GETUGV04: A Phase II Trial Evaluating an Organ-conserving Strategy by Radiochemotherapy for Muscle-infiltrative Bladder Cancer

Sponsor

Institut du Cancer de Montpellier - Val d'Aurelle (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01495676

Collaborator

(none)

Enrollment

Location

Arms

168

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

If radical cystectomy remains the standard of care for muscle invasive bladder cancer, consequences of this surgical procedure are often harsh. Over the past years, concurrent chemo-radiotherapy has imposed itself as an alternative treatment. Published data on concomitant radiochemotherapy (radiotherapy/cisplatin or radiotherapy/cisplatin/5-fluorouracil combinations) showed local control rates with bladder preservation at 5 years ranging from 40% to 65% according to the disease stage, and overall survival probabilities ranging from 40% to 50% at 5 years. In order to improve local and systemic prognosis, evaluation of other chemotherapy agents with higher radiosensitizing effect, such as gemcitabine, is justified. Gemcitabine possesses its own anti-cancer activities on urothelial diseases and has a synergetic activity with cisplatin. The investigators completed a monocenter phase I study combining radiotherapy, cisplatin, and twice-weekly gemcitabine, and determined a recommended dose of gemcitabine 25 mg/m². The objective of the present study is to evaluate the combination of radiotherapy + cisplatin + gemcitabine in terms of disease-free survival in non metastatic muscle invasive urothelial cancer patients.

Condition or Disease	Intervention/Treatment	Phase
Infiltrating Bladder Urothelial Carcinoma	Other: Radiation + cisplatin Other: Radiation + cisplatin + gemcitabine	N/A

Detailed Description

The objective of the present study is to evaluate the combination of radiotherapy + cisplatin

gemcitabine in terms of disease-free survival in non metastatic muscle invasive urothelial cancer patients.

Study Design

Study Type:

Interventional

Actual Enrollment :

69 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Phase II Trial Evaluating an Organ-conserving Strategy With Radiotherapy + CDDP + Gemcitabine vs Radiotherapy + CDDP in Muscle-infiltrative Bladder Cancer

Study Start Date :

Sep 1, 2011

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Sep 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Radiotherapy + cisplatin	Other: Radiation + cisplatin RT will encompass bilateral internal and external iliac lymph nodes at a dose of 45 Gy and the bladder up to 63 Gy. Fractionation will be 1.8 Gy per fraction. Cisplatin: 20 mg/m2/day through continuous iv perfusion for 4 consecutive days, from D2 to D5 and from D23 to D26 for the first part of the treatment, then from D2 to D5 if an additional treatment is decided. A cystoscopy with a transurethral resection will be performed 3 weeks after the last day of the first part of radio-chemotherapy. In the absence of tumor cells, the 2nd part will start on the 4th week or at latest on the 5th week after the last day of the 1st part of radio-chemotherapy. In case of a microscopic tumor residue or of a local tumor progression, operability will be re-evaluated in view of a radical cystectomy and the patient will exit the study.
Experimental: Radiotherapy + cisplatin + gemcitabine	Other: Radiation + cisplatin + gemcitabine Radiotherapy will encompass bilateral internal and external iliac lymph nodes at a dose of 45 Gy and the bladder up to 63 Gy. Fractionation will be 1.8 Gy per fraction. Cisplatin: 20 mg/m2/day through continuous iv perfusion for 4 consecutive days, from D2 to D5 and from D23 to D26 for the first part of the treatment, then from D2 to D5 for the second part of the treatment if an additional treatment is decided. Gemcitabine: iv injection for 30 minutes, twice a week at a dose of 25 mg/m2 on days 2, 5, 9, 12, 16, 19, 23, 26, 30, and 33 for the 1st part of treatment, then on days 2, 5, 9, and 12 for the 2nd part of treatment if an additional treatment is decided (cystoscopy with a transurethral resection). RT will be delivered between 2 and 6 hours after completion of the gemcitabine injection.

Arm

Intervention/Treatment

Active Comparator: Radiotherapy + cisplatin

Other: Radiation + cisplatin

RT will encompass bilateral internal and external iliac lymph nodes at a dose of 45 Gy and the bladder up to 63 Gy. Fractionation will be 1.8 Gy per fraction. Cisplatin: 20 mg/m2/day through continuous iv perfusion for 4 consecutive days, from D2 to D5 and from D23 to D26 for the first part of the treatment, then from D2 to D5 if an additional treatment is decided. A cystoscopy with a transurethral resection will be performed 3 weeks after the last day of the first part of radio-chemotherapy. In the absence of tumor cells, the 2nd part will start on the 4th week or at latest on the 5th week after the last day of the 1st part of radio-chemotherapy. In case of a microscopic tumor residue or of a local tumor progression, operability will be re-evaluated in view of a radical cystectomy and the patient will exit the study.

Experimental: Radiotherapy + cisplatin + gemcitabine

Other: Radiation + cisplatin + gemcitabine

Radiotherapy will encompass bilateral internal and external iliac lymph nodes at a dose of 45 Gy and the bladder up to 63 Gy. Fractionation will be 1.8 Gy per fraction. Cisplatin: 20 mg/m2/day through continuous iv perfusion for 4 consecutive days, from D2 to D5 and from D23 to D26 for the first part of the treatment, then from D2 to D5 for the second part of the treatment if an additional treatment is decided. Gemcitabine: iv injection for 30 minutes, twice a week at a dose of 25 mg/m2 on days 2, 5, 9, 12, 16, 19, 23, 26, 30, and 33 for the 1st part of treatment, then on days 2, 5, 9, and 12 for the 2nd part of treatment if an additional treatment is decided (cystoscopy with a transurethral resection). RT will be delivered between 2 and 6 hours after completion of the gemcitabine injection.

Outcome Measures

Primary Outcome Measures

Disease-free survival [Two years after the end of the complete therapeutic sequence]
The time to relapse is defined as the time from the date of randomisation to the date of the first event. Time to relapse for patients without any event (local, regional, distance, or death) will be censored at the date of latest information.

Secondary Outcome Measures

Overall survival [Up to 5 years]
The time to death is defined as time from the randomization to the date of death from any cause, or to the date on which latest information is obtained.
Acute and late toxicities [Up to 5 years]
Acute and late toxicities will be scored according to the NCI-CTC v4.0.
measurement of Quality of life [Up to 5 years]
Questionnaires QLQ C30 + QLQ-BLM30 + QLQ-ELD15 + Oncodage
Correlation between lymphocyte apoptosis and severity of late toxicities. [Up to 5 years]
Before starting radiotherapy, 5ml of blood will be sampled in a 5ml heparinised tube to prospectively measure the rate of CD8 radio-induced lymphocyte apoptosis before any radiotherapy treatment. A correlation between the low rate of lymphocyte apoptosis and the severity of late toxicities will be studied to confirm the predictive power of this biological test on radio-induced side-effects.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Muscle invasive urothelial cancer (front line or following the progression of a superficial tumor), pT2-pT3 stage without lymphatic impairment (N0) and without detectable metastases (M0). An optimal macroscopic resection (TURB) have to be performed
The proof of invasive tumor to the muscle should be brought by a transurethral resection under anaesthesia less than 8 weeks before or, in the absence, by superficial biopsies and formal imaging. Multiples biopsies in the bladder must also be performed.
Age ≥ 18 years
Life expectancy ≥ 6 months
Kanorfsky index ≥ 70 % (WHO 0, 1, 2)
Biological criteria: neutrophils ≥ 1500/mm3, Platelets ≥ 100 000/mm3, haemoglobin ≥ 10 g/dl, creatinine clearance > 60 ml/mn
No distant metastases (Thorax, abdomen, and pelvic CT-scan, bone scan)
Efficient contraception for premenopausal women, maintained during the whole treatment and up to two months after the completion of radiotherapy.
No radiotherapy or chemotherapy history except for in situ bladder lesions.
No carcinological history except for non melanoma skin tumours, in situ uterine cervix cancer
No contraindication to gemcitabine or cisplatin.
No contraindication to radiotherapy
Information letter and informed consent signed
Patient covered by social security