title: Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status.
abstract: BACKGROUND
  Retrospective studies suggest that p53 alteration is prognostic for recurrence in patients with urothelial bladder cancer and predictive for benefit from combination methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) adjuvant chemotherapy.
  
  
  METHODS
  Patients with pT1/T2N0M0 disease whose tumors demonstrated ≥ 10% nuclear reactivity on centrally performed immunohistochemistry for p53 were offered random assignment to three cycles of adjuvant MVAC versus observation; p53-negative patients were observed. By using a log-rank test with one-sided α = .05 and β = .10, 190 p53-positive patients were planned to be randomly assigned to detect an absolute improvement in probability of recurring by 3 years from 0.50 to 0.30.
  
  
  RESULTS
  A total of 521 patients were registered, 499 underwent p53 assessment, 272 (55%) were positive, and 114 (42%) were randomly assigned. Accrual was halted on the basis of the data and safety monitoring board review of a futility analysis. Overall 5-year probability of recurring was 0.20 (95% CI, 0.16 to 0.24) with no difference on the basis of p53 status. Only 67% of patients randomly assigned to MVAC received all three cycles with 12 patients receiving no treatment. There was no difference in recurrence in the randomly assigned patients (hazard ratio, 0.78; 95% CI, 0.29 to 2.08; P = .62).
  
  
  CONCLUSIONS
  Neither the prognostic value of p53 nor the benefit of MVAC chemotherapy in patients with p53-positive tumors was confirmed, but the high patient refusal rate, lower than expected event rate, and failures to receive assigned therapy severely compromised study power.
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Seth P
authors.initials: SP
authors.lastname: Lerner
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.forename: John P
authors.initials: JP
authors.lastname: Stein
authors.forename: Shan-Rong
authors.initials: SR
authors.lastname: Shi
authors.forename: Derek
authors.initials: D
authors.lastname: Raghavan
authors.forename: David
authors.initials: D
authors.lastname: Esrig
authors.forename: Gary
authors.initials: G
authors.lastname: Steinberg
authors.forename: David
authors.initials: D
authors.lastname: Wood
authors.forename: Laurence
authors.initials: L
authors.lastname: Klotz
authors.forename: Craig
authors.initials: C
authors.lastname: Hall
authors.forename: Donald G
authors.initials: DG
authors.lastname: Skinner
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cote
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002278:Carcinoma in Situ / Q000188:drug therapy / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D058990:Molecular Targeted Therapy; D011446:Prospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014747:Vinblastine / Q000008:administration & dosage
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014747:Vinblastine; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate