Radiation Therapy and Chemotherapy in Treating Patients With Stage I Bladder Cancer

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin, mitomycin C, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with cisplatin may kill more tumor cells. PURPOSE: This phase II trial is studying how well radiation therapy given together with chemotherapy works in treating patients with stage I bladder cancer.

Detailed Description
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After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and annually thereafter until termination of the study.

Official Title
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A Phase II Protocol for Patients With Stage T1 Bladder Cancer to Evaluate Selective Bladder Preserving Treatment by Radiation Therapy Concurrent With Radiosensitizing Chemotherapy Following a Thorough Transurethral Surgical Re-Staging

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: 5-fluorouracil
* Drug: Mitomycin
* Radiation: Three-Dimensional Conformal Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Pathologically proven diagnosis of carcinoma of the bladder within 105 days prior to registration. • Operable patients whose initial tumor is a primary high grade urothelial carcinoma of the bladder exhibiting histologic evidence of invasion into the lamina propria (disease clinical stage T1) or a high grade stage Ta urothelial carcinoma without hydronephrosis; patients who have involvement of the prostatic urethra with urothelial carcinoma and have no evidence of stromal invasion of the prostate remain eligible. If the patient's initial tumor was a high grade stage Ta urothelial carcinoma then his/her recurrent tumor must be a high grade stage T1 urothelial carcinoma to be eligible. Patients must have a high grade urothelial carcinoma stage Ta or T1 that has recurred within 540 days after completion of the initial treatment [TURBT and intravesical Bacillus Calmette Guerin (BCG) immunotherapy] or on initial presentation with a T1 high grade tumor, the participating urologist judged BCG therapy is contraindicated or unsuitable because the patient is found to be intolerant of BCG therapy or because this patient may be immuno-compromised in ways other than that mentioned in Exclusion Criteria 2.8 or because the patient refuses BCG therapy. With the presentations as described in Section 2, the participating urologist judges that the standard next therapy, based on present urologic guidelines for this patient, is radical cystectomy. If radiologic evaluation of a lymph node is interpreted as positive, this must be evaluated further either by lymphadenectomy or by percutaneous needle biopsy. Patients with histologically or cytologically confirmed node metastases will not be eligible. Patients must have an adequately functioning bladder as judged by the participating urologist and radiation oncologist and have undergone a re-staging TURBT by the participating urologist that showed (or was present in the outside pathology specimen) a high grade stage Ta or T1 tumor with uninvolved muscularis propria in the specimen and, if on prostatic urethral biopsy mucosal carcinoma is present, there is no evidence on biopsy in the prostatic stroma of tumor invasion. Patient must be considered able to tolerate systemic chemotherapy combined with pelvic radiation therapy, and a radical cystectomy (if necessary) by the joint agreement of the participating urologist, radiation oncologist, and medical oncologist. Appropriate stage for protocol entry, based upon the following minimum diagnostic workup within 60 days prior to registration: • History/physical examination including weight, performance data, body surface area Zubrod Performance Status ≤ 1 Age ≥ 18 Complete blood count (CBC)/differential obtained no more than 30 days prior to registration on study, with adequate bone marrow function defined as follows: White blood cell count (WBC) ≥ 4,000/ml Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3 Platelets ≥ 100,000 cells/mm3 Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable.) If the patient is to be treated with cisplatin, the serum creatinine should be ≤ 1.5 mg%; serum bilirubin of ≤ 2.0 mg% Glomerular filtration rate (GFR) > 25 ml/min [For patients receiving cisplatin, GFR ≥ 60 ml/min] 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 Prior systemic chemotherapy for bladder cancer; prior chemotherapy for a different cancer is allowable 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 or a urothelial carcinoma of the upper urinary tract stage pTa, pTis or pT1 that has not been free of disease after treatment for more than a 2-year period Patients with pN+ or > T1 disease or who have not had a visibly complete TURBT Patients receiving any drugs that have potential nephrotoxicity or ototoxicity (such as an aminoglycoside) Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields 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; Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; 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. Acquired Immune Deficiency Syndrome (AIDS) based upon the current Centers for Disease Control and Prevention (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 drugs (cisplatin, mitomycin, 5FU) involved in this

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3DCRT + CT<br>Concurrent three-dimensional conformal radiation therapy (3DCRT) and radiosensitizing chemotherapy (CT) consisting of either cisplatin alone or the combination of mitomycin and 5-fluorouracil. Protocol treatment must begin with 15 weeks after a transurethral resection of the tumor (TURBT). | Drug: cisplatin<br>* 60-minute intravenous (IV) infusion of 15 mg/m^2 on days 1, 2, 3, 15, 16, 17, 29, 30, and 31 of radiation treatment.<br>Drug: 5-fluorouracil<br>* Continuous IV infusion of 500 mg/m^2/24 hrs for 5 consecutive days during weeks 1 and 4 of radiation treatment.<br>* Other names: 5FU;Drug: Mitomycin<br>* IV bolus dose of 12 mg/m^2 on day 1 of radiation treatment.<br>Radiation: Three-Dimensional Conformal Radiation Therapy<br>* Total dose to the gross bladder volume of 61.2 Gy as 34 daily fractions 5 days/week, for approximately 7 weeks.<br>* Other names: 3D CRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Free From Radical Cystectomy at 3 Years | The number of participants who did not undergo a radical cystectomy within three years divided by the number of analyzed participants. | Three years from registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Free From Radical Cystectomy at 5 Years | The number of participants who did not undergo a radical cystectomy within five years divided by the number of analyzed participants. | Five years from registration | 
| Percent of Participants With Distant Disease Progression at 3 Years | Distant disease progression is defined as the first appearance of disease in a non-regional lymph node, solid organ or bone. Time to distant disease progression is defined as time from registration to the date of first distant disease progression, last known follow-up (censored), or death without distant disease progression (competing risk). Distant disease progression rate is estimated using the cumulative incidence method. | From registration to three years | 
| Percent of Participants With Distant Disease Progression at 5 Years | Distant disease progression is defined as the first appearance of disease in a non-regional lymph node, solid organ or bone. Time to distant disease progression is defined as time from registration to the date of first distant disease progression, last known follow-up (censored), or death without distant disease progression (competing risk). Distant disease progression rate is estimated using the cumulative incidence method. | From registration to five years | 
| Percentage of Participants With Progression to Tumor Stage T2 or Greater at 3 Years | Primary tumor stage T2 = tumor invades muscle; T3 = tumor invades perivesical tissue; T4 = tumor invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall. Time to progression is defined as time from registration to the date of first progression, last known follow-up (censored), or death without tumor progression (competing risk). Tumor progression rates was to be estimated using the cumulative incidence method. | From registration to three years | 
| Percentage of Participants With Progression to Tumor Stage T2 or Greater at 5 Years | Primary tumor stage T2 = tumor invades muscle; T3 = tumor invades perivesical tissue; T4 = tumor invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall. Time to progression is defined as time from registration to the date of first progression, last known follow-up (censored), or death without tumor progression (competing risk). Tumor progression rate was to be estimated using the cumulative incidence method. | From registration to five years | 
| Percentage of Participants Who Have Died From Bladder Cancer at 5 Years (Disease-specific Survival) | Time to death from bladder cancer is defined as time from registration to death from bladder cancer, last known follow-up (censored), or death from other cause (competing risk). More specifically, death absent a distant metastasis, death from non-bladder cancer, and death absent local recurrence comprise the competing risk. Death from bladder cancer rate is estimated using the cumulative incidence method. | From registration to five years | 
| Percentage of Participants Alive at 3 Years | Overall survival time is defined as time from registration to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. | From registration to three years | 
| Percentage of Participants Alive at 5 Years | Overall survival time is defined as time from registration to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. | From registration to five years | 
| Distribution of Participants by Highest Grade Adverse Event | Common Terminology Criteria for Adverse Events (CTCAE) version 4 grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. | Adverse events are evaluated 8-10 weeks after end of study treatment (approximately 7 weeks), then every 3 months for one year, every 4 months for one year, every 6 months for 3 years, then annually. Maximum follow-up at time of reporting was 8.6 years. | 
| Percentage of Participants With Local Recurrence at 3 Years | Time to local recurrence is defined as time from registration to the date of first local recurrence, last known follow-up (censored), or death without local recurrence (competing risk). Local recurrence rate is estimated using the cumulative incidence method. | From registration to three years | 
| American Urological Association Total Symptom Score at Baseline and at 3 Years | The American Urological Association Total symptom score measures the severity of enlarged prostate symptoms. Possible scores range from 0 to 35, with higher scores indicating worse symptoms. | Baseline and 3 years | 

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