Overview

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

Each patient will be followed during 3 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) more than 6 months after completion of peri-operative chemotherapy
5. Completion of the 1st line metastatic treatment (systemic therapy by chemotherapy and/or immunotherapy by immune check-point inhibitor according to standard recommendations)
6. No disease progression after standard first-line systemic therapy according to RECIST v1.1
7. No more than 3 residual metastatic lesions following standard first-line systemic therapy
8. 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. 6 weeks or less between last cycle 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