PHASE II TRIAL OF NEOADJUVANT ESTRAMUSTINE AND ETOPOSIDE PLUS RADICAL PROSTATECTOMY FOR LOCALLY ADVANCED PROSTATE CANCER PETER E. CLARK, DAVID M. PEEREBOOM, ROBERT DREICER, HOWARD S. LEVIN, SARAH B. CLARK, AND ERIC A. KLEIN ABSTRACT Objectives. To report the results of a Phase II trial of neoadjuvant estramustine and etoposide before radical prostatectomy in patients with locally advanced disease. Methods. Treatment consisted of three cycles of estramustine (10 mg/kg/day) and etoposide (50 mg/m 2 / day) orally on days 1 through 21, repeated every 28 days, followed by radical prostatectomy. The eligibility criteria included locally advanced prostate cancer (clinical Stage T2b/c or T3, prostate-specific antigen [PSA] level of 15 ng/mL or greater, or Gleason score of 8 or higher) without evidence of metastatic disease. The median PSA level was 14 ng/mL (range 5.3 to 50), the median Gleason score was 7 (range 6 to 9), and 44% had Stage T2b/c or T3 disease. The primary endpoint was feasibility of neoadjuvant therapy and radical prostatectomy, including drug and surgery-related toxicities. Secondary endpoints included the pre-pros- tatectomy PSA level, local response, pathologic outcomes, and time to PSA failure. Results. Eighteen patients were entered and completed all three cycles of therapy, and 16 (89%) underwent radical prostatectomy. A local response occurred in 15 (94%) of 16 patients with palpable tumors, and the serum PSA reached undetectable levels after therapy and before radical prostatectomy in 9 patients (50%). Five patients (28%) experienced grade 3 toxicity (two with deep venous thrombosis, two with neutropenia, and one with diarrhea) and one (6%) experienced grade 4 toxicity (pulmonary embolus) before surgery. The median operative time was 125 minutes, the mean blood loss was 665 mL, and the mean length of stay was 2.5 nights. Five minor surgical complications occurred in 4 patients. The pathologic analysis demonstrated residual carcinoma with squamous metaplasia and androgen deprivation effect in all patients. Five patients (31%) had organ-confined disease and 9 patients (56%) had specimen-confined disease. All patients achieved an undetectable PSA level postoperatively and at a median follow-up of 14 months (range 5 to 20) and without additional therapy, all 14 patients with negative lymph nodes were disease free. Conclusions. This trial confirms the feasibility of radical prostatectomy with acceptable surgical morbidity after neoadjuvant therapy with estramustine and etoposide in patients with locally advanced prostate cancer. However, this regimen is associated with estramustine-induced thromboembolic toxicity. The results of the pathologic analysis suggest a higher than expected rate of organ-confined and specimen-confined disease, but little histologic evidence of antitumor effect beyond that associated with androgen deprivation. Additional study of this paradigm with other drug regimens is warranted. UROLOGY 57: 281–285, 2001. © 2001, Elsevier Science Inc. P atients with locally advanced prostate cancer as determined by the preoperative characteristics of Gleason score, T stage, and serum prostate-spe- cific antigen (PSA) level have worse outcomes after radical prostatectomy (RP) than those with more favorable parameters. 1–6 In a recent review of our experience with RP as monotherapy for localized disease, patients with unfavorable pretreatment characteristics (PSA greater than 10 ng/mL, Glea- son score of 7 or greater, or Stage T2b/c or T3 From the Urology Institute, Cleveland Clinic Taussig Cancer Center, and Departments of Hematology/Oncology and Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio Reprint requests: Eric A. Klein, M.D., Section of Urologic On- cology, Desk A-100, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland OH 44195 Submitted: August 1, 2000, accepted (with revisions): Septem- ber 20, 2000 ADULT UROLOGY © 2001, ELSEVIER SCIENCE INC. 0090-4295/01/$20.00 ALL RIGHTS RESERVED PII S0090-4295(00)00914-6 281