Apoptosis and downstaging after preoperative radiotherapy for muscle-invasive bladder cancer

Purpose: To determine the relationship between pretreatment apoptosis levels and clinical-to-pathologic down-staging resulting from preoperative radiotherapy. Methods and Materials: Between 1960-1983, 338 patients were dispositioned to receive preoperative radiotherapy 4-6 weeks prior to radical cystectomy for muscle-invasive transitional cell carcinoma of the bladder. Of these, adequate hematoxylin and eosin stained tissue sections for morphologic analysis of apoptosis were available in 158 patients. These patients were treated to a median dose of 50 Gy at 2 Gy per fraction. Median follow-up was 90 months. The apoptotic index (AI) was calculated from the ratio of the number of apoptotic cells divided by the total counted and multiplied by 100. A minimum of 500 cells were counted from each patient. Results: The average AI for the whole group (n = 158) was 2.0 +/- 1.3 (+/- SD), with a median of 1.8. The association of AI to clinical stage was significant with AI averages of 1.8 for Stage T2 (n = 56), 1.9 for T3a(iz = 51), and 2.4 for T3b (p = 0.038, Kendall Correlation). The relationship of AI to radiotherapy response also was significant with an average of 2.2 for those who were downstaged (n = 103), 1.9 for those in whom the stage remained unchanged (n = 20), and 1.7 for those who were upstaged (n = 35, p = 0.054, Kendall Correlation). The other significant correlations with AI were for the factors, grade, mitotic index, number of tumors, and gender. The AI was then categorized into three groups (less than or equal to 1, >1, and less than or equal to 3, and >3) to examine the prognostic significance of this parameter. The distributions of patients by clinical stage, grade, mitotic index, number of tumors, radiotherapy response, and hemoglobin level were significantly associated with AI using this grouping. When the analysis of the distribution of patients by radiation response and AI was segregated by stage, a significant correlation was observed only for those with Stage T3b disease (p = 0.006); 93% of T3b patients with an AI >3 were downstaged, while in 7% the stage remained unchanged and none were upstaged. The relationship of AI to 5-year actuarial patient outcome was investigated using several end points and although no significant correlations were observed, a trend was seen for improved survival when AI was >3 (71% vs. 41%,p = 0.09) for Stage T3b patients. Conclusion: The AI correlated most strongly with radiotherapy response for patients with clinical stage T3b disease, the one subgroup of patients wherein preoperative radiotherapy is likely to be of the most benefit. Further investigation of pretreatment apoptosis levels as a marker of anticancer response is needed, especially for patients treated with chemotherapy and radiotherapy with the goal of bladder preservation.