Impact of dose density of adjuvant chemotherapy for locally advanced urothelial cancer.

Abstract

4567 Background: To investigate the importance of dose density for two chemotherapy regimens, gemcitabine and cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) during the adjuvant treatment of patients (pts) with locally advanced urothelial cancer after radical cystectomy. Methods: The USC Urology cystectomy database yielded 187 pts who received adjuvant chemotherapy from Apr. 1985 to Nov. 2007. Exact chemo doses and dates administered were available for 94 pts treated at USC (49 GC, 45 MVAC). Median age for the cohort is 65 years (range: 41-87), 83% male, 67% LN+. With median follow-up of 7.4 years (median 3.8 for GC, 12.7 for MVAC) there have been 23 deaths in the GC group and 28 in the MVAC group. In an exploratory analysis, we calculated the dose density for cisplatin, doxorubicin and gemcitabine as mg/m2/week. Using Cox regression the effect of chemo density on survival and recurrence was modeled as a continuous variable after adjusting for age, gender, and lymph node status. Results: For MVAC, full cisplatin density is 17.5 mg/m2/week and for GC given as a 21 day cycle it is 25.0 mg/m2/week. In our pts the median cisplatin density was 13.6 for MVAC and 23.3 for GC; the number of dose reductions and delays did not differ among the two groups. Cisplatin density correlated significantly with density of doxorubicin (r=0.84, p<0.001) and gemcitabine (r=0.90, p<0.001). Higher cisplatin density standardized by intended dose density had modest effect with improved recurrence-free survival (HR=0.95, p=0.058) and overall survival (HR=0.96, p=0.088). The effect was observed to be stronger in the GC group. The time from cystectomy to start of adjuvant chemo was significantly associated with recurrence and survival after controlling for age, gender, lymph node involvement, and treatment group. For pts with time to adjuvant chemo start >100 days the hazard ratio for death was 3.27 times higher (p=0.002) and for recurrence it was 3.23 times higher (p=0.002) than those starting adjuvant chemo within 100 days. Conclusions: These data yield a hypothesis that initiating treatment within 100 days of surgery, and maintaining or increasing the density of cisplatin during adjuvant chemotherapy, may be important for outcomes. No significant financial relationships to disclose.