This phase III trial compares the effect of decreased number of radiation (ultra-hypofractionated) treatments to the usual radiation number of treatments (hypofractionation) with standard of care chemotherapy, with cisplatin, gemcitabine or mitomycin and 5-fluorouracil for the treatment of patients with muscle invasive bladder cancer. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a short period of time. Ultra-hypofractionated radiation therapy delivers radiation over an even shorter period of time than hypofractionated radiation therapy. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill tumor cells. Chemotherapy drugs, such as mitomycin-C and 5-fluorouracil (5-FU), work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ultra-hypofractionated radiation may be equally effective as hypofractionated therapy for patients with muscle invasive bladder cancer.
Histologically proven, cT2-T3,N0M0 urothelial carcinoma of the bladder prior to randomization.
Note: Patients with mixed urothelial carcinoma will be eligible for the trial, but the presence of small cell carcinoma will make a patient ineligible
Must undergo a transurethral resection of bladder tumor (TURBT) prior to randomization. Patients may have either completely or partially resected tumors as long as the treating urologist attempted maximal resection
Must undergo radiological staging prior to randomization. Imaging of chest, abdomen, and pelvis must be performed using CT or MRI (with or without contrast is acceptable). Patients must not have evidence of T4 or node positive disease. Fluorodeoxyglucose (FDG) PET imaging is acceptable for radiological staging
None
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo blood, tissue, and urine sample collection
Cisplatin
DrugGiven IV
Computed Tomography
Procedure/SurgeryUndergo CT scan
Fluorouracil
DrugGiven IV
Gemcitabine
DrugGiven IV
Hypofractionated Radiation Therapy
RadiationUndergo hypofractionated radiation therapy
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Mitomycin
DrugGiven IV
Positron Emission Tomography
Procedure/SurgeryUndergo PET scan
Survey Administration
Other interventionAncillary studies
Ultrahypofractionated Radiation Therapy
RadiationUndergo ultrahypofractionated radiation therapy.
Bladder-intact event-free survival (BI-EFS)
Defined as histologically proven presence of muscle invasive bladder cancer (MIBC), radiographic evidence of nodal or metastatic disease, performance of radical cystectomy, or death from any cause. Time to event will be calculated from the date of randomization. BI-EFS will be estimated in the two treatment groups using the Kaplan-Meier method and the hazard ratio between ultra-hypofractionation and hypofractionation estimated by fitting a Cox proportional hazards regression model, including a treatment arm indicator variable and adjusting for the three stratification factors employed in the randomization.
Incidence of urinary adverse events
Will be graded per Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v 5.0). The proportion of patients experiencing grade 3 or higher urinary/bowel toxicity within two years of initiation of treatment will be compared between the two treatment groups using a chi-square test. The 95% confidence interval (CI) width for the true difference will be at most ± 8.9%.
Incidence of bowel adverse events
Will be graded per CTCAE v 5.0. The proportion of patients experiencing grade 3 or higher urinary/bowel toxicity within two years of initiation of treatment will be compared between the two treatment groups using a chi-square test. The 95% CI width for the true difference will be at most ± 8.9%.
Quality of life
As measured by the Functional Assessment of Cancer Therapy-Bladder instrument.
Event free survival
Kaplan-Meier curves will be generated and the groups compared using a stratified logrank test (stratified by the randomization stratification factors). In addition, a Cox regression model will be fit, including treatment arm and the stratification factors.
ctDNA
Will be analyzed as prognostic markers by fitting Cox regression models for BI-EFS.
Tissue free minimal residual disease
Will be obtained at the time of progression to determine if it captures the presence of disease. Will be analyzed as prognostic markers by fitting Cox regression models for BI-EFS.
Urine tumor deoxyribonucleic acid
Will be analyzed as prognostic markers by fitting Cox regression models for BI-EFS.
Primary outcome treatment effect by sex
The corresponding 95% CIs will be provided.
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