Investigator Decision - Insufficient Accrual

Bladder preservation in patients with complete response after neoadjuvant chemotherapy will lead to equivalent or superior relapse free rates compared to cystectomy rates from historical controls.

1. Transurethral Resection of the Bladder Tumor (TURBT) and Cystoscopy performed by participating urologist:

   • cystoscopic evaluation
   • bimanual examination under anesthesia,
   • as thorough as possible a transurethral resection (TUR) of the bladder tumor,
   • and a biopsy of the prostatic urethra including both mucosa and stroma using a resection loop.

2. Neoadjuvant Chemotherapy, per standard of care: All patients will receive the neoadjuvant course of chemotherapy. The recommended neoadjuvant chemotherapy regimen consists of Gemcitabine and Cisplatin given on a 21-day cycle.This regimen will begin within 8 weeks following the TURBT and cystoscopic evaluation by the urologic surgeon;

3. Post-Neoadjuvant Evaluation: This evaluation will take place ≤ 6 weeks following the completion of the neoadjuvant chemotherapy. Evaluation will include:

   • urine cytology,
   • cystoscopy,
   • tumor site transurethral biopsy,
   • and bimanual examination after biopsy
   • and biopsy of TURBT site

4. For subjects with complete response to neoadjuvant chemotherapy: Chemoradiation within 6 weeks after post-neoadjuvant evaluation. Intensity Modulated Radiation Therapy (IMRT/VMAT), and concurrent Cisplatin therapy, per standard of care; OR

5. For subjects with pT1 or worse tumor response to neoadjuvant chemotherapy: Radical Cystectomy within 12 weeks after post-neoadjuvant evaluation;

6. Post-Consolidation Endoscopic Evaluations: The first post-treatment evaluation will be 30 days +/- 14 days within the end of chemoradiation, surgery or at progression. Subsequent cystoscopic evaluation will be every three months in the first year, every four months in the second year, and every six months in the third year (all evaluations to occur +/- 14 days). Each evaluation will include serum, plasma, whole blood, urine cytology.

Inclusion Criteria:

1. Pathologically proven diagnosis of primary carcinoma of the bladder(transitional cell cancer). Must be operable patients with muscularis propria invasion and American Joint Committee on Cancer (AJCC) clinical stages T2-4a, N0 or N+, M0. Patients with prostatic urethra involvement with transitional cell cancer (TCC) are eligible if it is completely resected and the patient has no evidence of stromal invasion of the prostate.

2. Patients must be able to tolerate systemic chemotherapy combined with pelvic radiation therapy and radical cystectomy.

3. Zubrod Performance Status of ≤1.

4. Age ≥18.

5. Complete Blood Count (CBC)/differential obtained no more than 8 weeks prior to enrollment on study, with adequate bone marrow function defined as follows:

   • White Blood Cell (WBC) ≥ 4000/ml
   • Absolute neutrophil count (ANC) ≥1,800 cells/mm
   • Platelets ≥100,000 cells/mm
   • Hemoglobin ≥ 10.0 mg/dl (Note: the use of transfusion or other intervention to achieve this level is acceptable)

6. Serum bilirubin of 2.0mg or less;

7. Serum creatinine of 1.5mg or less; creatinine clearance of 60ml/min or greater no more than 8 weeks prior to enrollment (Note: calculated creatinine clearance is permissible, using Cockcroft-Gault formula. If the creatinine clearance is greater than 60ml/min, then a serum creatinine of up to 1.8mg is allowable at the discretion of the principal investigator.)

   Note: Prechemotherapy laboratory investigations and Eastern Cooperative Oncology Group (ECOG) evaluation must meet inclusion criteria irrespective of where they were drawn, retroactive, prior to cycle 1 of cisplatin/gemcitabine. Inclusion criteria from these initial investigations will be used for evaluation of enrollment eligibility.

8. Patients must be willing and able to provide study-specific informed consent prior to study entry

Exclusion Criteria:

1. Tumor related untreated active hydronephrosis

2. Evidence of distant metastases.

3. Diffuse bladder carcinoma in situ (CIS) not able to be encompassed in a boost radiotherapy volume.

4. Previous systemic chemotherapy (for any cancer) or pelvic radiation therapy

5. A prior or concurrent malignancy of any other site or histology unless the patient has been disease free for greater than or equal to five years except for non-melanoma skin cancer and/or stage T1a prostate cancer or carcinoma in situ of the uterine cervix

6. Patients that are not candidates for radical cystectomy (T4b disease are considered unresectable)

7. Pregnancy or women of childbearing potential [not post-menopausal or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy)] and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic

8. Severe active co-morbidity:

   • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
   • Transmural myocardial infarction within the last 6 months
   • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
   • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of enrollment
   • History of hepatic insufficiency resulting in clinical jaundice and/or coagulation defects (Note: laboratory tests for liver function and coagulation parameters are not required for enrollment into this protocol)
   • Known diagnosis of Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition (Note: HIV testing is not required for enrollment into this protocol). The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
   • As determined by the investigator or principal investigator