Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Urinary Bladder Neoplasms

Carcinoma, Transitional Cell

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Transitional Cell Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Fluorouracil

Cisplatin

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

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.

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.

15 mg/m\^2 administered as a 60-minute infusion on days 1,2,3,8,9,10,15,16,17.

induction cisplatin

400mg/m\^2 administered as a 24-hour infusion on days 1,2,3, and 15,16,17.

induction 5-fluorouracil

27 mg/m\^2 administered as a 30-minute infusion on days 1, 4, 8, 11, 15, 18, 22, 25.

induction gemcitabine

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.

Induction BID radiation therapy

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.

Induction QD radiation therapy

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.

Consolidation BID radiation therapy

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.

Consolidation QD radiation therapy

27 mg/m\^2 administered as a 30-minute infusion on days 1, 4, 8, 11, 15 of consolidation.

consolidation gemcitabine

400 mg/m\^2 administered as a 24-hour infusion on days 1, 2, 3 and 8, 9, 10 of consolidation.

consolidation 5-fluorouracil

15 mg/m\^2 administered as a sixty-minute infusion on days 1, 2, 8, 9 of consolidation.

consolidation cisplatin

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.

radical cystectomy

Urine cytology, cystoscopy, tumor site transurethral biopsy, and bimanual examination after biopsy.

Post-Induction Chemoradiotherapy Endoscopic Response Evaluation

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.

adjuvant gemcitabine

70 mg/m\^2 administered as a sixty-minute infusion on day 1 of each 21-day cycle for four cycles.

adjuvant cisplatin

John J. Coen, MD

Philip J. Saylor, MD

Cheryl T. Lee, MD

Chin-Lee Wu, MD, PhD

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.

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

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

Distant metastasis occurrence is defined as the first appearance of disease (with radiographic evidence) in a non-regional lymph node, solid organ or bone.

Treatment administration data was centrally reviewed to determine if patients completed each treatment component per protocol.

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.

Patients will be considered as having a clinical complete response when all biopsies are negative at the site(s) of the pretreatment tumor(s).

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.

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.

National Cancer Institute (NCI)

Radiation Therapy Oncology Group

Adverse event population = eligible patients who started protocol treatment.

Patients receive induction therapy comprising fluorouracil IV, cisplatin IV, and radiotherapy in weeks 1-4. Patients then undergo either radical cystectomy or receive consolidation therapy comprising fluorouracil IV, cisplatin IV, and radiotherapy in weeks 8-10.

Arm I

Patients receive induction therapy comprising gemcitabine hydrochloride IV and radiotherapy in weeks 1-4. Patients then undergo either radical cystectomy or receive consolidation therapy comprising gemcitabine hydrochloride IV and radiotherapy in weeks 8-10.

Arm II

5-FU and Cisplatin + BID Irradiation

Gemcitabine + QD Irradiation

Total

<= 49 years

50-59 years

60-69 years

>= 70 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Measure Description: 0 - Asymptomatic; 1 - Symptomatic but completely ambulatory; 2 - Symptomatic, \<50% in bed during the day; 3 - Symptomatic, \>50% in bed, but not bedbound; 4 - Bedbound; 5 - Death

Zubrod Performance Status

Tumor stage per the American Joint Committee on Cancer (AJCC) 6th ed. refers to the size and/or extent of the main tumor. The higher the number after the T, the larger the tumor or the more it has grown into nearby tissues. T's may be further divided to provide more detail, such as T3a and T3b.

T Stage

Adverse event data was updated when outcome measure 5 was entered.

Wendy Seiferheld, M.S.

The confidence interval of the rate was calculated by Clopper-Pearson's exact binomial confidence intervals methods with one-sided type I error of 0.1. The study required 32 analyzable patients in each arm, which would warrant a 10% chance of observing a percentage of patients without distant metastasis by 3 years of less than 75% if the true rate was 86%. With the actual number of evaluable patients, the study instead warrants a 13-14% chance.

If the percentage of patients without distant metastasis by 3 years for either arm was greater than or equal to 75%, then it would be strongly considered as a potential arm in a subsequent phase III study, assuming treatment delivery and adverse events (AEs) were acceptable. If both arms met the criteria, then the treatment arm with less toxicity would be chosen.

Percentage of Patients Without Distant Metastases by Three Years

Induction Therapy

Consolidation Therapy

Adjuvant Therapy

Eligible patients who started each treatment component (induction, consolidation, adjuvant)

Percentage of Patients Who Completed Treatment Per Protocol

During Treatment

Between End of Treatment and 180 days after

Eligible patients with adverse event data for corresponding time period

Percentage of Patients With Grade 3 or Higher Genitourinary, Gastrointestinal, or Hematologic Adverse Events

Eligible patients who started induction therapy

Number of Patients Experiencing Complete Response of the Primary Tumor After Induction Therapy

Eligible participants with five-year data

Number of Participants With Progression or Removal of Bladder Five Years After Therapy

Sensation of Not Emptying Bladder

Urinate Again < 2 Hours After Urinating

Stopped and Started When Urinating

Difficult to Postpone Urination

Weak Urinary Stream

Push or Strain to Begin Urination

How Often Get Up at Night to Urinate

AUA Total Symptom Score

Eligible patients with baseline and 3-year scores

Change in American Urological Association Symptom Index (AUASI) Score at 3 Years

The protocol did not provide sufficient detail to meet National Cancer Institute requirements for release of specimens from our tissue bank for the protocol-specified analysis, therefore no assays were performed and no data were collected for this outcome measure. Specimen use will require federal approval and funding separate from this trial.

Determining Potentially Predictive Biomarkers for Acute and Late Toxicities

Determining Potentially Predictive Biomarkers for Cystectomy-free Survival

Within 8 weeks following pre-study transurethral resection (TUR) patients receive 2.5 weeks of induction chemoradiotherapy (induction 5-fluorouracil, induction cisplatin, induction BID \[twice daily\] 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.

Within 8 weeks following pre-study transurethral resection (TUR) patients receive 2.5 weeks of induction chemoradiotherapy (induction gemcitabine and induction QD \[once a day\] 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.

Spots Global Cancer Trial Database for consolidation bid radiation therapy