Long‐term follow‐up of a neoadjuvant chemohormonal taxane‐based phase II trial before radical prostatectomy in patients with non‐metastatic high‐risk prostate cancer

Abstract

OBJECTIVE To assess the feasibility and activity of a neoadjuvant treatment combining a luteinizing hormone‐releasing hormone (LHRH)‐analogue, estramustine and docetaxel before radical retropubic prostatectomy (RRP) in patients with high‐risk prostate cancer. PATIENTS AND METHODS High‐risk patients were defined as clinical stage ≥T3 and/or a prostate‐specific antigen (PSA) level of ≥15 ng/mL, and/or biopsy a Gleason sum of ≥8. Patients received LHRH analogue treatment until the PSA nadir (a stable PSA level for two consecutive determinations) and then, continuing hormone therapy, a combined regimen of estramustine and docetaxel. Patients had RRP within a month of completing the neoadjuvant regimen. All patients were assessed for toxicity and surgical complications. A clinical response was defined as complete (CR, the disappearance of all palpable and radiological abnormalities and a decline in PSA level of ≥90%) or partial (PR, a decline in PSA level of half or more with stable or improved palpable and/or radiological abnormalities). A pathological response was defined as ‘complete’ (undetectable cancer), ‘substantial’ (residual cancer in ≤10% of the surgical specimen) or ‘minimal’ (residual cancer in >10% of the surgical specimen). The biomarkers p53, bcl‐2, MIB1, erbB2 and factor VIII were also evaluated. RESULTS Of 22 patients enrolled between March 1999 and January 2002, 21 (mean age 63 years; mean PSA level 61 ng/mL; median biopsy Gleason sum 8) completed the neoadjuvant therapy. The clinical stage was organ‐confined in three patients (15%); five (25%) had pelvic lymphadenopathy on computed tomography. The neoadjuvant treatment was well tolerated, with only one grade 2 toxicity (Eastern Cooperative Oncology Group grading). All PSA values decreased by >90% from baseline after hormonal therapy only, and the mean reduction from before to after chemotherapy was statistically significant (P = 0.001). Three patients (15%) had a CR, 16 (80%) had a PR and one (5%), with sarcomatoid tumour, had progression; 19 had non‐nerve‐sparing RRP and there were no major complications during or after RRP. The pathological assessment showed that one patient (5%) had no tumour (pT0) and six (32%) had a ‘substantial’ response. The overall rate of organ‐confined disease was 58%, vs a mean 8% predicted likelihood from the Kattan nomogram. Five patients (26%) had positive surgical margins and four (21%) had positive lymph nodes. At a median follow‐up of 53 months, eight patients (42%) were disease‐free. Organ‐confined disease (P = 0.022), residual cancer at pathology in ≤10% of the surgical specimen (P = 0.007) and no seminal vesicle invasion (P = 0.001) correlated with disease‐free survival. CONCLUSION A neoadjuvant chemohormonal regimen before RRP is feasible and active in patients with high‐risk prostate cancer. The rate of pathological organ‐confined disease was higher than expected and responding patients had an 85% disease‐free survival rate at 5 years.

Phase II trial of short-term neoadjuvant docetaxel and complete androgen blockade in high-risk prostate cancer

“…The 6% of pCR in our study is in the range of the previously reported studies with longer duration therapy with D and hormonal therapy (Prayer-Galetti et al, 2007;Chi et al, 2008). In the whole series, 47% of patients had pathological organconfined disease, similar to expected rates with neoadjuvant hormonal therapy alone.…”

“…As mentioned earlier, no relationship between the percentage of pCRs to neoadjuvant hormonal treatment and patient outcome has been reported to date (Gleave et al, 1996;Prezioso et al, 2004;Klotz et al, 2005;Pendleton et al, 2007;D'Amico et al, 2008). However, in an earlier study of neoadjuvant D and hormone therapy, a correlation between the presence of residual tumour in o10% of the surgical specimen and a better DFS was observed (Prayer-Galetti et al, 2007). In our trial, longterm outcome was not objective and the limited sample size as well as the fact that a significant percentage of patients received adjuvant radiation therapy might further limit the correct interpretation of any possible effect on outcome.…”

“…At 53 months of follow-up, 42% of the patients were disease free. In that trial, organ-confined disease (P ¼ 0.022), residual cancer in p10% of the surgical specimen (P ¼ 0.007) and no seminal vesicle invasion (P ¼ 0.001) correlated with DFS (Prayer-Galetti et al, 2007). A large phase II multicentre study of 6 months of androgen ablation with weekly D included 72 patients with high-risk PC, with 64 of them completing protocol therapy.…”

Long-term control or possible cure? Treatment of stage D2 prostate cancer under chemotherapy using cisplatin and estramustine phosphate followed by maximal androgen blockade

“…We recently reported that combination chemotherapy with taxane, EMP and carboplatin synergistically induced very high antitumor effects against HRPC [1,2]. In addition, neoadjuvant therapy before radical prostatectomy (RP) and adjuvant/salvage chemotherapy after RP using docetaxel have proven useful against high-risk hormone-naïve PC [8][9][10]. Furthermore, the novel third-generation platinum compound satraplatin displays excellent activity against HRPC and has the major advantage of being orally bioavailable.…”

Innovations in the systemic therapy of prostate cancer

“…the neo adjuvant combi nation chemotherapy and hormonal therapies have focused on docetaxelbased regimens. [53][54][55] in two subsequent trials of docetaxel and estramustine, patients with localized prostate cancer received either complete androgen block ade with four 3week cycles of a single dose of docetaxel 70 mg/m 2 with 5 days estramustine or four cycles of an lHrH agonist with a single dose of docetaxel 70 mg/m 2 with daily estramustine. 54,55 of the 44 patients enrolled in these two trials, only one patient had a complete patho logic response; organ confined disease after chemo therapy was noted in 58% and 64% of patients in the two series, respectively.…”