder Cancer (Gemcitabine Epirubicin Normal SAline) (GENSA)

A Prospective Phase III Randomized Clinical Trial Comparing the Effectiveness of Immediate Postoperative Intravesical Instillation With Either Gemcitabine Hydrochloride or Epirubicin Hydrochloride in Patients With Urinary Bladder Cancer (Gemcitabine Epirubicin Normal SAline)

The natural history of non-muscle-invasive bladder cancer is characterised by recurrence and progression. We compare the effectiveness of gemcitabine hydrochloride and epirubicin hydrochloride, in combination with continuous saline irrigation, as an immediate single intravesical instillation in the potential reduction of the disease recurrence as well as progression.

Study Overview

• Status: Recruiting
• Conditions: Bladder Cancer
• Intervention / Treatment: Drug: Gemcitabine Hydrochloride combined with continuous saline irrigation; Drug: Epirubicin Hydrochloride combined with continuous saline irrigation

Detailed Description

Bladder cancer (BLCa) is the seventh most commonly diagnosed cancer in the male population worldwide, while it drops to tenth when both genders are considered. At diagnosis about 75% of the patients suffer from non-muscle-invasive BLCa. The natural history of this disease is characterised by recurrence and progression. In order to reduce the possibilities for recurrence, and therefore progression, an immediate single intravesical instillation (ISIVI) of a chemotherapeutic agent has been shown to act by destroying circulating tumour cells after transurethral resection of urinary bladder tumors (TURB), and by an ablative effect on residual tumour cells at the resection site and on small overlooked tumours. Several agents, among them gemcitabine and epirubicin, have been used for the ISIVI so far. Moreover, four large meta-analyses comprising 1,476 to 3,103 patients have consistently shown that after TURB, ISIVI significantly reduces the recurrence rate compared to TURB alone. Furthermore, two meta-analyses suggest efficacy of continuous saline irrigation (CSI) in the prevention of early recurrences. The prevention of tumour cell implantation should be initiated within the first few hours after TURB. After that, tumour cells are firmly implanted and are covered by the extracellular matrix. In all ISIVI studies, the instillation was administered within 24 hours. Until today, no randomised comparisons of individual drugs, combined or not with CSI, have been conducted.

After the initial TURB, the patients will be treated with CSI for 24 hours. Then, they will be randomised, either to gemcitabine or epirubicin, and within 6 hours after the TURB they will receive an ISIVI with gemcitabine or epirubicin, as follows:

- GROUP A: Gemcitabine hydrochloride 2gr in 100ml 0.9% NaCl for 45-60 minutes

- GROUP B: Epirubicin hydrochloride 50mg in 50ml 0.9% NaCl for 45-60 minutes

During the ISIVI the CSI will be stopped.

The ISIVI will not be applied in the following cases:

• Active bleeding, which does not allow to interrupt the CSI
• Postoperative fever > 38°C
• Deep resection of the tumor, which could be associated with bladder perforation and therefore potential extravasation of the administered drug
• Known allergy to gemcitabine or epirubicin

The postoperative follow-up for patients with disease stage pTis, Ta, T1 low grade (LG) / high grade (HG), will be done according to the Guidelines of the European Association of Urology (EAU) for non-muscle-invasive bladder cancer, as follows:

• 1st and 2nd year: Cystoscopy & cytological examination of urine every 3 months, CT Urography every 12 months for HG patients
• 3rd year: Cystoscopy & cytological examination of urine every 6 months, CT Urography every 12 months for HG patients

• Study Type: Interventional
• Enrollment (Anticipated): 180
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Vasileios Tzortzis, Professor; Phone Number: 00302413502811; Email: urologydpt.uth@gmail.com
• Study Contact Backup: Name: Lampros Mitrakas, Consultant; Phone Number: 00302413501325; Email: lamprosmit@gmail.com

Study Locations

• Greece
  • Larissa/Thessaly
    • Larissa, Larissa/Thessaly, Greece, 41110
      • Recruiting
      • Urology Department, University of Thessaly, University Hospital of Larissa
      • Contact: Vasileios Tzortzis, Professor; Phone Number: 00302413502811; Email: urologydpt.uth@gmail.com
      • Contact: Lampros Mitrakas, Consultant; Phone Number: 00302413501325; Email: lamprosmit@gmail.com
      • Principal Investigator: Vasileios Tzortzis, Professor
      • Sub-Investigator: Lampros Mitrakas, Consultant

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 96 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Primary urinary bladder tumor
• Secondary urinary bladder tumor (recurrence)
• Bipolar or monopolar resection
• Creat <2.2mg/dl
• 35% <Hct <52%
• White bloode cells count WBC ≥3000 / μL
• 75000 <PLT <500000 / μL
• Urine culture: negative / sterile
• Alkaline phosphatase, total bilirubin, SGOT, SGPT: values as high as 2 times above the upper normal limit
• Good clinical condition (according to Eastern Cooperative Oncology Group PS ≤ 1)
• CT Urography without findings suggesting an upper urinary tract tumor in the last 3 months before the transurethral resection of the bladder tumor

Exclusion Criteria:

• More than 2 low grade / high differentiation (low grade / LG) histologically confirmed bladder tumors in the last 18 months before the transurethral resection of the bladder tumor
• High grade / low differentiation (HG) histologically confirmed bladder tumor in the last 9 months before the transurethral resection of the bladder tumor
• Those who undergo a transurethral resection of a bladder tumor according to the Guidelines of the European Association of Urology for non-muscle-invasive bladder cancer: incomplete resection of tumor, absence of muscle fibers in the sample with the exception of: Ta / LG-G1, primary Cis and finally, pT1 tumors
• Intravesical instillation of chemotherapeutic agent or BCG in the last 6 months before the transurethral resection of the bladder tumor
• History of non-urothelial bladder cancer
• Stage of disease pT2 (muscle-invasive bladder cancer)
• Presence of a tumor in the urethra
• Upper urinary tract malignancy (present or anamnestically)
• History of pelvic radiotherapy
• Histrory of another malignancy in the last 5 years before the transurethral resection of the bladder tumor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Gemcitabine; Bladder cancer patients, who are treated with a transurethral resection of a bladder tumor, receive postoperatively, within 6 hours after the resection, an immediate single intravesical instillation with gemcitabine hydrochloride 2gr in 100ml of saline for 45-60 minutes and continuous saline irrigation for 24 hours	Drug: Gemcitabine Hydrochloride combined with continuous saline irrigation; Immediate single intravesical instillation with gemcitabine combined with continuous saline irrigation in bladder cancer patients who are treated with a transurethral resection of the tumor; Other Names: GROUP A
Active Comparator: Epirubicin; Bladder cancer patients, who are treated with a transurethral resection of a bladder tumor, receive postoperatively, within 6 hours after the resection, an immediate single intravesical instillation with epirubicine hydrochloride 50mg in 50ml of saline for 45-60 minutes and continuous saline irrigation for 24 hours	Drug: Epirubicin Hydrochloride combined with continuous saline irrigation; Immediate single intravesical instillation with epirubicin combined with continuous saline irrigation in bladder cancer patients who are treated with a transurethral resection of the tumor; Other Names: GROUP B

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bladder cancer recurrence	Histologically proven bladder cancer recurrence	At 3 months after the transurethral resection of a bladder tumor
Bladder cancer progression	Histologically proven bladder cancer progression	At 3 months after the transurethral resection of a bladder tumor
Bladder cancer recurrence	Histologically proven bladder cancer recurrence	At 12 months after the transurethral resection of a bladder tumor
Bladder cancer progression	Histologically proven bladder cancer progression	At 12 months after the transurethral resection of a bladder tumor

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bladder cancer recurrence	Histologically proven bladder cancer recurrence	At 24 months after the transurethral resection of a bladder tumor
Bladder cancer progression	Histologically proven bladder cancer progression	At 24 months after the transurethral resection of a bladder tumor

Collaborators and Investigators

• Sponsor: University of Thessaly
• Investigators: Principal Investigator: Vasileios Tzortzis, Professor, Urology Department, University of Thessaly, University Hospital of Larissa, Greece

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2021
• Primary Completion (Anticipated): October 1, 2025
• Study Completion (Anticipated): October 1, 2026

Study Registration Dates

• First Submitted: June 17, 2021
• First Submitted That Met QC Criteria: June 25, 2021
• First Posted (Actual): July 1, 2021

Study Record Updates

• Last Update Posted (Actual): January 26, 2022
• Last Update Submitted That Met QC Criteria: January 25, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Gemcitabine; Epirubicin; Postoperative intravesical instillation
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Gemcitabine; Epirubicin
• Other Study ID Numbers: 11006/28.04.2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All IPD that underlie results in a publication
• IPD Sharing Time Frame: After a publication and for a period of 2 years
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No