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

Institut du Cancer de Montpellier - Val d'Aurelle69 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Infiltrating Bladder Urothelial Carcinoma

Interventions

Radiation + cisplatinOTHER

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.

Radiation + cisplatin + gemcitabineOTHER

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 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

Locations (12)

Institut Bergonié

Bordeaux, France

Centre Francois Baclesse

Caen, France

Hopital Henri Mondor

Créteil, France

CRLC GF Leclerc

Dijon, France

CRLC Val d'Aurelle-Paul Lamarque

Montpellier, France

Centre azuréen de Cancérologie

Mougins, France

Centre Antoine Lacassagne

Nice, France

Hopital saint Louis

Paris, France

HEGP

Paris, France

Institut de Cancérologie Lucien Neuwirth

Saint-Priest-en-Jarez, France

...and 2 more locations

Outcomes

Primary Outcomes

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. Patients without relapse and living at 2 years will be considered a success

Time frame: Two years after the end of the complete therapeutic sequence

Secondary Outcomes

Overall Survival

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.

Time frame: Up to 5 years

Acute and Late Toxicities

Acute and late toxicities will be scored according to the NCI-CTC v4.0. Grade 0 : no toxicity Grade 4 : worse toxicity

Time frame: Up to 5 years

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. Percentage of Cell Death Measured by Apoptosis This Outcome Measure was pre-specified to report based on toxicity event instead of assigned intervention

Time frame: Up to 5 years