URINARY CYTOKINES DURING INTRAVESICAL BACILLUS-CALMETTE-GUERIN THERAPY FOR SUPERFICIAL BLADDER-CANCER - PROCESSING, STABILITY AND PROGNOSTIC VALUE

Purpose: An accurate prognostic indicator to identify nonresponding pa tients with superficial transitional cell carcinoma of the bladder at an early stage of intravesical bacillus Calmette-Guerin (BCG) therapy is urgently needed. Materials and Methods: The processing conditions a nd stability of several BCG induced urinary cytokines were analyzed, a s was the possible correlation between these cytokines (indicating imm une responsiveness to BCG) and bladder tumor recurrence. We studied 23 patients with superficial transitional cell carcinoma of the bladder. Monitoring was performed by serial collection of urine during the fir st 24 hours after each of the 6 consecutive weekly intravesical BCG in stillations. Baseline pre-therapy cytokine levels were 3.9 +/- 4.7 pg. /mu mol. creatinine for interleukin-1 beta, 0.0 +/- 0.0 units per mu m ol. creatinine for interleukin-2, 8.9 +/- 12.9 pg./mu mol. creatinine for interleukin-6 and 0.1 +/- 0.2 pg./mu mol. creatinine for tumor nec rosis factor-ct (all measured by enzyme-linked immunosorbent assay). T o investigate the correlation between interleukin-2 and bladder tumor recurrence, patients were stratified into 2 groups based on an early ( 6 months or less) or late (greater than 6 months) recurrent tumor. For each patient the highest cytokine value measured during the 6-week BC G treatment course was evaluated. Results: The results were positive i f the level in urine exceeded 0.34 units interleukin-2 per mu mol. cre atinine. A significant correlation between urinary interleukin-2 and t umor recurrence was found (p = 0.003, 23 patients). Of the studied cyt okines obtained from BCG treated patients, interleukin-1 beta, 2 and 6 but not tumor necrosis factor-alpha were stable in urine at 4C and 20 C. At 37C all cytokines were unstable. Interferon-gamma could only be detected in immediately dialyzed urine and its occurrence correlated m ost with that of interleukin-2. Processing of urine by centrifugation to remove leukocytes immediately after collection was not required for reliable measurements of interleukins-2 and 6. Based on these results interleukins-2 and 6 were preferred for extensive monitoring of the B CG induced immune reaction. Conclusions: Our study provides significan t evidence for a correlation between urinary cytokine induction and cl inical response following intravesical BCG therapy. Particularly, moni toring of interleukin-2 may have the potential for prognostic value pr ovided that strict precautions regarding urine collection, such as max imal 2-hour sampling and immediate cooling, are taken.