Overview

This is a phase II, multicenter, randomized open-label and comparative study designed to evaluate whether local consolidative radiotherapy plus standard of care improves overall survival as compared to standard of care in patients with limited metastatic urothelial bladder cancer and without progression following the initial phase of first-line systemic therapy.

Each patient will be followed during 4 years from the date of randomization.

Eligibility

Inclusion Criteria:

1. Age ≥ 18 years
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
3. Urothelial bladder cancer histologically proven (both pure urothelial cancers and mixed histologic features are allowed)
4. Metastatic patients (AJCC v8: M1a or M1b) documented with contrast-enhanced CT-scanner of the chest, abdomen and pelvis, either de novo or presenting first distant relapse following cystectomy (with no local recurrence in the cystectomy bed)
5. Completion of the initial phase (4-6 cycles) of 1st line metastatic treatment (systemic therapy by chemotherapy and/or immunotherapy by immune check-point inhibitor according to standard recommendations). Patients having started maintenance therapy are eligible.
6. No disease progression after the initial phase of first-line metastatic systemic therapy according to RECIST v1.1
7. No more than 3 residual metastatic lesions following the initial phase of first-line metastatic systemic therapy:
   1. The number of residual lesions is determined on the basis of the imaging modality for tumor response assessment performed after systemic treatment according to local habits (CT-scan or 18FDG PET-CT if performed):

      In case of response assessment by CT-scanner only: residual lesions are all remaining visible lesions

      In case of response assessment by additional 18FDG PET-CT: residual lesions are only the lesions with residual hyperfixation

   2. Regarding distant lymph nodes metastases:

             If evaluation is performed by CT-scanner only, residual lymph nodes are considered
             pathological according to one or several criteria among:
               -  Short axis ≥ 1cm
               -  Central necrosis
               -  Heterogeneous contrast enhancement
             Residual para-aortic nodes involvement accounts for one lesion, even if several
             para-aortic nodes are involved.
             Other nodes: each involved node accounts for one lesion.
          8. Residual metastases (if applicable) eligible for SBRT in terms of dose constraints to
             the organs at risk, with no prior radiotherapy interfering with SBRT
          9. 8 weeks or less between last cycle of the initial phase of systemic treatment and
             randomization
         10. No contraindication to pelvic radiotherapy
         11. Signed informed consent
         12. Patient able to participate and willing to give informed consent prior performance of
             any study-related procedures and to comply with the study protocol
         13. Patient affiliated to a Social Health Insurance in France.
        Exclusion Criteria:
          1. Non-transitional cell histology (Squamous cell carcinoma, adenocarcinoma or
             neuroendocrine carcinoma of the bladder)
          2. Brain metastases before systemic treatment
          3. Liver metastases before systemic treatment
          4. Absence of target to be irradiated (i.e. previous cystectomy + no residual lesions
             following systemic treatment + no pelvic or para-aortic nodes at metastatic
             presentation)
          5. Patient with relapse following definitive chemoradiation of the bladder
          6. Local recurrence in the cystectomy bed following cystectomy
          7. Previous pelvic irradiation
          8. Prior radiotherapy near the residual metastatic lesions precluding ablative SBRT
          9. Active inflammatory bowel disease
         10. Contraindication to SBRT of a lesion due to organ dysfunction; in particular, patients
             with lung lesions and documented or suspected interstitial lung disease should not be
             included
         11. History of scleroderma
         12. Current or past history of second neoplasm diagnosed within the last 5 years (except
             basocellular carcinoma and prostate cancer incidentally discovered during previous
             cystoprostatectomy and pelvic lymph node dissection and with a good prognosis [T stage
             <pT3b and Gleason <8 and pN- and post-operative PSA <0.1 ng/mL])
         13. Pregnancy or breast feeding or inadequate contraceptive measures
         14. Known psychiatric or substance abuse disorders that would interfere with cooperation
             with the requirements of the trial
         15. Any psychological, familial, geographic or social situation, according to the judgment
             of investigator, potentially preventing the provision of informed consent or
             compliance to study procedure
         16. Patient who has forfeited his/her freedom by administrative or legal award or who is
             under legal protection (curatorship and guardianship, protection of justice)
         17. Concurrent enrolment in another interventional therapeutic clinical study