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

Phase 2

Completed

• Conditions: Bladder Cancer
• Interventions: Drug: induction cisplatin; Drug: induction gemcitabine; Drug: induction 5-fluorouracil; Radiation: Induction QD radiation therapy; Radiation: Induction BID radiation therapy; Radiation: Consolidation QD radiation therapy; Radiation: Consolidation BID radiation therapy; Drug: consolidation gemcitabine; Drug: consolidation 5-fluorouracil; Drug: consolidation cisplatin; Procedure: Post-Induction Chemoradiotherapy Endoscopic Response Evaluation; Procedure: radical cystectomy; Drug: adjuvant gemcitabine; Drug: adjuvant cisplatin

• Registration Number: NCT00777491
• Lead Sponsor: Radiation Therapy Oncology Group

Brief Summary

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

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2008-10-21
• Study First Submitted QC: 2008-10-21
• Study First Posted: 2008-10-22
• Study Start: 2008-12
• Primary Completion: 2018-02-18
• Results First Submitted: 2019-05-31
• Results First Submitted QC: 2019-08-01
• Results First Posted: 2019-08-21
• Status Verified: 2022-05
• Study Completion: 2022-05-20
• Last Update Submitted: 2022-05-23
• Last Update Posted: 2022-06-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 70

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
5-FU and Cisplatin + BID Irradiation	induction cisplatin	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.
5-FU and Cisplatin + BID Irradiation	induction 5-fluorouracil	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.
5-FU and Cisplatin + BID Irradiation	consolidation 5-fluorouracil	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.
5-FU and Cisplatin + BID Irradiation	consolidation cisplatin	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.
5-FU and Cisplatin + BID Irradiation	adjuvant gemcitabine	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.
5-FU and Cisplatin + BID Irradiation	adjuvant cisplatin	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.
Gemcitabine + QD Irradiation	induction gemcitabine	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.
Gemcitabine + QD Irradiation	adjuvant gemcitabine	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.
Gemcitabine + QD Irradiation	adjuvant cisplatin	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.
Gemcitabine + QD Irradiation	Post-Induction Chemoradiotherapy Endoscopic Response Evaluation	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.
5-FU and Cisplatin + BID Irradiation	Induction BID radiation therapy	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.
5-FU and Cisplatin + BID Irradiation	Consolidation BID radiation therapy	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.
5-FU and Cisplatin + BID Irradiation	radical cystectomy	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.
Gemcitabine + QD Irradiation	Consolidation QD radiation therapy	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.
5-FU and Cisplatin + BID Irradiation	Post-Induction Chemoradiotherapy Endoscopic Response Evaluation	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.
Gemcitabine + QD Irradiation	Induction QD radiation therapy	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.
Gemcitabine + QD Irradiation	radical cystectomy	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.
Gemcitabine + QD Irradiation	consolidation gemcitabine	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Patients Without Distant Metastases by Three Years	From randomization to 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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Patients With Grade 3 or Higher Genitourinary, Gastrointestinal, or Hematologic Adverse Events	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.	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.
Number of Participants With Progression or Removal of Bladder Five Years After Therapy	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.	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.
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
Percentage of Patients Who Completed Treatment Per Protocol	After each treatment component (induction, consolidation, adjuvant). Timing varies bases on arm, tumor response at multiple time points, and allowed time ranges.	Treatment administration data was centrally reviewed to determine if patients completed each treatment component per protocol.
Number of Patients Experiencing Complete Response of the Primary Tumor After Induction Therapy	3-4 weeks following induction therapy (approximately maximum 8 weeks from start of treatment depending on treatment arm and allowed time windows)	Patients will be considered as having a clinical complete response when all biopsies are negative at the site(s) of the pretreatment tumor(s).
Change in American Urological Association Symptom Index (AUASI) Score at 3 Years	Baseline and 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.
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

Trial Locations

Locations (11)

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

Georgia Cancer Center for Excellence at Grady Memorial Hospital; 🇺🇸 Atlanta, Georgia, United States

Parkview Regional Cancer Center at Parkview Health; 🇺🇸 Fort Wayne, Indiana, United States

Hudner Oncology Center at Saint Anne's Hospital - Fall River; 🇺🇸 Fall River, Massachusetts, United States

Cancer Institute at St. John's Hospital; 🇺🇸 Springfield, Illinois, United States

Saint Joseph Mercy Cancer Center; 🇺🇸 Ann Arbor, Michigan, United States

St. Agnes Hospital Cancer Center; 🇺🇸 Baltimore, Maryland, United States

University of Michigan Comprehensive Cancer Center; 🇺🇸 Ann Arbor, Michigan, United States

West Michigan Cancer Center; 🇺🇸 Kalamazoo, Michigan, United States

McGill Cancer Centre at McGill University; 🇨🇦 Montreal, Quebec, Canada