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 preopera tive radiotherapy. Methods and Materials: Between 1960-1983, 338 patie nts were dispositioned to receive preoperative radiotherapy 4-6 weeks prior to radical cystectomy for muscle-invasive transitional cell carc inoma 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 i ndex (AI) was calculated from the ratio of the number of apoptotic cel ls divided by the total counted and multiplied by 100. A minimum of 50 0 cells were counted from each patient. Results: The average AI for th e 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 aver ages of 1.8 for Stage T2 (n = 56), 1.9 for T3a(iz = 51), and 2.4 for T 3b (p = 0.038, Kendall Correlation). The relationship of AI to radioth erapy response also was significant with an average of 2.2 for those w ho 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 A I were for the factors, grade, mitotic index, number of tumors, and ge nder. The AI was then categorized into three groups (less than or equa l to 1, >1, and less than or equal to 3, and >3) to examine the progno stic significance of this parameter. The distributions of patients by clinical stage, grade, mitotic index, number of tumors, radiotherapy r esponse, and hemoglobin level were significantly associated with AI us ing this grouping. When the analysis of the distribution of patients b y radiation response and AI was segregated by stage, a significant cor relation 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 A I to 5-year actuarial patient outcome was investigated using several e nd points and although no significant correlations were observed, a tr end was seen for improved survival when AI was >3 (71% vs. 41%,p = 0.0 9) for Stage T3b patients. Conclusion: The AI correlated most strongly with radiotherapy response for patients with clinical stage T3b disea se, the one subgroup of patients wherein preoperative radiotherapy is likely to be of the most benefit. Further investigation of pretreatmen t apoptosis levels as a marker of anticancer response is needed, espec ially for patients treated with chemotherapy and radiotherapy with the goal of bladder preservation.