MVAC IN BLADDER CANCER BASED ON P53 STATUS

Project: Research project

Description

DESCRIPTION: In this proposal for translational research, it is planned to assess the significance of the expression of p53 mutations in specimens of bladder cancer after cystectomy on the impact of adjuvant MVAC chemotherapy in a controlled clinical trial. The proposal, under the Chairmanship of a young investigator, Dr. David Esrig, plans to build on previous laboratory and preliminary clinical data. Tumor progression in transitional cell carcinoma (TCC) of the urinary bladder is believed to occur through a multistep accumulation of genetic alterations. p53 alterations/mutations have been shown to be involved in the transformation of normal urothelium to carcinoma in situ of the bladder and in the progression to invasive disease. The investigators have shown that (1) adjuvant chemotherapy may prolong recurrence free survival in patients with invasive TCC at high risk for recurrence; (2) detection of p53 alterations in a tumor is significantly associated with progression of cancer in patients with organ-confined TCC managed by radical cystectomy; (3) expression of p21 may abrogate the impact of the expression of p53. The unifying hypothesis of this proposal is that p53 alterations/mutations in organ-confined TCC of bladder significantly increase the risk of recurrence and death, and that adjuvant chemotherapy may improve survival in these high risk patients. To test this hypothesis, 23 academic institutions, with records of treatment/research in bladder cancer, have been recruited to participate in this prospective randomized trial. All patients in the trial will have already undergone a radical cystectomy with a pathological diagnosis of P1-P3a,NOMO bladder TCC. The tumors will be tested for p53 alterations. Patients with p53 alterations will be randomized to three cycles of adjuvant MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) chemotherapy or observation (Arms I and II). This prospective randomized trial will (1) compare the recurrence free and overall survival of those patients demonstrating alterations in the p53 gene who are treated with adjuvant MVAC versus those who are only observed after surgery; (2) compare prospectively the recurrence free and overall survival of patients with tumors demonstrating alterations in p53 versus tumors without p53 alterations, both groups being followed by observation only after cystectomy; (3) study the expression of other genes, especially RB, p21 and p16, involved in cell cycle regulation that may be involved in the response to chemotherapy; (4) provide a biorepository of paraffin embedded tumor tissue for future studies of genetic markers of tumor progression.
StatusFinished
Effective start/end date5/1/973/31/09

Funding

  • National Institutes of Health: $638,420.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $551,197.00
  • National Institutes of Health: $269,741.00
  • National Institutes of Health: $503,260.00
  • National Institutes of Health: $456,329.00
  • National Institutes of Health: $548,428.00

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Urinary Bladder Neoplasms
Urinary Bladder
Vinblastine
Transitional Cell Carcinoma
Methotrexate
Doxorubicin
Cisplatin
Cystectomy
Recurrence
Neoplasms
Survival
Adjuvant Chemotherapy
Drug Therapy
Observation
Urothelium
Research Personnel
Mutation
p53 Genes
Carcinoma in Situ
Cell Cycle

ASJC

  • Medicine(all)