Chemotherapy and Radiation Therapy 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.

- Induction therapy (weeks 1-4):

- Arm I: Patients receive fluorouracil IV continuously over 72 hours on days 1-3 and
15-17 and cisplatin IV over 1 hour on days 1-3, 8-10, and 15-17. Patients also
undergo radiotherapy twice daily on days 1-5, 8-12, and 15-17.

- Arm II: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 4,
8, 11, 15, 18, 22, and 25. Patients also undergo radiotherapy once daily on days
1-5, 8-12, 15-19, and 22-26.

All patients undergo evaluation of response at 3-4 weeks after completion of induction
therapy. Patients with pT1 or worse tumor response undergo radical cystectomy within 3-8
weeks after response evaluation. Patients with pT0, Ta, or Tis tumor response (at site
distant from original tumor) proceed to consolidation therapy within 7-14 days after response
evaluation.

- Consolidation therapy (weeks 8-10):

- Arm I: Patients receive fluorouracil IV continuously over 72 hours on days 1-3 and
8-10 and cisplatin IV over 1 hour on days 1, 2, 8, and 9. Patients also undergo
radiotherapy twice daily on days 1-5 and 8-10.

- Arm II: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 4,
8, 11, and 15. Patients also undergo radiotherapy once daily on days 1-5, 8-12, 15,
and 16.

Patients proceed to adjuvant therapy 12 weeks after completion of consolidation therapy OR
8-12 weeks after radical cystectomy.

- Adjuvant therapy (weeks 21-33 or 17-29): Patients receive gemcitabine hydrochloride IV
over 30-60 minutes on days 1 and 8 and cisplatin IV over 1 hour on day 1. Treatment
repeats every 21 days for a total of 4 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study therapy, patients are followed every 3 months for 1 year, every 4
months for 1 year, every 6 months for 3 years, and then annually thereafter.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed primary transitional cell carcinoma (TCC) of
the bladder within the past 8 weeks

- Exhibits histological evidence of muscularis propria invasion

- Clinical stage T2-T4a, NX or N0, M0 disease

- TCC involvement of the prostatic urethra allowed provided it was visibly
completely resected AND there is no evidence of stromal invasion of the prostate

- No histologically or cytologically confirmed lymph node metastases

- Radiologic evidence of lymph node positivity allowed provided the lymph node
is further evaluated by lymphadenectomy or percutaneous needle biopsy AND
confirmed to be negative

- No evidence of distant metastases

- Operable disease

- Has undergone transurethral resection of the bladder tumor within the past 8
weeks

- Judged to be a candidate for radical cystectomy

- Adequately functioning bladder after thorough evaluation by an urologist

- No tumor-related hydronephrosis

PATIENT CHARACTERISTICS:

- Zubrod performance status 0-1

- White blood cell count (WBC) ≥ 4,000/mm^3

- Absolute neutrophil count (ANC) ≥ 1,800/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)

- Creatinine clearance ≥ 60 mL/min

- Serum creatinine ≤ 1.5 mg/dL (serum creatinine ≤ 1.8 mg/dL allowed provided creatinine
clearance is > 60 mL/min)

- Serum bilirubin ≤ 2.0 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Able to tolerate systemic chemotherapy combined with pelvic radiotherapy and a radical
cystectomy as determined by the urologist, radiation oncologist, and medical
oncologist

- No other malignancy within the past 5 years except for nonmelanoma skin cancer, stage
T1a prostate cancer, or carcinoma in situ of the cervix

- No severe, active co-morbidities, including any of the following:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the past 6 months

- Transmural myocardial infarction within the past 6 months

- Acute bacterial or fungal infection requiring IV antibiotics

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
that requires hospitalization or precludes study therapy

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

- AIDS

- No prior allergic reaction to any of the study drugs

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No prior pelvic radiotherapy

- No prior systemic chemotherapy for any cancer

- No concurrent drugs that have potential nephrotoxicity or ototoxicity (e.g.,
aminoglycosides)

- No concurrent intensity-modulated radiotherapy