Daily Online Adaptive Short-Course Radiation Therapy and Concurrent Chemotherapy for Muscle-Invasive Bladder Cancer

Inclusion Criteria: 1. Age ≥ 18 years. 2. Patients must have histologically proven cT2-T4aN0M0 (AJCC v8) urothelial carcinoma of the bladder with an intact bladder. Mixed urothelial histology is permitted as long as there is some urothelial histology component and no small cell component present. 3. Patients must have undergone an attempt at maximal transurethral resection of bladder tumor (TURBT) within 70 days prior to enrollment. 4. A negative pelvic nodal status is to be confirmed by one or more of the following studies/procedures: PET/CT scan, CT scan, MRI scan, fine needle biopsy, extra peritoneal biopsy, or laparoscopic biopsy, per institutional standard of care. 5. Patients must be planning to undergo concurrent pelvic radiation and chemotherapy with curative intent. 6. ECOG performance status ≤2 (Karnofsky ≥60%). 7. Ability to complete required patient questionnaires. 8. Ability to understand and the willingness to sign a written informed consent document. 9. Patients must have normal organ and marrow function as defined below, obtained within 28 days prior to enrollment: * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/mcL * hemoglobin ≥9 g/dL (can be transfused with red blood cells pre-study) * total bilirubin ≤1.5 × institutional upper limit of normal (ULN) unless the patient has Gilbert's syndrome who must have total bilirubin \<3.0 mg/dL * AST(SGOT)/ALT(SGPT) ≤3 × ULN * alkaline phosphatase ≤2.5 × ULN * creatinine clearance ≥30 ml/min. We recommend avoiding cisplatin for patients with creatinine clearance \<50 ml/min. For the purpose of estimating the creatinine clearance, this formula may be used: Estimated creatinine clearance=((140-age)×wt (kg) ×0.85 (if female))/(72 x creatinine (mg/dl) ) 10. Female patients of childbearing potential (defined as having a menses at any time in the preceding 12 months) must have a negative serum pregnancy test prior to enrollment. Patients must not be pregnant or nursing because of the potential risk of injury to the fetus/child. Exclusion Criteria: 1. Grade ≥ 2 CTCAE GI or grade ≥ 3 GU symptoms/conditions at baseline (including ongoing refractory gross hematuria post TURBT) 2. Patients with clinically involved nodes (nodes consistent morphologically with malignancy and which are greater than 1 cm on short axis on CT or MRI). 3. Patients with cT4b disease. Patients with T4 disease after 8 subjects with T4 disease have been enrolled. 4. Bilateral hydronephrosis or diffuse carcinoma in situ based on cystoscopy or biopsy. Unilateral hydronephrosis is allowed provided the patient's kidney function meets the trial criteria. Patients should be evaluated for consideration of stenting or nephrostomy tubes for moderate-to-severe unilateral hydronephrosis prior to initiation of chemo-radiotherapy. 5. Prior radiation therapy to the pelvis or abdominal cavity, prior systemic chemotherapy/systemic therapy for bladder cancer. Prior intravesical therapy (BCG, interferon, intravesical chemotherapy) is allowed provided the time interval from completion of intravesical therapy is at least 3 months. 6. Prior cystectomy or partial cystectomy. 7. Prior malignancy (except for non-melanoma skin cancer) unless disease-free for at least 2 years. Prior non-muscle invasive bladder cancer is allowed. Patients must not have a history of urothelial carcinoma or variant histology at any site outside of the urinary bladder within the previous 24 months except Ta/T1/carcinoma in situ of the upper urinary tract (including renal pelvis and ureter) provided the patient has undergone complete nephroureterectomy and still meets trial eligibility for creatinine clearance. Patients with localized prostate cancer who are being followed on an active surveillance program are also eligible. 8. Prior allogeneic bone marrow transplantation or prior solid organ transplantation. 9. Prior systemic anticancer therapy due to a diagnosis of cancer (e.g., chemotherapy, targeted therapy, immunotherapy) within 3 years prior to entering the study or induction chemotherapy prior to the start of concurrent chemo-radiotherapy 10. Serious medical comorbidities precluding RT and/or chemotherapy (e.g., active uncontrolled infection ) 11. Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease. 12. Patients with scleroderma. Patients who are symptomatic from other auto-immune diseases or patients on biologic therapies for auto-immune diseases are also excluded. 13. Patients with active tuberculosis (TB). 14. Patients who are pregnant or actively breastfeeding and who do not agree to discontinue breastfeeding before the initiation of radiation treatment planning or bladder cancer therapy. 15. Women of childbearing potential and men who do not agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of protocol treatment, and for 5 months after the last study treatment. 16. Patients with a prior known history or current diagnosis of bowel fistula. 17. Patients who undergo a pelvic or para-aortic lymph node dissection prior to planned chemoradiation therapy. 18. Patients with known active infection of HIV. 19. Patients with bilateral hip prosthetics. Select patients with unilateral hip prosthetics are eligible provided that a diagnostic CT scan permits good visualization of the entire bladder and adjacent bowel. Patients with poor visualization of the bladder/bowel on diagnostic CT scan prior to simulation should not be enrolled. 20. Patients with poorly visualized bladder and bowel on diagnostic CT \[either due to body habitus or artifact (motion, artifact, etc.)\] are excluded. 21. Patients who in the opinion of the investigator are not able to spend 30 minutes lying on the radiation therapy treatment couch due to significant urinary frequency/urgency or other co-morbidities.