This phase II trial compares the use of pembrolizumab and radiation therapy to chemotherapy with cisplatin, gemcitabine, 5-fluorouracil or mitomycin-C and radiation therapy for the treatment of non-muscle invasive bladder cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as cisplatin, gemcitabine, 5-fluorouracil or mitomycin-C, 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. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Giving pembrolizumab with radiation may kill more tumor cells than chemotherapy with radiation therapy in patients with non-muscle invasive bladder cancer.
Pathologically (histologically) proven diagnosis of T1 high-grade non-muscle invasive urothelial carcinoma of the bladder without radiographic evidence of regional nodal disease or metastatic disease (N0, M0) on CT, MRI, or positron emission tomography (PET)/CT scan who would otherwise be treated with cystectomy off-trial. Patients should have cystectomy recommended disease but do not need to be medically operable for a cystectomy to be eligible for the trial.
NOTE: Patients with nodal disease ≥ 1 cm on short-axis or with suspicious nodes that are PET-avid of any size are not eligible
Histologically confirmed recurrence with high-grade T1 urothelial carcinoma (+/- focal carcinoma in situ [CIS]) in the bladder following initial transurethral resection of bladder tumor (TURBT) and at least one induction course of intravesical therapy. Adequate induction course is defined as ≥ 5 doses of intravesical Bacillus Calmette-Guerin (BCG) or intravesical chemotherapy when BCG is not available.
T1 with pathologic high-risk features (lymphovascular invasion [LVI] or variant histology of micropapillary, sarcomatoid, or plasmacytoid features) post initial TURBT. (No prior intravesical therapy required)
None
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo blood and urine sample collection
Cisplatin
DrugGiven IV
Computed Tomography
Procedure/SurgeryUndergo CT
Fluorouracil
DrugGiven IV
Gemcitabine
DrugGiven IV
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Mitomycin
DrugGiven IV
Pembrolizumab
Biological/VaccineGiven IV
Questionnaire Administration
Other interventionAncillary studies
Radiation Therapy
RadiationUndergo radiation therapy
Bladder intact event-free survival (BIEFS)
Defined as time free of histologically proven recurrent T1-T4 recurrence, clinical evidence of nodal or distant metastasis, radical cystectomy (either for disease progression or due to toxicity), or death from any cause. Analysis will consist of estimation of the BIEFS curves via the Kaplan-Meier estimator and testing of the primary hypothesis using the stratified logrank test (one-sided). Additionally, the Cox proportional hazards model will be used to estimate the hazard ratio adjusting for stratification variables and any other baseline covariates that demonstrate any degree of imbalance by treatment arm.
Global quality of life
Assessed using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) global quality of life domain.
Complete response by cystoscopy
The proportion achieving complete response will be compared using the two-sample binomial test. Further analysis may consist of using a binary outcome regression model (i.e., logistic regression) to compute the relative odds of response adjusted for any factors that may appear imbalanced by treatment arm.
Disease free survival
Defined in standard specification as time free of any disease failure (local/regional/distant), or death from any cause. Will be evaluated via the Kaplan-Meier estimator and logrank test.
Local-regional control
Will be estimated via the cumulative incidence estimator, treating death as a competing event.
Metastasis free survival
Will be evaluated via the Kaplan-Meier estimator and logrank test.
Quality adjusted survival
Index scores from the European Quality of Life Five Dimension Five Level Scale will be calculated at each time point and change from baseline to post-treatment scores compared between treatment arms using a t-test with a 2-sided significance level of 0.05. If there are significant differences, then a quality-adjusted life year (QALY) analysis will be conducted. QALYs are defined by the weighted sum of different time episodes added up to a total quality-adjusted survival time. The difference in QALYs between arms will be reported along with the 95% confidence interval.
Fatigue
Using Patient Reported Outcomes Measurement Information System Fatigue-4A. Calculated by summing all 4 questions (all 4 questions are required to be completed to score the tool). Raw scores range from 4 to 20 and are standardized to a T score following the scoring instructions.
Cumulative global quality of life
Using the EORTC-QLQ-C30 and Bladder Cancer Index.
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