This is a randomized multicentre study in patients with high-risk MIBC to investigate adjuvant radiotherapy after radical cystectomy and pelvic lymph node dissection.

The objective of the study is to provide evidence that adjuvant radiotherapy improves loco-regional control with potential benefits in survival. The study will also evaluate the quality of life of patients and the tolerance of the treatment.

INDICATION:

Patients with pathological high-risk muscle invasive bladder cancer treated by radical cystectomy and pelvic lymph nodes dissection

METHODOLOGY:

Multicenter randomised phase II study in high-risk bladder cancer patients treated by radical cystectomy with pelvic lymph nodes dissection assessing :

• Experimental Arm: adjuvant pelvic radiotherapy consisting of 28 x 1.8 Gy fractions (total dose of 50.4 Gy), 5 days per week, 1 fraction /day (duration of RT is 38 days).
• Standard Arm: surveillance. Eligible patients will be randomised, in a 3:1 ratio, to receive either: adjuvant pelvic radiotherapy (Experimental Arm), or surveillance (Standard Arm).

PRIMARY OBJECTIVE:

The primary objective of the trial is to assess the efficacy of adjuvant radiotherapy in patients with high-risk bladder cancer after radical cystectomy and pelvic lymph nodes dissection. Efficacy will be assessed in terms of pelvic recurrence-free survival (PRFS) at 3 years.

SECONDARY OBJECTIVES:

For each treatment arm (adjuvant pelvic radiotherapy [Experimental Arm], or surveillance [Standard Arm]), these objectives will be evaluated independently.

• To evaluate 5-year pelvic recurrence-free survival (PRFS)
• To evaluate disease-free survival (DFS) at 3 and 5 years.
• To evaluate overall survival (OS) at 3 and 5 years.
• To evaluate metastasis-free survival (MFS) at 3 and 5 years.
• To evaluate disease-specific survival (DSS) at 3 and 5 years.
• To evaluate the tolerance and safety of each treatment strategy.
• To evaluate patients' quality of life.

Ancillary studies Objectives:

• Investigation of individual predisposition to develop radiotherapy induced late digestive toxicity using the radiation-induced lymphocyte apoptosis (RILA) assay
• The analyse of genomic and transcriptome correlation between different clusters and oncological outcomes
• Dosimetric banking to evaluate the correlation of Dose-Volume Histogram with:
• Gastrointestinal toxicity grade ≥2;
• Pelvic recurrence (radiotherapy volumes, mapping of recurrences).

Inclusion Criteria:

To be eligible, the patients must fulfil all of the following inclusion criteria:

1. Patients with histologically-confirmed muscle-invasive bladder cancer, either with pure urothelial carcinomas, or dominant urothelial carcinomas (>50%) combined with other histological variants including: micropapillary, epidermoid, or adenocarcinomas, are eligible. Patients with small cell variants, pure adenocarcinomas, or pure epidermoid carcinomas are not eligible.

2. Patients with radical cystectomy and pelvic lymph nodes dissection with no microscopic residual disease (R0 and R1).

   Note that only R1 patients without urinary diversion as orthotropic neo-bladder replacement are eligible for the study, to limit cystectomy bed radiation induced toxicities.

3. Patients with tumours of TNM staging: pN0-2, M0 by imagery, and pT3a, pT3b, pT4a, and pT4b, as well as, pTX-pN1-2, pTX-NX-R1 are eligible.

4. Patients having received neo-adjuvant or adjuvant chemotherapy treatment are eligible. Randomization is allowed only if AE due to chemotherapy are ≤grade 2 at randomization.

5. Patients ≥18 years old.

6. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

7. Absolute neutrophil count (ANC) ≥1500 cells/mm³.

8. Platelets ≥100000 cells/mm³.

9. Haemoglobin ≥8 g/dL (Note: following a blood transfusion or another intervention if required).

10. Adequate hepatic function: aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤2.5 x upper limit of normal (ULN); or ≤3.5 x ULN in the case of concurrent disease with known etiology and for which a corrective treatment is possible.

11. Adequate renal function: clearance >30 mL/min (MDRD).

12. Patients having provided written informed consent prior to any study-related procedures.

13. Patients affiliated to the social security scheme.

14. Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures indicated in the protocol.

Exclusion Criteria:

Patient must not be enrolled if he/she fulfils any of the following non-inclusion criteria:

1. Patients with R1 resection and with orthotropic neo-bladder reconstruction as urinary diversion are not eligible.

2. Patients with clinical or radiological evidence of metastases or N3 staged bladder cancer are not eligible.

3. Prior invasive solid tumours or haematological malignancies unless disease free for a minimum of 3 years prior to randomisation except:

   • skin basal cell carcinoma,
   • in situ epithelioma of the cervix,
   • or prostate cancer: incidentally discovered during cystoprostatectomy and pelvic lymph node dissection and with a good prognosis (T stage \