Comparison of Immediate and Delayed Adjuvant Chemotherapy in Treating Patients Who Have Undergone a Radical Cystectomy for Stage III or Stage IV Transitional Cell Carcinoma of the Bladder Urothelium

European Organisation for Research and Treatment of Cancer (EORTC)

Status and phase: Completed; Phase 3

Conditions: Stage III Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Stage IV Bladder Cancer

Treatments: Drug: doxorubicin hydrochloride; Drug: methotrexate; Biological: filgrastim; Drug: gemcitabine hydrochloride; Drug: cisplatin; Drug: vinblastine sulfate

Study type: Interventional

Funder types: Other; NETWORK; NIH

Identifiers

NCT00028756

2005-003741-13 (EudraCT Number)

FNCLCC-GETUG-EORTC-30994

UKCCCR-EORTC-30994

EORTC-30994

NCRI-BLADDER-EORTC-30994

EORTC 30994

CDR0000069130

N02CM62212 (Other Grant/Funding Number)

ACOSOG-EORTC-30994

CAN-NCIC-EORTC-30994

Details and patient eligibility

About

Randomized phase III trial to compare the effectiveness of immediate adjuvant chemotherapy with that of adjuvant chemotherapy given when the cancer returns in treating patients who have undergone a radical cystectomy for stage III or stage IV transitional cell carcinoma of the bladder urothelium. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug and giving them after surgery may kill any remaining tumor cells. It is not yet known if adjuvant chemotherapy is more effective when given immediately after radical cystectomy (surgery to remove the bladder) or when the cancer returns.

Full description

PRIMARY OBJECTIVES:

I. Compare the overall and progression-free survival of patients with stage III or IV transitional cell carcinoma of the bladder urothelium treated with immediate versus deferred adjuvant chemotherapy after radical cystectomy.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, tumor status (pT1-2 vs pT3 vs pT4), and node status (node positive vs node negative with 15 or more nodes sampled vs node negative with less than 15 nodes sampled). Patients are randomized to one of two treatment arms.

ARM I: Beginning within 90 days of radical cystectomy, patients receive a total of 4 courses of adjuvant chemotherapy.

ARM II: Beginning at the time of clinical relapse, patients receive a total of 6 courses of adjuvant chemotherapy.

Patients in both arms receive one of the following chemotherapy regimens to be determined by participating center:

REGIMEN A (Classical M-VAC): Patients receive classical M-VAC comprising methotrexate IV on days 1, 15 and 22; vinblastine IV on days 2, 15, and 22; and doxorubicin IV and cisplatin IV on day 2. Courses repeat every 28 days.

REGIMEN B (High-dose M-VAC): Patients receive high-dose M-VAC comprising methotrexate IV on day 1 and vinblastine IV, doxorubicin IV, and cisplatin IV on day 2. Patients also receive filgrastim (G-CSF subcutaneously once daily on days 4-10. Courses repeat every 14 days.

REGIMEN C (Gemcitabine and cisplatin): Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 followed by cisplatin IV on day 1 or 2. Courses repeat every 28 days.

Patients are followed every 3 months for 1 year, every 6 months for 5 years, and then annually thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK and EORTC.

Enrollment: 285 patients

Sex: All

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

• Histologically confirmed transitional cell carcinoma of the bladder urothelium

  • T3-4, N1-3, M0

• No pure squamous cell or adenocarcinoma tumors

• No more than 90 days since prior radical cystectomy and bilateral lymphadenectomy without evidence of microscopic residual disease

• Performance status - WHO 0-1

• WBC at least 3,500/mm^3

• Platelet count at least 120,000/mm^3

• SGOT/SGPT less than 2.5 times upper limit of normal (ULN)

• Alkaline phosphatase less than 2.5 times ULN

• Bilirubin normal

• Glomerular filtration rate greater than 60 mL/min

• No clinically significant cardiac arrhythmia

• No congestive heart failure

• No complete bundle branch block

• No New York Heart Association class III or IV heart disease

• Not pregnant or nursing

• Fertile patients must use effective contraception during and for 6 months after study

• Considered fit for cisplatin-containing combination chemotherapy

• No clinically abnormal auditory function

• No known hypersensitivity to E. coli-derived drug preparations

• No grade 2 or greater peripheral neuropathy

• No other prior or concurrent malignancy except adequately treated carcinoma in situ of the cervix, treated basal cell skin cancer, or treated incidental prostate cancer (pT2, Gleason score no greater than 6, and PSA less than 0.5 ng/mL)

• No psychological, familial, sociological, or geographical condition that would preclude study involvement

• No prior systemic chemotherapy

• No prior radiotherapy to the bladder

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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285 participants in 2 patient groups

Arm I (immediate chemotherapy)

Active Comparator group

Description:

Beginning within 90 days of radical cystectomy, patients receive a total of 4 courses of adjuvant chemotherapy.

Treatment:

Drug: vinblastine sulfate

Drug: cisplatin

Biological: filgrastim

Drug: gemcitabine hydrochloride

Drug: methotrexate

Drug: doxorubicin hydrochloride

Arm II (deferred chemotherapy)

Experimental group

Description:

Beginning at the time of clinical relapse, patients receive a total of 6 courses of adjuvant chemotherapy.

Treatment:

Drug: vinblastine sulfate

Drug: cisplatin

Biological: filgrastim

Drug: gemcitabine hydrochloride

Drug: methotrexate

Drug: doxorubicin hydrochloride