Authors: Stadler WM et al, ASCO 2009. Reviewed by: Dr. Lori Wood Abstract: 5017

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Randomized Trial of p53 Targeted Adjuvant Therapy for Patients (pts) With Organ-Confined Node-Negative

Urothelial Bladder Cancer (UBC)

Authors: Stadler WM et al, ASCO 2009.Reviewed by: Dr. Lori WoodAbstract: 5017Date posted: June 12, 2009

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RTreatment A:

Adjuvant MVAC x 3

Treatment B:

Observation

pT1-T2 N0M0 urothelialcancer, post cystectomy

and PLND

p53 positiven = 272 (p53 positive)n = 114 randomized

primary endpoint =time to recurrence

(goal: improvement by 20% at 3 years)

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STUDY RATIONALE

• Previous small studies showed that p53 positive tumors had probability of recurrence post resection in organ confined bladder cancer.

• Prior USC randomized trial of adjuvant chemotherapy versus observation showed improved outcome in p53 positive tumors.

• p53 positive cells may be more susceptible to chemotherapy agents that damage DNA.

• Hypothesis:

• p53 IHC is a valid biomarker

• p53 IHC is prognostic

• p53 IHC is predictive for benefit from DNA damaging chemotherapy

Cole et al, Nature 1997; 385:123

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RESULTS

• 521 patients registered

• 499 had successful p53 assessment

• 272 p53 positive ( 10% nuclear reactivity)

• 158 refused randomization

• 114 randomized (only 42% of p53 positive)

• 56 observation

• 46 MVAC

• 12 refused

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RESULTS (CONTINUED)

• n = 499; 5-year relapse-free survival = 80%.

• no difference if p53 positive or negative

• n = 114; 5-year relapse-free survival = 83%.

• no difference if MVAC or observation

• Therefore, p53 positivity was not of prognostic or predictive value.

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STUDY COMMENTARY

• Study was halted early by DSMB after review of futility analysis.

• Only 42% of p53 positive patients were randomized.

• Lower than expected event rate and failure (i.e.: 15% recurrence rate at 3 years) and the a priori hypothesis was 50%; therefore, study very underpowered.

• Lower event rate probably because only pT1-T2 N0 disease and excluded pT3-T4 or N+ disease.

• p53 positivity not predictive or prognostic.

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BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS

• p53 as assessed by IHC will not help guide therapeutic decisions in resected bladder cancer at this point in time.

• The role of adjuvant chemotherapy in all stages of (pT1-T4 N0 or N+) resected bladder cancer is still very controversial and understudied.