Apoptosis, proliferation and p53, cyclin D1, and retinoblastoma gene expression in relation to radiation response in transitional cell carcinoma of the bladder

Purpose: To determine whether the apoptotic index, the Ki67 index, and the expression of the p53, cyclin D1, and retinoblastoma genes correlate with l ocal control, overall survival, and time to distant metastases in invasive bladder cancer treated with external beam radiation. Methods and Materials: Paraffin-embedded pretreatment biopsies from 83 pati ents with invasive transitional cell carcinoma of the bladder were scored m orphologically for apoptosis and immunohistochemically for Ki67, p53, cycli n DI, and retinoblastoma gene expression. Survival analysis methods were us ed to assess overall survival, local control, and freedom from distant meta stases. A multiple proportional hazard (PH) regression analysis was perform ed to study the prognostic value of the abovementioned biologic parameters (all divided into two categories, except Ki67) in addition to classical pro gnostic factors such as T stage, histologic grade, multifocality of the tum or, and completeness of transurethral resection. All patients were treated with external beam radiation as sole treatment. Median follow-up for the 19 patients still living was 7.5 years. Results: Apoptotic index varied from 0% to 3.4% with a mean of 0.8% and a m edian of 0.6%. Ki67 index varied from 0% to 60% with a mean of 14% and a me dian of 12%. P53 protein was detectable in 61% of the tumors. Overexpressio n of cyclin D1 was observed in 39% of the tumors and loss of retinoblastoma protein in 23% of the tumors. High Ki67 index was found to be significantl y associated with p53 expression (p = 0.04) and cyclin DI overexpression (p = 0.023). Cyclin D1 overexpression was found more often in Rb-positive tum ors than in Rb-negative tumors (p = 0.006). Other associations between the markers are less clear. Biologic markers were not correlated with T stage o r grade. In the PEI analysis local control was found to be significantly be tter for tumors with wild-type p53 (p = 0.028). Also, tumors with an apopto tic index above the median value (0.6%) had a significantly better local co ntrol rate (p = 0.035). Ki67 index (p = 0.35), retinoblastoma gene expressi on (p 0.30) and cyclin D1 overexpression (p = 0.61) were not found to have an additional predictive value regarding local tumor control. None of the t ested biologic parameters were found to be associated with overall survival . Time to distant metastases was significantly shorter for tumors with high Ki67 index (p = 0.01) and tumors with an apoptotic index less than median (p = 0.009). Conclusions: The results of our study provide evidence for a prognostic val ue of p53 expression and apoptotic index with respect to the radiation resp onse in bladder cancer in addition to more conventional prognosticators. Th e value of these parameters as a predictive assay for radiation response wa rrants confirmation in larger and prospective studies. (C) 2001 Elsevier Sc ience Inc.