Chemotherapy and Radiation Therapy in Treating Patients With Stage II or Stage III Bladder Cancer That Was Removed by Surgery

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as fluorouracil, cisplatin, and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy together with radiation therapy may kill more tumor cells. PURPOSE: This randomized phase II trial is studying two different chemotherapy and radiation therapy regimens to see how they work in treating patients with stage II or stage III bladder cancer that was removed by surgery.

Detailed Description
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OBJECTIVES: Primary To estimate the rate of distant metastasis at 3 years in patients who have undergone transurethral resection of the bladder tumor for stage II or III muscle-invasive bladder cancer treated with chemoradiotherapy comprising fluorouracil, cisplatin, and radiotherapy vs gemcitabine hydrochloride and radiotherapy followed by selective bladder preservation and adjuvant chemotherapy comprising gemcitabine hydrochloride and cisplatin. Secondary To estimate the treatment completion rate in these patients. To estimate acute and late grade toxicities (≥ grade 3 genitourinary, gastrointestinal, and hematologic toxicities) of these regimens in these patients. To estimate the efficacy of these regimens, in terms of achieving complete response of the primary tumor, in these patients. To estimate the efficacy of these regimens, in terms of preserving the native, tumor-free bladder 5 years after completion of therapy, in these patients. To estimate the value of tumor histopathologic, molecular genetic, DNA content, metabolomic, and proteomic parameters as possible significant prognostic factors for initial tumor response and recurrence-free survival. To analyze for American Urological Association (AUA) Symptom scores at baseline and at 3 years from patients on both arms. To find potentially predictive biomarkers for cystectomy-free survival. To find potentially predictive biomarkers for acute and late toxicities. OUTLINE: This is a multicenter study. Patients are stratified according to tumor stage (T2 vs T3-4a). Patients are randomized to 1 of 2 treatment arms.

Official Title
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A Phase II Randomized Study For Patients With Muscle-Invasive Bladder Cancer Evaluating Transurethral Surgery And Concomitant Chemoradiation By Either BID Irradiation Plus 5-Fluorouracil And Cisplatin Or QD Irradiation Plus Gemcitabine Followed By Selective Bladder Preservation And Gemcitabine/Cisplatin Adjuvant Chemotherapy

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: induction cisplatin
* Drug: induction 5-fluorouracil
* Drug: induction gemcitabine
* Radiation: Induction BID radiation therapy
* Radiation: Induction QD radiation therapy
* Radiation: Consolidation BID radiation therapy
* Radiation: Consolidation QD radiation therapy
* Drug: consolidation gemcitabine
* Drug: consolidation 5-fluorouracil
* Drug: consolidation cisplatin
* Procedure: radical cystectomy
* Procedure: Post-Induction Chemoradiotherapy Endoscopic Response Evaluation
* Drug: adjuvant gemcitabine
* Drug: adjuvant cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Pathologically (histologically or cytologically) proven diagnosis of primary carcinoma of the bladder (transitional cell cancer) within 8 weeks of registration. Operable patients whose tumors are primary carcinomas of the bladder and exhibit histologic evidence of muscularis propria invasion and are American Joint Committee on Cancer (AJCC) clinical stages T2-T4a, Nx or N0, M0 (Appendix IV) without hydronephrosis; patients who have involvement of the prostatic urethra with transitional cell cancer (TCC) that was visibly completely resected and no evidence of stromal invasion of the prostate remain eligible. T2a, T2b, T3a, T3b -substages‖ are not usually able to be determined with clinical (TURBT) staging. If radiologic evaluation of a lymph node is interpreted as positive, this must be evaluated further either by lymphadenectomy or percutaneous needle biopsy. Patients with histologically or cytologically confirmed node metastases will not be eligible. Patients must have an adequately functioning bladder after thorough evaluation by an urologist and have undergone as thorough a transurethral resection of the bladder tumor as is judged safely possible. Patients must be considered able to tolerate systemic chemotherapy combined with pelvic radiation therapy, and a radical cystectomy by the joint agreement of the participating Urologist, Radiation Oncologist, and Medical Oncologist. History and physical examination including weight, performance status, and body surface area within 8 weeks prior to study registration Zubrod Performance Status ≤ 1 Age ≥ 18 Complete blood count (CBC)/differential obtained no more than 4 weeks prior to registration on study, with adequate bone marrow function defined as follows: 8.1 White blood cell count (WBC) ≥ 4000/ml 8.2 Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3; 8.3 Platelets ≥ 100,000 cells/mm3; 8.4 Hemoglobin (hgb) ≥ 10.0 mg/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable.); Serum creatinine of 1.5 mg% or less; serum bilirubin of 2.0 mg% or less; creatinine clearance of 60 ml/min or greater no more than 4 weeks prior to registration; Note: Calculated creatinine clearance is permissible. If the creatinine clearance is > 60 ml/min, then a serum creatinine of up to 1.8 mg% is allowable at the discretion of the study chair; Serum pregnancy test for female patients of childbearing potential, ≤ 72 hours prior to study entry; women of childbearing potential and male participants must practice adequate contraception. Patient must be able to provide study-specific informed consent prior to study entry. Exclusion criteria: Evidence of tumor-related hydronephrosis Evidence of distant metastases or histologically or cytologically proven lymph node metastases Previous systemic chemotherapy (for any cancer) or pelvic radiation therapy A prior or concurrent malignancy of any other site or histology unless the patient has been disease-free for ≥ 5 years except for non-melanoma skin cancer and/or stage T1a prostate cancer or carcinoma in situ of the uterine cervix Patients judged not to be candidates for radical cystectomy; patients with pN+ or T4b disease are considered to have unresectable disease Patients receiving any drugs that have potential nephrotoxicity or ototoxicity (such as an aminoglycoside) Severe, active co-morbidity, defined as follows: 7.1 Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; 7.2 Transmural myocardial infarction within the last 6 months; 7.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; 7.4 Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; 7.5 Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol. 7.6 Acquired Immune Deficiency Syndrome (AIDS) based upon current Center for Disease Control (CDC) definition; note, however, that HIV testing is not required for entry 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. Protocol-specific requirements may also exclude immuno-compromised patients. Pregnancy or women of childbearing potential 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. Prior allergic reaction to the study drug(s) involved in this protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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 |
| --- | --- |
| Experimental: 5-FU and Cisplatin + BID Irradiation<br>Within 8 weeks following pre-study transurethral resection (TUR) patients receive 2.5 weeks of induction chemoradiotherapy (induction 5-fluorouracil, induction cisplatin, induction BID radiation therapy). Consolidation chemoradiotherapy begins 7-14 days following post-induction chemoradiotherapy endoscopic response evaluation. Patients achieving a complete response receive 1.5 weeks of consolidation chemoradiotherapy (consolidation 5-fluorouracil, consolidation cisplatin, consolidation BID radiation therapy). Patients without a complete response undergo radical cystectomy. Outpatient adjuvant chemotherapy (adjuvant gemcitabine, adjuvant cisplatin) begins 4-5 weeks following the post-consolidation endoscopic evaluation or 8-12 weeks following radical cystectomy, and continues for 12 weeks. | Drug: induction cisplatin<br>* 15 mg/m^2 administered as a 60-minute infusion on days 1,2,3,8,9,10,15,16,17.<br>Drug: induction 5-fluorouracil<br>* 400mg/m^2 administered as a 24-hour infusion on days 1,2,3, and 15,16,17.<br>* Other names: 5-FU;Radiation: Induction BID radiation therapy<br>* Twice daily (BID) on days 1-5,8-12,15-17. The first daily treatment consists of 1.6 Gy delivered to the pelvis. The second fraction consists of 1.5 Gy to the bladder for the first 5 treatment days. Then, 1.5 Gy is delivered to bladder tumor volume as the second treatment for the remaining 8 treatment days. The bladder tumor volume receives a total of 40.3 Gy.<br>Radiation: Consolidation BID radiation therapy<br>* Twice daily (BID) for 8 days on days 1,2,3,4,5,8,9,10 of consolidation. 1.5 Gy per fraction for a total of 24 Gy delivered to the pelvis.<br>Drug: consolidation 5-fluorouracil<br>* 400 mg/m^2 administered as a 24-hour infusion on days 1, 2, 3 and 8, 9, 10 of consolidation.<br>* Other names: 5-FU;Drug: consolidation cisplatin<br>* 15 mg/m^2 administered as a sixty-minute infusion on days 1, 2, 8, 9 of consolidation.<br>* Other names: cisplatin;Procedure: radical cystectomy<br>* Operable patients who have a pT1 or worse tumor response on re-evaluation following initial transurethral resection and induction chemoradiotherapy will have a radical cystectomy 3-8 weeks following the post-induction response evaluation.<br>Procedure: Post-Induction Chemoradiotherapy Endoscopic Response Evaluation<br>* Urine cytology, cystoscopy, tumor site transurethral biopsy, and bimanual examination after biopsy.<br>* Other names: TUR;Drug: adjuvant gemcitabine<br>* 1000 mg/m^2 administered intravenously over 30-60 minutes (preferably 30 minutes) on days 1 and 8 of each 21-day cycle for four cycles.<br>* Other names: gemcitabine hydrochloride;Drug: adjuvant cisplatin<br>* 70 mg/m^2 administered as a sixty-minute infusion on day 1 of each 21-day cycle for four cycles.<br>|
| Experimental: Gemcitabine + QD Irradiation<br>Within 8 weeks following pre-study transurethral resection (TUR) patients receive 2.5 weeks of induction chemoradiotherapy (induction gemcitabine and induction QD radiation therapy). Consolidation chemoradiotherapy begins 7-14 days following post-induction chemoradiotherapy endoscopic response evaluation. Patients achieving a complete response receive 1.5 weeks of consolidation chemoradiotherapy (consolidation gemcitabine and consolidation QD radiation therapy). Patients without a complete response undergo radical cystectomy. Outpatient adjuvant chemotherapy (adjuvant gemcitabine and adjuvant cisplatin) begins 4-5 weeks following the post-consolidation endoscopic evaluation or 8-12 weeks following radical cystectomy, and continues for 12 weeks. | Drug: induction gemcitabine<br>* 27 mg/m^2 administered as a 30-minute infusion on days 1, 4, 8, 11, 15, 18, 22, 25.<br>* Other names: gemcitabine hydrochloride;Radiation: Induction QD radiation therapy<br>* Once daily (QD) on days (1-5,8-12,15-19,22-26). For the first 10 treatment days, 2 Gy is delivered to the pelvis. Then, 2 Gy is delivered to the bladder for the next 4 treatment days, followed by 2 Gy to the bladder tumor volume for the remaining 6 treatment days. The bladder tumor volume receives a total of 40 Gy.<br>Radiation: Consolidation QD radiation therapy<br>* Once daily (QD) pelvic radiation therapy for 12 days on days 1-5,8-12,15-16 of consolidation. 2 Gy per fraction for a total of 24 Gy delivered to the pelvis.<br>Drug: consolidation gemcitabine<br>* 27 mg/m^2 administered as a 30-minute infusion on days 1, 4, 8, 11, 15 of consolidation.<br>* Other names: gemcitabine hydrochloride;Procedure: radical cystectomy<br>* Operable patients who have a pT1 or worse tumor response on re-evaluation following initial transurethral resection and induction chemoradiotherapy will have a radical cystectomy 3-8 weeks following the post-induction response evaluation.<br>Procedure: Post-Induction Chemoradiotherapy Endoscopic Response Evaluation<br>* Urine cytology, cystoscopy, tumor site transurethral biopsy, and bimanual examination after biopsy.<br>* Other names: TUR;Drug: adjuvant gemcitabine<br>* 1000 mg/m^2 administered intravenously over 30-60 minutes (preferably 30 minutes) on days 1 and 8 of each 21-day cycle for four cycles.<br>* Other names: gemcitabine hydrochloride;Drug: adjuvant cisplatin<br>* 70 mg/m^2 administered as a sixty-minute infusion on day 1 of each 21-day cycle for four cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Without Distant Metastases by Three Years | Distant metastasis occurrence is defined as the first appearance of disease (with radiographic evidence) in a non-regional lymph node, solid organ or bone. | From randomization to three years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Who Completed Treatment Per Protocol | Treatment administration data was centrally reviewed to determine if patients completed each treatment component per protocol. | After each treatment component (induction, consolidation, adjuvant). Timing varies bases on arm, tumor response at multiple time points, and allowed time ranges. | 
| Percentage of Patients With Grade 3 or Higher Genitourinary, Gastrointestinal, or Hematologic Adverse Events | Highest grade adverse event (AE) per subject was counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. All adverse events are counted, regardless of reported relationship to protocol treatment. | From start of treatment to 180 days after the end of treatment. Treatment could last up to 40 weeks depending on arm, tumor response, and allowed time ranges. | 
| Number of Patients Experiencing Complete Response of the Primary Tumor After Induction Therapy | Patients will be considered as having a clinical complete response when all biopsies are negative at the site(s) of the pretreatment tumor(s). | 3-4 weeks following induction therapy (approximately maximum 8 weeks from start of treatment depending on treatment arm and allowed time windows) | 
| Number of Participants With Progression or Removal of Bladder Five Years After Therapy | Progression is defined as an increase of 50% or more in the largest diameter of the endoscopically appreciable tumor in the tumor-site biopsy specimen, the development of new bladder tumors, or the development of metastatic disease. | From start of treatment to five years after the end of therapy. Treatment could last up to 40 weeks depending on arm, tumor response, and allowed time ranges. | 
| Change in American Urological Association Symptom Index (AUASI) Score at 3 Years | The AUASI is a validated 7-item measure used to assess urinary symptoms. A higher score indicates more severe symptoms for the individual questions and overall total. Six questions ask about frequency of symptoms over the past month with possible responses: 0= Not at all; 1 = Less than 1 time in 5; 2 = less than half the time, 3 = About half the time, 4 = More than half the time, 5 = Almost always. An additional question asks the number of times one gets up to urinate after going to bed, with response indicating the exact number of times ranging from 0 to 5. The total score is the sum of the questions and ranges from 0 to 35. Change is calculated as 3-year score - baseline score such that a negative change indicates improvement. | Baseline and 3 years | 
| Determining Potentially Predictive Biomarkers for Acute and Late Toxicities |  | The protocol did not provide sufficient detail to meet National Cancer Institute requirements for release of specimens from the NRG tissue bank for the protocol-specified analysis, therefore no assays were performed and no data were collected for this out | 
| Determining Potentially Predictive Biomarkers for Cystectomy-free Survival |  | The protocol did not provide sufficient detail to meet National Cancer Institute requirements for release of specimens from the NRG tissue bank for the protocol-specified analysis, therefore no assays were performed and no data were collected for this out | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II bladder cancer, stage III bladder cancer, transitional cell carcinoma of the bladder