Phase II trial of neoadjuvant estramustine and etoposide plus radical prostatectomy for locally advanced prostate cancer

Objectives. To report the results of a Phase II trial of neoadjuvant estram ustine 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 ever y 28 days, followed by radical prostatectomy The eligibility criteria inclu ded 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 feasibilit y of neoadjuvant therapy and radical prostatectomy, including drug and surg ery-related toxicities. Secondary endpoints included the pre-prostatectomy PSA level, local response, pathologic outcomes, and time to PSA failure. Results. Eighteen patients were entered and completed all three cycles of t herapy, and 16 (89%) underwent radical prostatectomy. A local response occu rred in 15 (94%) of 16 patients with palpable tumors, and the serum PSA rea ched undetectable levels after therapy and before radical prostatectomy in 9 patients (50%). Five patients (28%) experienced grade 3 toxicity (two wit h deep venous thrombosis, two with neutropenia, and one with diarrhea) and one (6%) experienced grade 4 toxicity (pulmonary embolus) before surgery. T he median operative time was 125 minutes, the mean blood loss was 665 mL, a nd the mean length of stay was 2.5 nights. Five minor surgical complication s occurred in 4 patients. The pathologic analysis demonstrated residual car cinoma with squamous metaplasia and androgen deprivation effect in all pati ents. Five patients (31%) had organ-confined disease and 9 patients (56%) h ad specimen-confined disease. All patients achieved an undetectable PSA lev el postoperatively and at a median follow-up of 14 months (range 5 to 20) a nd without additional therapy, all 14 patients with negative lymph nodes we re disease free. Conclusions. This trial confirms the feasibility of radical prostatectomy w ith acceptable surgical morbidity after neoadjuvant therapy with estramusti ne and etoposide in patients with locally advanced prostate cancer. However , this regimen is associated with estramustine-induced thromboembolic toxic ity. 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 deprivat ion. Additional study of this paradigm with other drug regimens is warrante d. UROLOGY 57: 281-285, 2001. (C) 2001, Elsevier Science Inc.