• prostate cancer;
  • high-risk;
  • neoadjuvant;
  • chemotherapy;
  • taxane;
  • prostatectomy


  1. Top of page
  2. Abstract


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.


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.


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.


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.


neoadjuvant hormonal treatment


(positive) surgical margin


radical retropubic prostatectomy


Eastern Cooperative Oncology Group


extracapsular extension


complete (partial) response


progressive disease


disease-free survival


seminal vesicle involvement


organ-confined disease


total androgen blockade.


  1. Top of page
  2. Abstract

Patients with non-metastatic locally advanced (cT3) high-grade (biopsy Gleason score ≥ 7) prostate cancer and a baseline PSA level of ≥ 15 ng/mL are at high risk of local and distant relapse after radical surgery [1–5]. Neoadjuvant hormonal treatments (NHTs) have been proposed before surgery in high-risk patients to decrease the local and systemic disease recurrence rate. Although there was a lower rate of positive surgical margins (PSMs) after NHT, randomized trials with mature endpoints investigating short (3 months) or long (8 months) NHT failed to detect any improvement in the time to biochemical relapse after radical retropubic prostatectomy (RRP) [6–8,9–11]. Preclinical models of prostate cancer suggest that androgen-independent clones appear at an early stage of disease [12] and might be responsible for the limited results of NHT. Recently taxanes, drugs that target nuclear matrix and microtubular function [13,14], were reported to be effective for treating hormone-refractory prostate cancer [15,16]. The association of estramustine and taxanes was reportedly an active combination for hormone-refractory prostate cancer [17,18] and neoadjuvant phase II trials using these two drugs were reported [19–25]. We describe the long-term results of a phase II neoadjuvant chemohormonal regimen (estramustine, docetaxel and triptorelin) before RRP in patients with high-risk prostate cancer.


  1. Top of page
  2. Abstract

The eligibility criteria for patients with high-risk disease (Table 1) [26–28] were clinical stage ≥T3, and/or a PSA level of ≥15 ng/mL, and/or a biopsy Gleason sum of ≥8. Diagnostic biopsies were reviewed centrally; the local stage was assessed by a DRE, TRUS and endorectal-coil MRI. Clinical stage T3 was not assigned on the basis of TRUS findings alone. A chest X-ray, abdominopelvic CT and total-body bone scan were required from all patients before study entry. The clinical and pathological stages were assigned based on the 1997 TNM staging system [26]. Continence after RRP was defined as the use of no pads.

Table 1.  The eligibility criteria
  • *

    ECOG [27]; AST, aspartate aminotransferase; ALT, alanine transaminase; PTT, prothrombin time; ASA, American Society of Anesthesiologists [28].

InclusionHistologically documented prostate cancer
Clinical stage cT3 (any grade, any PSA), and/or
PSA ≥15 ng/mL (any stage, any grade), and/or biopsy Gleason sum ≥8 (any stage, any PSA)
ECOG* performance status 0–2
ASA comorbidity index 1–2
Life-expectancy ≥ 10 years
Laboratory values; blood cell count ≥3000 cells/µL
neutrophil count ≥1500/µL
platelet count ≥100,000/µL
serum creatinine and bilirubin ≤1.25 times upper normal limit
AST and ALT ≤twice the upper normal limit normal prothrombin and PTT
Written informed consent
ExclusionEvidence of metastasis on bone scan or abdominopelvic CT
Previous or concurrent therapy for prostate cancer
Previous malignancy (except basal cell carcinoma) with no evidence of ≥5 years of DFS
Previous history of significant cardiac or thromboembolic disease

For the treatment plan, eligible patients received first a triptorelin 3.75 mg depot every 28 days alone, until the PSA nadir (defined as a stable PSA level for two consecutive measurements at least 7 days apart). At the PSA nadir a combined treatment consisting of four 3-week cycles of estramustine (600 mg/m2 daily from day 1–21) and docetaxel (70 mg/m2 on day 1) was administered. All patients continued LHRH analogue treatment until surgery. A complete blood count, chemistry, PSA testing and DRE were conducted before each cycle of chemotherapy. If there was no significant toxicity, all cycles were administered as planned. All patients were assessed for toxicity using the Eastern Cooperative Oncology Group (ECOG) scale, during treatment [27]. Each patient was re-staged by a DRE and CT before surgery. Patients showing a clinical response were considered eligible for RRP. Patients had RRP within a month of completing the neoadjuvant regimen, with bilateral pelvic lymphadenectomy, removing bilaterally the obturator, external iliac and common iliac lymph nodes [28] in all patients. An open RRP was done by one experienced surgeon (F.P.), as described by Walsh [29], using a non-nerve-sparing technique. Peri-operative transfusions and complications during and after RRP were recorded prospectively. The catheter was removed if there was no leakage on a retrograde cystogram taken 6 days after surgery. The drains were routinely removed the following day if dry.

Surgical specimens were fixed in formalin for 24 h, inked in two colours, sectioned at 3-mm intervals in planes perpendicular to the rectal surface, and processed routinely into paraffin wax. Slides were cut at 5 µm, examined by light microscopy and evaluated as whole-mount sections by the same pathologist (M.G.). The pathological evaluation included evidence and the approximate volume of residual cancer, extracapsular extension (ECE) and SM status. Residual tumour volume in the surgical specimen was assessed; the approximate volume of residual cancer was defined as the degree (%) of involvement within each slide. The percentage of ECE was defined as cancer in the extraprostatic tissue. PSMs were defined as tumour touching the inked margin. Due to the presence of therapy effects, a Gleason sum was not assigned to the tumours. The expression of factor VIII, MIB1, erbB2, bcl2 and p53 was also evaluated in all surgical specimens.

The clinical response was defined according to Hussain et al.[23] as follows: complete (CR), the disappearance of all abnormalities on DRE and radiology, when applicable, and a decline in PSA level of ≥90% from baseline values; partial (PR), a decline in PSA level of half or more from baseline values, with stable or improved palpable and/or radiological abnormalities; stable disease, not meeting either the response or progression criteria; progressive disease (PD), two consecutive increases (at least 2 weeks apart) in PSA level from the nadir value and/or a palpable worsening on DRE and/or appearance of new lesions.

The pathological response was defined as: ‘complete’, undetectable cancer (pT0N0); ‘substantial’, cancer in ≤10% of the surgical specimen; or ‘minimal’, residual cancer in >10% of the surgical specimen.

After RRP patients were followed with a DRE and PSA levels at 1 month, every 3 months during the first year, and thereafter at 6-month intervals. Biochemical relapse was defined as a PSA level of >0.2 ng/mL on two separate determinations at least 2 weeks apart. No additional therapy was planned until biochemical or clinical progression. Patients receiving early hormone therapy were considered as treatment failures. Continence after RRP was defined as the use of no pads during the day or night.

The study was a phase II trial to determine the feasibility, safety and activity of the treatment regimen. Seeking to exclude a pathological response probability of <20% and to find a level of pathological response that showed useful activity (40%), assuming α = 0.05 and β = 0.20, we calculated that 20.6 patients were required, according to Simon [30]. Variables were compared using the Wilcoxon and chi-square tests, and Kaplan–Meier methods were used for the survival estimates and evaluated as univariate potential prognostic factors for biochemical disease-free survival (DFS). The differences in crude DFS were assessed by the log-rank statistic, with statistical significance defined as P < 0.05 for all tests, and all were two-sided.


  1. Top of page
  2. Abstract

Twenty-two Caucasian men were enrolled between March 1999 and January 2002; their clinical characteristics are shown in Table 2. The median (range) duration of hormonal therapy before chemotherapy was 3 (4–12) months. One patient refused the fourth chemotherapy cycle after achieving an undetectable PSA level; he had RRP but was excluded from the study. One patient refused RRP after completing the neoadjuvant regimen because he reached an undetectable PSA level. Therefore, 21 patients (96%) were evaluable for toxicity and clinical response. In all, 29% of the patients were aged <60 years; the mean (median, 95% CI) baseline PSA level was 61 (41, 26) with 16 patients (76%) having a PSA level of ≥15 ng/mL. The median biopsy Gleason sum was 8; at biopsy, one patient (cT3b, initial PSA level 1.44 ng/mL) had a Gleason 9 cancer with sarcomatoid features. The clinical stage was extraprostatic in 18 patients (86%); five (24%) had unilateral pelvic lymphadenopathy at CT (one of these had nodal metastasis on final pathology).

Table 2.  The characteristics of the 21 patients
  • *

    ECOG [27];

  • 1997 American Joint Committee on Cancer Classification [26];

  • predicted from Kattan nomogram [31].

Median (range) age, years63 (55–73)
Performance status*, n
 1 3
 2 1
n (%):
with initial PSA level, ng/mL,
 ≤4 2 (10)
 4.1–10.0 0
 10.1–20.0 3 (14)
 ≥20.116 (76)
Clinical stage
 T2a 1 (5)
 T2b 2 (10)
 T318 (86)
 N+ 5 (24)
Biopsy Gleason sum
 5 1 (5)
 6 2 (10)
 7 7 (33)
 8 7 (33)
 9 2 (10)
 10 2 (10)
High-risk inclusion criteria
 1 2 (10)
 215 (71)
 3 4 (19)
Mean predicted OCD rate, % 8

Overall, the 21 patients receiving the neoadjuvant treatment had 84 cycles of chemotherapy. One patient (who declined surgery) discontinued estramustine at home. During treatment there was no more toxicity than that expected from medical castration (Table 3), and no toxicity was noted during NHT alone. Five patients (24%) had at least one episode of toxicity during chemotherapy; overall, there were 10 episodes of grade 1 toxicity. Except for one grade 2 toxicity (candidiasis) requiring reduction of the estramustine dose, no other grade ≥2 haematological or non-haematological toxicity was noted. There was no vein thrombosis or toxicity requiring hospitalization.

Table 3.  The toxicity of the chemohormonal treatment
  • *

    ECOG scale [27].

Skin rash201000
Max. toxicity by grade164100

The mean PSA nadir after NHT was 1 ng/mL and all PSA values decreased by >90% from baseline levels after a mean time of NHT of 65 days. Two patients had a PSA nadir of >0.5 ng/mL. After chemotherapy all patients had a PSA level of ≤ 0.6 ng/mL (mean 0.17). The reduction from before to after chemotherapy was statistically significant (Wilcoxon test, P = 0.001). Based on protocol-defined criteria, three patients (14%) had a clinical CR and 17 (81%) a PR; the patient with sarcomatoid tumour had local progression after chemotherapy, despite a biochemical response; he had TURP only (pathology showed a Gleason 10 cancer), and died 5 months later from PD. The PSA recurrence-free survival was significantly different by Cox proportional-hazards regression estimates for the subgroups stratified based on the pathological response and seminal vesicle involvement (SVI, P = 0.001).

In all, 19 patients (91%) had RRP after completing systemic therapy (Table 4). There were no complications of the standard pelvic lymphadenectomy in all patients. Dissecting the prostate from the rectum was described as more difficult than for an average RRP in 32% of the patients, because of periprostatic fibrosis. No difficulties were reported in making the urethrovesical anastomosis. The median (range) operative duration and overall early surgical complication rate were similar to those in untreated patients with cT2 disease having RRP, and was 120 (90–150) min. The median estimated blood loss and median number of transfusions were slightly higher than usual (i.e. 700 mL and one, respectively). There were no major surgical complications. One patient required 2 units of blood for self-limiting haemorrhage after RRP. After discharge, one patient was re-admitted for an infected urinoma, which was treated with percutaneous drainage. The median time to catheter removal was 6 days and the median hospital stay was 7 days. Continence was reported in 18 patients, while one had persistent urinary incontinence with moderate exercise, requiring >2 pads/day.

Table 4.  Surgical data during and after RRP (19 patients)
VariableMedian (range) or n (%)
  • *

    From skin incision to skin closure;

  • †Within a month from surgery.

Operative duration, min*150 (120–180)
Estimated blood loss, mL800 (100–2000)
No. of transfused units  2 (0–4)
Hospital stay, days  9 (7–15)
Time to catheter removal, days  8 (6–14)
Overall early complication rate, n (%)  3 (16)

Of the 19 patients who had RRP the pathological organ-confined disease (OCD) rate was 58% (Fig. 1). The mean predicted likelihood of OCD in these patients, according to the Kattan nomogram, was 8%[31]. One (5%) patient had a pathological CR (pT0), and in six the residual tumour was confined to small foci, <10% of the prostate volume, and comprised single cells or small groups of tumour glands. The neoplastic cells showed prominent cytoplasmic vacuolization with monomorphic nuclei and smaller nucleoli. In 12 patients residual tumour involved >10% of the gland. In the patient who had pT0, all stained sections were carefully searched and the entire prostatic tissue was re-processed by an independent pathologist, to confirm the absence of tumour. No specimen from the 19 patients who had RRP showed necrosis.


Figure 1. The pathological outcome of 19 patients after chemohormonal neoadjuvant treatment and RRP. OC, OCD; Predicted rate of OCD (8%) is based on the standard model of Kattan nomogram [31].

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Among the eight patients with ECE (42%), five (26%) had PSMs, with SVI present in seven (37%) and four of these (21%) had microscopic nodal metastasis. Only one of these four patients with pN+ had enlarged nodes at CT before surgery, but he was considered eligible for surgery because his PSA level declined from 43.0 to 0.06 ng/mL. Comparing pathological and clinical stages, the downstaging rate was 42% (eight patients) and five (26%) had the disease stage increased. Neither the variables before RRP (age, baseline PSA level, PSA nadir and PSA after chemotherapy, percentage decrease in PSA after neoadjuvant treatment, biopsy Gleason sum, clinical stage and clinical response) nor biomarker expression were related to the pathological stage.

At a median (range) follow-up of 53 (30–64) months, eight patients (42%) remained disease-free, nine (47%) had biochemical recurrence and two (11%) had local recurrence. The estimate of PSA progression-free survival (DFS) is shown in Fig. 2. All patients were treated with LHRH analogues at the time of progression and those with measurable local recurrence also had pelvic radiotherapy. The mean (range) time to recurrence was 23 (6–40) months, with disease-free patients having a mean follow-up of 50 (41–55) months.


Figure 2. The cumulative PSA recurrence-free survival (Kaplan–Meier estimate) of 19 patients with high-risk prostate cancer treated with RRP after the neoadjuvant chemohormonal regimen.

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The DFS was related to organ confinement of the disease (P = 0.022), pathological response (P = 0.007) and absence of SVI (P = 0.001). There was no correlation between DFS and age, baseline PSA level, time to PSA nadir, PSA nadir value, PSA level after chemotherapy, clinical response, duration of hormonal therapy or response of biomarkers. The mean (95% CI) 5-year DFS probability at 53 months was 80 (46–100)% for those responding and 20 (0–44)% for those not responding. The pathological response and SVI were also used to stratify the DFS (Fig. 3).


Figure 3. The PSA recurrence-free survival (Cox proportional-hazards regression estimates) for subgroups stratified by pathological response and SVI was significantly different (P = 0.001). PR, cancer in ≤ 10% of the prostate specimen; LR, limited response, cancer in >10% of the prostate specimen; SVI present (+) or absent (−).

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  1. Top of page
  2. Abstract

Neoadjuvant treatment before surgery in high-risk patients is not new and many trials were proposed to decrease the local and systemic recurrence rate. The goal of the present phase II study was to evaluate the feasibility and activity of a neoadjuvant treatment regimen combining androgen deprivation with a taxane-based systemic chemotherapy, and to assess this with a long-term follow-up.

Clinical data [32] and preclinical evidence in animals [33,34] show that simultaneous is better then sequential chemohormonal therapy in reducing disease progression. Other phase I/II trials showed the feasibility of a treatment plan using a cytotoxic regimen, with or with no androgen deprivation, before RRP [19–25], with limited toxicity. There was significant haematological toxicity reported by Pettaway et al.[21] in 12% of 33 high-risk patients treated with ketoconazole and doxorubicin, alternating with vinblastine, estramustine and total androgen blockade (TAB) before RRP. Konety et al.[19] treated 36 high-risk patients with estramustine, paclitaxel, vinblastine and LHRH analogue, followed by RRP, reporting that 22% had subsequent deep vein thrombosis. In the present study toxicity was no higher than that expected from medical castration and 25% of patients had ECOG grade 1–2 toxicity. Only one patient (5%) required a lower dose of docetaxel.

There was a 95% clinical response rate and three patients (14%) had a clinical CR. The reduction in PSA level from before to after chemotherapy was also statistically significant (Wilcoxon test, P = 0.001) but it is impossible to define if this was due only to chemotherapy or to a late effect of prolonging hormonal treatment.

Only one patient, with a low baseline PSA level and a Gleason score 10 tumour with sarcomatoid differentiation, had PD during treatment. It is arguable whether it is appropriate to include a patient with a sarcomatoid tumour in such a trial. The patient expressed a strong wish to be involved in the trial and was enrolled after having extensive information about the possible disadvantages of treatment. The outcome for this patient suggests that these patients should be excluded from future phase III trials or, when included, to be considered at high risk of PD during the trial.

Hussain et al.[23], using the same definition of response for 21 patients treated with neoadjuvant docetaxel and estramustine, reported a 100% response rate, with 52% having a CR. That study included only 25% of patients with cT3 disease, compared to 86% in the present study, and their mean pretreatment PSA level was lower (33.2 ng/mL) than in the present study (61.0 ng/mL). Moreover, only 10 patients had RRP, with negative SMs in seven.

As reported in other NHT trials [20,21,25], and in the present experience, dissection of the prostate from the rectum was more difficult than in standard RRP, but there was no rectal injury. The median operative duration (120 min) was only slightly longer than usual. The minor complication rate after RRP was 16%, and there were no major complications.

To our knowledge, no previous neoadjuvant chemohormonal study before RRP has reported a pT0 outcome [20–23,25]. In the present trial, one patient (5%) was pT0, but this rate is in the range reported using NHT alone (0–9%) [6,9]. The observed 58% rate of OCD was significantly higher than the expected 8% rate based on the Kattan nomogram [31]. We think that this large difference is clinically meaningful. The downstaging rate was 42%, although we realise that, as in other trials of NHT, downstaging is hard to define [35]. Pathological OCD has been previously reported in 10–20% of patients with cT3 disease treated with RRP alone [35–37] and in 30–36% of those submitted to neoadjuvant chemohormonal treatment and RRP [19–21,23].

The PSM rate was 26% and the incidence of lymph node metastasis was 21%. All four patients with pN+ had a microscopic nodal involvement on pathological evaluation. Only one of these four patients had enlarged nodes at CT before surgery, but he was considered as eligible for surgery because his PSA level decreased from 43.0 to 0.06 ng/mL.

The present response rates are similar to those previously reported in large series of NHT [11,19–21,23] but were achieved in patients with higher pretreatment PSA levels and clinical stage. Our data might support the hypothesis that chemotherapy has direct activity on the primary tumour, adjunctive to the effect of hormonal treatment alone.

The present study has some limitations; several small trials using neoadjuvant chemotherapy before a curative treatment were reported previously; there can be no assessment of the correlation between tumour volume and biomarker expression before chemotherapy; when the trial was undertaken, the sextant scheme was the accepted biopsy strategy, and thus based on the available pretreatment sextant biopsy data, no reliable conclusion can be drawn on the tumour burden before treatment.

To overcome these limitations we chose a long-term follow-up that might support the pathological data in evaluating treatment activity. The 53-month median follow-up (Fig. 1) is longer than that in any other published phase II or III neoadjuvant chemotherapy trial [19–21,23].

After RRP all patients had an undetectable PSA level. Pummer et al.[37] previously reported an extended progression-free survival when treating 117 patients with metastatic and 28 with advanced prostate cancer with TAB and epirubicin vs TAB alone. In the present study the PSA progression-free survival at the 53-month median follow-up was 42%. Previously Konety et al.[19] reported a 45% PSA progression-free survival rate, but at a shorter 29-month median follow-up.

The mean time to recurrence was 23 (6–40) months, with disease-free patients having a mean follow-up of 50 (41–55) months. The patient with a CR (pT0) is still alive with no PSA progression at the 50-month follow-up. Seven (37%) of the 19 patients had residual cancer involving <10% of the surgical specimen and had an 80% DFS rate the 53-month follow-up, despite a mean baseline PSA level of 75 ng/mL.

Although it is very difficult to define risk groups for 19 patients, OCD, the percentage of residual cancer in the surgical specimen and absence of SVI correlated with PSA recurrence-free survival (Fig. 3). There was no correlation between DFS and baseline PSA level, time to PSA nadir, PSA nadir value, PSA level after chemotherapy, or the duration of NHT.

Patients with cancer in <10% of the prostate specimen had a better prognosis than those with cancer in >10% (P = 0.007). Furthermore, in the latter group the presence of SVI was a negative predictive variable (P = 0.001). The rationale for subdividing into > or <10% residual cancer in the surgical specimen relies on the observation that a tumour volume of >0.5 mL is an independent predictor of progression after RP [38] and that 10% of carcinoma in surgical sections is related to a tumour volume of 0.5 mL [39]. Therefore it can be assumed that <10% residual cancer in a surgical section identifies tumour of <0.5 mL. Our data also support the relevance of residual tumour volume within the prostate in treated patients.

Unlike in previous studies [40–43] there was no correlation between the biomarkers MIB1, erbB2, bcl2, p53 and factor VIII expression within the tumour and the patients’ clinical outcome.

No previous neoadjuvant short- or long-term trial of androgen withdrawal has reported similar follow-up data in the treatment of prostate cancer [44,45]. Although identifying a benefit in clinical outcome in an unrandomized phase II trial is difficult, the mean (95% CI) 5-year DFS probability at 53 months was 80 (46–100)% for patients with ≤ 10% residual cancer in the gland and 20 (0–44)% for those with >10%.

We think that there is a subset of patients with a higher sensitivity to combined chemohormonal taxane-based treatment, which is active against the primary tumour. Long-term follow-up data support the hypothesis that the observed degree of residual cancer it is not an artefact and relates to clinical outcome.

Future phase III trials must include a more extensive pretreatment biopsy sampling strategy to better evaluate baseline tumour volume and biomarker expression [46]. Adjunctive data will probably come from the Cancer and Leukaemia Group B 90203 trial [47], that will enrol ≈700 men during a 48-month period to determine if estramustine and docetaxel before RP is better than RP alone in treating men with high-risk, clinically localized adenocarcinoma of the prostate (stage T1–T3a, NXM0). Moreover, the combination with added radiation therapy or long-term systemic therapy might be explored in the future [48].

In conclusion, taxane-based neoadjuvant chemohormonal treatment before RRP is feasible and active against the primary tumour in patients with high-risk prostate cancer. The pathological OCD rate was higher than expected, based on the last version of the Kattan nomogram. A subgroup of seven (37%) of 19 patients who had ≤10% residual tumour in the RRP specimen had a promising 80% DFS at 5 years.


  1. Top of page
  2. Abstract
  • 1
    Partin AW, Yoo J, Carter HB et al. The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993; 150: 1104
  • 2
    Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281: 15917
  • 3
    Van den Ouden D, Hop WC, Schroder FH. Progression and survival of patients with locally advanced prostate cancer (T3) treated with radical prostatectomy as monotherapy. J Urol 1998; 160: 13927
  • 4
    D’Amico AV, Moul J, Carroll PR, Sun L, Lubeck D, Chen MH. Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol 2003; 21: 216372
  • 5
    Srigley JR, Amin M, Boccon-Gibod L et al. Prognostic and predictive factors in prostate cancer: historical perspectives and recent international consensus initiatives. Scand J Urol Nephrol Suppl 2005; 216: 819
  • 6
    Fair WR, Betancourt JE. Update on Memorial Sloan-Kettering Cancer Center studies of neoadjuvant hormonal therapy for prostate cancer. Mol Urol 2000; 4: 24150
  • 7
    Gleave M, Goldenberg S, Chin J et al. Randomized comparative study of 3 vs 8 months of neoadjuvant hormonal therapy prior to radical prostatectomy: 3 year PSA recurrence rates. J Urol 2003; 169: 690A
  • 8
    Klotz LH, Goldenberg SL, Jewett MA et al.; Canadian Uro-Oncology Group. Long-term followup of a randomized trial of 0 versus 3 months of neoadjuvant androgen ablation before radical prostatectomy. J Urol 2003; 170: 7914
  • 9
    Soloway MS, Sharifi R, Wajsman Z, McLeod D, Wood DP Jr, Puras-Baez A. Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer. The Lupron Depot Neoadjuvant Prostate Cancer Study Group. J Urol 1995; 154: 4248
  • 10
    Goldenberg SL, Klotz LH, Srigley J et al. Randomized, prospective, controlled study comparing radical prostatectomy alone and neoadjuvant androgen withdrawal in the treatment of localized prostate cancer. Canadian Urologic Oncology Group. J Urol 1996; 156: 8737
  • 11
    Aus G, Abrahamsson P, Ahlgren G et al. Hormonal treatment before radical prostatectomy: a 3-year follow-up. J Urol 1998; 159: 20137
  • 12
    Sokoloff MH, Rinker-Schaeffer CW, Chung LW, Brendler CB. Adjunctive therapy for men with high risk localized and locally advanced prostate cancer: targeting disseminated tumor cells. J Urol 2004; 172: 253944
  • 13
    Laing N, Dahllof B, Hartley-Asp B, Ranganathan S, Tew KD. Interaction of estramustine with tubulin isotypes. Biochemistry 1997; 36: 8718
  • 14
    Ranganathan S, Benetatos C, Colarusso P, Dexter DW, Hudes GR. Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells. Br J Cancer 1998; 77: 5626
  • 15
    Obasaju C, Hudes G. Paclitaxel and docetaxel in prostate cancer. Hematol Oncol Clin North Am 2001; 15: 52545
  • 16
    Picus J, Schultz M. Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 1999; 26 (Suppl. 17): 148
  • 17
    Savarese DM, Halabi S, Hars V et al. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B. J Clin Oncol 2001; 19: 250916
  • 18
    Petrylak DP, MacArthur R, O’Connor J et al. Phase I/II studies of docetaxel. (Taxotere) combined with estramustine in men with hormone-refractory prostate cancer. Semin Oncol 1999; 26 (Suppl. 17): 2833
  • 19
    Konety BR, Eastham JA, Reuter VE et al. Feasibility of radical prostatectomy after neoadjuvant chemohormonal therapy patients with high risk or locally advanced prostate cancer: results of a phase I/II study. J Urol 2004; 171: 70913
  • 20
    Clark PE, Peereboom DM, Dreicer R, Levin HS, Clark SB, Klein EA. Phase II trial of neoadjuvant estramustine and etoposide plus radical prostatectomy for locally advanced prostate cancer. Urology 2001; 57: 2815
  • 21
    Pettaway CA, Pisters LL, Troncoso P et al. Neoadjuvant chemotherapy and hormonal therapy followed by radical prostatectomy: feasibility and preliminary results. J Clin Oncol 2000; 18: 10507
  • 22
    Oh WK, George DJ, Kaufman DS et al. Neoadjuvant docetaxel followed by radical prostatectomy in patients with high-risk localized prostate cancer: a preliminary report. Semin Oncol 2001; 28 (Suppl. 15): 404
  • 23
    Hussain M, Smith DC, El-Rayes BF et al. Neoadjuvant docetaxel and extramustine chemotherapy in high-risk/locally advanced prostate cancer. Urology 2003; 61: 77480
  • 24
    Ko Y-L, Dewolf W, Olumi A, Sesterhern IA, Upton M, Bubley GJ. Neoadjuvant chemo-hormonal therapy followed by radical prostatectomy for high risk prostate cancer. Proceedings of ASCO 2002; 21: 162b, Abstract 2465
  • 25
    Dreicer R, Magi-Galluzzi C, Zhou M et al. Phase II trial of neoadjuvant docetaxel before radical prostatectomy for locally advanced prostate cancer. Urology 2004; 63: 113842
  • 26
    Fleming ID, Cooper JS, Henson DE et al. eds. AJCC. Cancer Staging Manual, 5th edn. Philadelphia: Lippincott Raven, 1998
  • 27
    Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of The Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 64955
  • 28
    DeVere White RW. Pelvic lymph node dissection. In GlenJ ed., Urologic Surgery, Chapt. 55. Philadelphia: Lippincot Co., 1991: 6114
  • 29
    Walsh PC. Anatomic radical retropubic prostatectomy. In WalshPC, RetikAB, VaughnED, WeinAJ eds, Cambell’s Urology, 7th edn. Philadelphia, PA: WB Saunders, 1998: 256588
  • 30
    Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 110
  • 31
    Ohori M, Kattan MW, Koh H et al. Predicting the presence and side of extracapsular extension: a nomogram for staging prostate cancer. J Urol 2004; 171: 18449
  • 32
    Eigl B, Eggener S, Baybik J et al. Timing is everything: preclinical evidence supporting simultaneous rather than sequential chemohormonal therapy for prostate cancer. Clin Cancer Res 2005; 11: 490511
  • 33
    Oudard S, Legrier ME, Boye K et al. Activity of docetaxel with or without estramustine phosphate versus mitoxantrone in androgen dependent and independent human prostate cancer xenografts. J Urol 2003; 169: 172934
  • 34
    Van Poppel H, Goethuys H, Callewaert P, Vanuytsel L, Van de Voorde W, Baert L. Radical prostatectomy can provide a cure for well-selected clinical stage T3 prostate cancer. Eur Urol 2000; 38: 3729
  • 35
    Lerner SE, Blute ML, Zincke H. Extended experience with radical prostatectomy for clinical stage T3 prostate cancer: outcome and contemporary morbidity. J Urol 1995; 154: 144752
  • 36
    Gerber GS, Thisted RA, Chodak GW et al. Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis. Eur Urol 1997; 32: 38590
  • 37
    Pummer K, Lehnert M, Stettner H, Hubmer G. Randomized comparison of total androgen blockade alone versus combined with weekly epirubicin in advanced prostate cancer. Eur Urol 1997; 32 (Suppl. 3): 815
  • 38
    Epstein JI, Carmichael M, Partin AW, Walsh PC. Is tumor volume an independent predictor of progression following radical prostatectomy? A multivariate analysis of 185 clinical stage B adenocarcinomas of the prostate with 5 years of follow-up. J Urol 1993; 149: 147881
  • 39
    Humphrey PA, Catalona WJ. Pathological features of prostatic carcinomas detected in a serum prostate specific antigen based screening program. Mod Pathol 1995; 8: 77A
  • 40
    Witjes WP, Schulman CC, Debruyne FM. Preliminary results of a prospective randomized study comparing radical prostatectomy associated with neoadjuvant hormonal combination therapy in T2–3, N0, M0 prostatic carcinoma. The European Study Group on Neoadjuvant Treatment of Prostate Cancer. Urology 1997; 49 (Suppl.): 6569
  • 41
    Bauer JJ, Sesterhenn I, Mostofi FK, McLeod DG, Srivastava S, Moul JW. Elevated levels of apoptosis regulator proteins p53 and bcl-2 are independent prognostic biomarkers in surgically treated clinically localized prostate cancer patients. J Urol 1996; 156: 15116
  • 42
    Grignon DJ, Caplan R, Sarkar FH et al. p53 status and prognosis of locally advanced prostatic adenocarcinoma: a study based on RTOG 8610. J Natl Cancer Inst 1997; 89: 15865
  • 43
    Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J. Tumor angiogenesis correlates with metastasis in invasive prostatic carcinoma. Am J Pathol 1993; 143: 4019
  • 44
    Beer TM, Garzotto M, Lowe BA et al. Phase I study of weekly mitoxantrone and docetaxel before prostatectomy in patients with high-risk localized prostate cancer. Clin Cancer Res 2004; 10: 130611
  • 45
    Febbo PG, Richie JP, George DJ et al. Neoadjuvant Docetaxel before radical prostatectomy in patients with high-risk localized prostate cancer. Clin Cancer Res 2005; 11: 523340
  • 46
    Gleave M, Kelly WK. High-risk localized cancer: a case for early chemotherapy. J Clin Oncol 2005; 23: 818691
  • 47
    Eastham JA, Kelly WK, Grossfeld GD, Small EJ; Cancer and Leukemia Group B. Cancer and Leukemia Group B (CALGB) 90203: a randomized phase 3 study of radical prostatectomy alone versus estramustine and docetaxel before radical prostatectomy for patients with high-risk localized disease. Urology 2003; 62 (Suppl. 1): 5562
  • 48
    Wang J, Halford S, Rigg A, Roylance R, Lynch M, Waxman J. Adjuvant mitozantrone chemotherapy in advanced prostate cancer. BJU Intl 2000; 86: 67580