A Randomized Phase II Trial Evaluating an Organ-conserving Strategy With Radiotherapy + CDDP + Gemcitabine vs Radiotherapy + CDDP in Muscle-infiltrative Bladder Cancer
Phase: NA
Conditions: Infiltrating Bladder Urothelial Carcinoma
Sponsor: Institut du Cancer de Montpellier - Val d'Aurelle

 
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A Randomized Phase II Trial Evaluating an Organ-conserving Strategy With 
Radiotherapy + CDDP + Gemcitabine vs Radiotherapy + CDDP in Muscle-
infiltrative Bladder Cancer 
 
Etude GETUG V04 
 
Version 6 du 22/07/2020 
 
EudraCT n°2011-000408-17 
VA = 2011/01 
NCT = NCT01495676  
coordinating investigator 
Pr David AZRIA 
Institut régional du Cancer- Montpellier (ICM) 
Département de Cancérologie Radiothérapie, 208, 
rue des Apothicaires 
34298 Montpellier Cedex 5 - France 
David.Azria@icm.unicancer.fr 
Project Manager 
Mme Laetitia MEIGNANT 
DRCI 
ICM   
208, rue des Apothicaires 34298 Montpellier   
Cedex 5 - France 
laetitia.meignant@icm.unicancer.fr 
 
 
 
              Promotor 
Institut régional du Cancer- Montpellier (ICM) 
208, rue des Apothicaires 34298   
Montpellier Cedex 5 - France 
Tél +33 4 67 61 31 00 
Fax +33 4 67 41 08 59 
http://www.montpellier.unicancer.fr 

 
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Title 
A Randomized Phase II Trial Evaluating an Organ-conserving Strategy With 
Radiotherapy + CDDP + Gemcitabine vs Radiotherapy + CDDP in Muscle-
infiltrative Bladder Cancer 
Conditions 
Infiltrating Bladder Urothelial Carcinoma 
Methodology 
 
Rationnal  
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 
Objectives 
Primary Outcome Measure: 
1.Disease-free survival 
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: 
1. Overall survival 
2. Acute and late toxicities 
Acute and late toxicities will be scored according to the NCI-CTC v4.0. 
3. measurement of Quality of life 
Questionnaires QLQ C30 + QLQ-BLM30 + QLQ-ELD15 + Oncodage 
4. Correlation between lymphocyte apoptosis and severity of late 
toxicities. 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. 
Inclusion 
criteria 
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. 

 
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 
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 
Exclusion Criteria: 
 
Bladder tumors without any muscle infiltration 
 
Epidermoid carcinoma or adenocarcinoma 
 
Distance metastases or extrapelvic node positivity 
 
Severe digestive history (ulcerative colitis, complicated diverticulitis) 
 
Pregnancy and breast feeding 
 
Treatment 
Bras A :  
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 
 
Bras B (experimental) : 
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. 

 
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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 
Number of 
subjects and 
statistical 
analysis 
Number of subjects required: 
The primary endpoint of this randomized clinical trial is disease-free survival 
(DFS). Patients without relapse and living at 2 years 
will be considered a success. The expected success rate in the control arm is 
70% (p0). The expected success rate in the experimental arm is 85% (p1). Using 
a one-step Fleming’s plan with   =0.05 and  =0.10, 65 patients 
eligible and evaluable will be required in the experimental arm. The control arm 
is used only to validate 
the initial assumption to ensure appropriate selection of 
patients. There are no plans to conduct formal statistical tests on the primary 
endpoint between the two arms. 
At the end of inclusions, if 51 patients or less among 65 patients 
if successful, the experimental treatment may be considered as insufficiently 
active. If at least 52 patients 
the experimental treatment is successful, it can be considered as sufficiently 
active to be studied in Phase III provided that the results of the control arm are 
close 
the expected results in this arm. 
With 1:2 randomization, it is planned to include 33 patients in the control arm 
and 65 patients in the experimental arm for a total of 98 evaluable patients. We 
take into account 
a potential loss of about 10% of the patients included in the evaluation, hence 
the need to randomize 109 patients. 
 
The final analysis will be over-done on the entire randomized and treated (ITT) 
population as well as on the eligible and evaluable population (per-protocol). 
 
Randomisation :  
The multicenter study has only one randomization sequence (1:2) between two 
arms. 
The stratification criteria are: 
A minimization randomization method will take into account the following 
factors: 
-  pT2/pT3 
-  Centre 
 
Analysis of results 
Statistical analyses will be detailed in the statistical analysis plan, developed 
prior to the freeze of the database. The 
qualitative variables will be presented by frequencies and percentages. For the 
categorical variables, initial demographic characteristics, initial disease, and 
treatment compliance will be compared between the two 
groups by chi-2 or Fisher test according to the minimum expected size. The 
quantitative variables will be presented as means, standard deviation, median, 
and extended. For 

 
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continuous variables, initial demographic characteristics, initial disease, and 
treatment compliance will be compared between the two groups by the non-
parametric Kruskal-Wallis test. 
All survival rates will be estimated using the Kaplan-Meier method and 
presented with a 95% confidence interval. Prognostic factors will be evaluated 
by the Cox model. 
Timetable 
Recruitment period : June 2011 - June 2025 
Duration of follow-up: 5 years 
Study follow-up completed: June 2030