Neoadjuvant docetaxel and capecitabine in patients (Pts) with high-risk prostate cancer (PCa): Final results of a phase II trial

Abstract

5147 Background: Docetaxel is the most active cytotoxic agent in PCa. Pre-clinically docetaxel increases the expression of thymidine phosphorylase (TP), an enzyme responsible for activation of capecitabine to 5-fluorouracil. We assessed the activity and safety of neoadjuvant docetaxel and capecitabine (DC) in pts with high risk PCa. Methods: Non-metastatic PCa pts with clinical stage >T2, or PSA = 15 ng/ml or biopsy Gleason sum (GS) = 8 received 3–6 cycles of docetaxel (36 mg/m2 IV on days 1, 8, and 15) and capecitabine (1,250 mg/m2/day PO on days 5–18) q 28 days, followed by local therapy. The primary endpoint of this 2-stage phase II trial was rate of = 50% decline in PSA. Secondary endpoints included safety and correlative measures of treatment effect (qualitative changes in histology, tissue TP and survivin expression, and CK18Asp396 [apoptosis marker] in serum). Results: Fifteen pts were enrolled with median age of 58 years, median GS =8 and PSA of 23.2 ng/mL. Five pts met 1, 7 met 2, and 3 met 3 entry criteria. 14 pts completed 3 or more cycles of DC, with a median follow up of 17.5 months (9–34). Six of the 15 patients (40%) experienced a = 50% decline in PSA, which was below the 7 required for expansion of the study. Median testosterone did not change post therapy. Eleven pts underwent radical prostatectomy (RP), with no increase in surgical complications. Six pts had positive margins, and 2 had lymph node involvement. Of the 8 patients who underwent RP alone, 5 developed a biochemical recurrence in a median time of 11 months. Grade 3 or 4 toxicities were diarrhea(3), mucositis(2), hand foot syndrome(1) and neutropenia(2). Post versus pre therapy tissue had only mild chemotherapy-effects (4/7 samples), including focal clear cell changes, apoptosis/pyknosis, and necrosis. While there was no discernable pattern of increased TP expression, 4/7 specimens showed decreased survivin expression, suggesting a possible mechanism for chemotherapy-induced apoptosis. There was no correlation of PSA response and survivin expression and no increase in serum CK18Asp396. Conclusions: Docetaxel and capecitabine in the neoadjuvant setting is well tolerated, but results in modest pathologic and PSA responses. Supported by Sanofi- Aventis. No significant financial relationships to disclose.