Consolidative Radiotherapy for Metastatic Urothelial Bladder Cancer Patients Without Progression and With no More Than Three Residual Metastatic Lesions Following First Line Systemic Therapy

Study Overview
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Brief Summary
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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.

Official Title
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Consolidative Radiotherapy for Metastatic Urothelial Bladder Cancer Patients Without Progression and With no More Than Three Residual Metastatic Lesions Following First Line Systemic Therapy: a Prospective Randomized Comparative Phase II Trial

Conditions
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Urothelial Bladder Cancer

Intervention / Treatment
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* Radiation: Experimental arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Urothelial bladder cancer histologically proven (both pure urothelial cancers and mixed histologic features are allowed) 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) 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. No disease progression after the initial phase of first-line metastatic systemic therapy according to RECIST v1.1 No more than 3 residual metastatic lesions following the initial phase of first-line metastatic systemic therapy: 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 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. Residual metastases (if applicable) eligible for SBRT in terms of dose constraints to the organs at risk, with no prior radiotherapy interfering with SBRT 8 weeks or less between last cycle of the initial phase of systemic treatment and randomization No contraindication to pelvic radiotherapy Signed informed consent Patient able to participate and willing to give informed consent prior performance of any study-related procedures and to comply with the study protocol Patient affiliated to a Social Health Insurance in France. Exclusion Criteria: Non-transitional cell histology (Squamous cell carcinoma, adenocarcinoma or neuroendocrine carcinoma of the bladder) Brain metastases before systemic treatment Liver metastases before systemic treatment 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) Patient with relapse following definitive chemoradiation of the bladder Local recurrence in the cystectomy bed following cystectomy Previous pelvic irradiation Prior radiotherapy near the residual metastatic lesions precluding ablative SBRT Active inflammatory bowel disease 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 History of scleroderma 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]) Pregnancy or breast feeding or inadequate contraceptive measures Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial 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 Patient who has forfeited his/her freedom by administrative or legal award or who is under legal protection (curatorship and guardianship, protection of justice) Concurrent enrolment in another interventional therapeutic clinical study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control arm<br>Standard of care | |
| Experimental: Experimental arm<br> | Radiation: Experimental arm<br>* Consolidative radiotherapy (pelvic irradiation and/or metastases irradiation) + standard of care +/- previous transurethral resection of bladder tumor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | 4 years for each patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival |  | 4 years for each patient | 
| Safety will be assessed by the toxicity grading of the National Cancer Institute (NCI-CTCAE v5) |  | 4 years for each patient | 
| Quality of life will be evaluated by the EORTC QLQ-C-30 questionnaire |  | 4 years for each patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urothelial bladder cancer