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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
70
15 mg/m\^2 administered as a 60-minute infusion on days 1,2,3,8,9,10,15,16,17.
400mg/m\^2 administered as a 24-hour infusion on days 1,2,3, and 15,16,17.
27 mg/m\^2 administered as a 30-minute infusion on days 1, 4, 8, 11, 15, 18, 22, 25.
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.
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.
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.
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.
27 mg/m\^2 administered as a 30-minute infusion on days 1, 4, 8, 11, 15 of consolidation.
400 mg/m\^2 administered as a 24-hour infusion on days 1, 2, 3 and 8, 9, 10 of consolidation.
15 mg/m\^2 administered as a sixty-minute infusion on days 1, 2, 8, 9 of consolidation.
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.
Urine cytology, cystoscopy, tumor site transurethral biopsy, and bimanual examination after biopsy.
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.
70 mg/m\^2 administered as a sixty-minute infusion on day 1 of each 21-day cycle for four cycles.
Georgia Cancer Center for Excellence at Grady Memorial Hospital
Atlanta, Georgia, United States
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States
Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center
Boise, Idaho, United States
Cancer Institute at St. John's Hospital
Springfield, Illinois, United States
Parkview Regional Cancer Center at Parkview Health
Fort Wayne, Indiana, United States
St. Agnes Hospital Cancer Center
Baltimore, Maryland, United States
Hudner Oncology Center at Saint Anne's Hospital - Fall River
Fall River, Massachusetts, United States
Saint Joseph Mercy Cancer Center
Ann Arbor, Michigan, United States
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
West Michigan Cancer Center
Kalamazoo, Michigan, United States
...and 1 more locations
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.
Time frame: From randomization to three years
Percentage of Patients Who Completed Treatment Per Protocol
Treatment administration data was centrally reviewed to determine if patients completed each treatment component per protocol.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: Baseline and 3 years
Determining Potentially Predictive Biomarkers for Acute and Late Toxicities
Time frame: 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
Time frame: 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
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