Surgery With or Without Postoperative Intensity Modulated Radiation Therapy in Treating Patients With Urothelial Bladder Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies the side effects and how well postoperative intensity modulated radiotherapy works after surgery in treating patients with urothelial bladder cancer. Radiation therapy uses high energy x-rays to kill tumor cells left behind in the pelvis after surgery. It is not yet known whether surgery followed by radiotherapy is more effective than surgery alone in treating patients with urothelial bladder cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the ability of postcystectomy adjuvant radiotherapy to safely reduce pelvic tumor recurrence, defined as pelvic recurrence-free survival. SECONDARY OBJECTIVES: I. Evaluate increase in disease-free survival. II. Evaluate toxicity of adjuvant pelvic radiotherapy. OUTLINE: Patients are randomized to 1 of 2 treatment arms. Patients are stratified by neoadjuvant preoperative or postoperative adjuvant chemotherapy. After completion of study treatment, patients are followed up at 6 weeks, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and then annually for 5 years.

Official Title
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Randomized Phase II Trial of Postoperative Adjuvant IMRT Following Cystectomy for pT3/T4 Urothelial Bladder Cancer

Conditions
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Stage III Bladder Cancer, Stage IV Bladder Cancer

Intervention / Treatment
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* Radiation: Intensity-Modulated Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (A patient cannot be considered eligible for this study unless ALL of the following conditions are met.): Initial histological diagnosis of muscle invasive urothelial carcinoma Patients must have undergone a radical cystectomy (reconstructed urinary diversion may be non-continent diversions (eg, ileal conduits) or continent non-orthotopic catheterizable diversions (eg, Indiana pouch) or continent orthotopic diversions (eg, Studer pouch or neobladder)for urothelial bladder carcinoma within 105 days prior to registration. Final cystectomy pathology must be either pure urothelial carcinoma or dominant urothelial carcinoma with admixture of other histologies excluding small cell variants. Neoadjuvant (preoperative) or adjuvant (postoperative) chemotherapy for the bladder cancer is permitted; however, all patients, even those who will receive adjuvant chemotherapy, must be registered within 105 days after completing cystectomy regardless of whether adjuvant chemotherapy has started. Patients who will be receiving adjuvant (postoperative) chemotherapy will be randomized within 28 days of completing that chemotherapy. Patients with the following pTNM stages per the American Joint Committee on Cancer (AJCC) 7th ed. are eligible: pT3apN0; pN1; pN2 provided less than 10 nodes dissected and/or positive surgical margins pT3bpN0; pN1; pN2 pT4apN0; pN1; pN2 pT4bpN0; pN1; pN2 Appropriate stage for study entry based on the following diagnostic workup: History/physical examination =< 45 days prior to registration; CT or MRI or positron emission tomography(PET)-CT that includes chest, abdomen and pelvis should be performed for initial radiological staging. This may be performed pre- or post-surgery ≤ 90 days prior to registration except in patients getting postoperative adjuvant chemotherapy, who will require CT, MRI or PET-CT including the chest and abdomen and pelvis no more than 30 days prior to registration. Imaging performed postoperatively should show no evidence of residual disease. Age >=18 Zubrod performance status 0-2 =< 45 days prior to registration Complete blood count (CBC)/differential obtained ≤ 14 days prior to registration with adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 Platelets >= 100,000 cells/mm^3 Hemoglobin >= 8.0 g/dl (NOTE: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) The patient must provide study-specific informed consent prior to study entry The patient must provide study-specific informed consent prior to study entry. Exclusion Criteria (Patients with any of the following conditions are NOT eligible for this study.): Definitive clinical or radiologic evidence of metastatic disease; pN3 disease is not allowed (positive common iliac node). Prior invasive solid tumor or hematological malignancy (except non-melanomatous skin cancer and incidentally discovered prostate cancer at time of cystoprostatectomy) unless disease free for a minimum of 3 years Prior radiotherapy to the pelvis Patients with a history of inflammatory bowel disease Patients who have required any treatment (medical or surgical) for bowel obstruction prior to diagnosis of bladder cancer or who have required surgical treatment for bowel obstruction after the cystectomy Severe, active co-morbidity defined as follows: 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; Severe hepatic disease, defined as a diagnosis of Child-Pugh Class B or C hepatic disease; HIV positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration. Note also that HIV testing is not required for eligibility for this protocol. Other major medical illness which requires hospitalization or precludes study therapy at the time of registration. Women who are breastfeeding

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: No Radiation Therapy<br>Patients do not receive radiation therapy (RT). | |
| Experimental: Intensity-modulated radiation therapy (IMRT)<br>Postoperative adjuvant intensity-modulated radiation therapy (IMRT). | Radiation: Intensity-Modulated Radiation Therapy<br>* Postoperative adjuvant IMRT radiotherapy 50.4 Gy in 28 fractions. In patients not getting postoperative adjuvant chemotherapy the radiation treatment must begin within 140 days after cystectomy. For patients getting adjuvant chemotherapy radiation treatment must start within 49 days of completing chemotherapy.<br>* Other names: IMRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pelvic Recurrence-free Survival (PRFS) | PRFS is defined as time free of pelvic recurrence or death, with patients who experience distant metastasis censored at the time of occurrence. Pelvic recurrence is specifically defined as soft tissue and /or lymph node tumor recurrence in the pelvis anywhere between the L5-S1 disc space superiorly and the pelvic floor inferiorly. This was to be determined on the basis of pelvic imaging (CT or MRI scan demonstrating soft tissue or nodal recurrence at least 1cm in linear dimension) or urethroscopy; biopsy was not required. PRFS was to be tested between arms in terms of a difference in cause-specific-hazards using the log-rank test and cumulative incidence of PRFS in the presence of competing risks was to be computed via cumulative incidence. Due to early termination with few patients, only counts of events have been calculated. | From randomization to study termination, maximum follow-up was 13.3 months, median follow-up was 1.9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival (DFS) | Disease free survival (DFS) is defined as the first occurrence of either: pelvic failure, distant metastasis, or death and was to be estimated by the Kaplan-Meier method and arms compared using the log-rank test. Pelvic recurrence is specifically defined as soft tissue and /or lymph node tumor recurrence in the pelvis anywhere between the L5-S1 disc space superiorly and the pelvic floor inferiorly. This was to be determined on the basis of pelvic imaging (CT or MRI scan demonstrating soft tissue or nodal recurrence at least 1cm in linear dimension) or urethroscopy; biopsy was not required. Distant metastases is defined as any hematogenous metastases and/or lymph node metastases above the L5-S1 interspace, documented by imaging (CT and/or MRI and/or bone scans). Due to early termination with few patients, only counts of events have been calculated. | From randomization to study termination, maximum follow-up was 13.3 months, median follow-up was 1.9 months | 
| Number of Patients With Bowel Toxicity | Adverse events (AE) evaluated using Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Bowel toxicity= abdominal distension/pain, colitis, colonic fistula/ hemorrhage/obstruction/perforation/stenosis/ulcer, diarrhea, enterocolitis, fecal incontinence/gastrointestinal/fistula/pain, ileal fistula/hemorrhage/obstruction/perforation/stenosis/ulcer, Ileus, jejunal fistula/hemorrhage/obstruction/perforation/stenosis/ulcer, lower gastrointestinal hemorrhage, rectal fistula/hemorrhage/mucositis/necrosis/obstruction/pain/perforation/stenosis/ulcer, small intestinal mucositis/obstruction/perforation/stenosis/ulcer, vomiting. Highest grade adverse event per subject counted. Grade refers to AE severity and ranges from 1 to 5 with unique clinical descriptions of severity for each AE based on this general guideline: 1 Mild, 2 Moderate, 3 Severe, 4 Life-threatening or disabling, 5 Death related to AE. | From randomization to study termination, maximum follow-up was 13.3 months, median follow-up was 1.9 months |