eMedicine Specialties > Urology > Cancer, Prostate

Prostate Cancer - Neoadjuvant Androgen Deprivation Therapy

Author: Vipul R Patel, MD, Consulting Surgeon, Global Robotics Institute, Florida Hospital Celebration Health
Coauthor(s): Raymond J Leveillee, MD, FRCS(Glasg), Professor of Clinical Urology, Radiology and Biomedical Engineering, Department of Urology, University of Miami Miller School of Medicine; Chief, Division of Endourology/Laparoscopy and Minimally Invasive Surgery, Department of Urology, Jackson Memorial Hospital; Asha D Shah, MD, Staff Physician, Department of Surgery, Division of Urology, The Ohio State University Medical Center; Rafael Ferreira Coelho, MD, Fellow, Department of Urology, Global Robotics Institute, Florida Hospital Celebration Health, Celebration, Florida; Department of Urology, University of Sao Paulo, Sao Paulo, Brazil
Contributor Information and Disclosures

Updated: Jun 29, 2009

Introduction

Over the last 20 years, public awareness of prostate cancer prevention, detection, and treatment has increased. The combined use of improved diagnostic modalities, such as prostate-specific antigen (PSA) score, digital rectal examination (DRE), and transrectal ultrasound (TRUS)–guided prostate biopsy, has contributed to a rapid rise in prostate cancer detection. Increased detection has changed the age and stage distribution of the disease, dramatically increasing the diagnosis of clinically localized and potentially curable prostate cancer. Most institutions report a shift in clinical stage from locally advanced (T3) to clinically organ–confined (T1-T2) tumors that are more amenable to curative treatment.

Despite the apparent survival advantage of early diagnosis conferred by PSA screening, a recent U.S. Preventive Services Task Force statement recommends against screening for prostate cancer in men aged 75 years or older. The statement also concludes that, currently, the balance of benefits versus drawbacks of prostate cancer screening in men younger than age 75 years cannot be assessed because of insufficient evidence.¹

The optimal treatment of clinically localized prostate cancer remains a matter of debate. In patients with organ-confined disease, radical prostatectomy (RP) provides an excellent chance of cure. However, the high incidence of clinical understaging due to the lack of sensitivity of currently available staging modalities has tempered the enthusiasm for surgery. Although the serum PSA level generally reflects tumor volume, it is not a reliable marker for tumor staging. Free PSA, PSA density, and ploidy status are also imperfect markers. DRE findings often underestimate the extent of tumor. The results from TRUS, CT scanning, and endorectal MRI have been disappointing.

Even among nonpalpable tumors (T1c) treated with RP, the incidence rate of capsular penetration ranges from 40%-50%, while the incidence rate of positive margins remains 5%-40%. A positive margin upon pathologic examination signifies the possibility of tumor extension beyond the boundaries of surgical resection and has been demonstrated to adversely affect disease-free survival. Paulson (1994) reported that 10% of patients with negative margins died of malignancy within 13.5 years after surgery, compared with 40% of those with positive surgical margins.² Therefore, the presence of a positive margin upon pathologic examination is an unfavorable prognostic indicator, and many men undergoing RP for clinically localized disease may have an unfavorable pathologic outcome.

The Partin tables are the best nomogram for predicting prostate cancer spread and prognosis.

For excellent patient education resources, visit eMedicine's Prostate Health Center and Cancer and Tumors Center. Also, see eMedicine's patient education article Prostate Cancer.

Neoadjuvant Androgen Deprivation

The high incidence of extracapsular penetration and positive margins following RP in patients with clinically localized prostate cancer is a cause for concern. Therefore, the higher risk of progression associated with these findings has led to efforts to improve preoperative staging and to find ways to facilitate complete tumor excision. Neoadjuvant androgen deprivation (NAD) has been proposed as a method to help down-stage clinically localized or locally advanced prostate carcinoma, with the hope of improving survival. Androgen deprivation induces programmed cell death (apoptosis) and inhibits cell proliferation in malignant prostate tissue.

In 1941, the initial pioneers, Huggins and Hodges, won the Nobel Prize for first demonstrating the effect of androgen withdrawal on benign and malignant prostate tissue.³ The role of androgen deprivation is now well established in the management of advanced prostatic carcinoma; however, its role preoperatively remains controversial. NAD is a systemic therapy administered after the diagnosis of cancer but prior to locoregional therapy such as RP or radiation.

The concept is not new; it was introduced more than a half a century ago by Vallet et al. Subsequently, others have studied this concept in more depth with the hope that NAD may pathologically down-stage the tumor by shrinking the cancer, increasing organ confinement, and decreasing the incidence of positive margins. Neoadjuvant therapy has also been theorized to treat occult regional and systemic micrometastasis, with the ultimate goal being improved long-term, disease-free survival.

In current practice, with the advent of safe and reversible forms of androgen deprivation such as luteinizing hormone-releasing hormone (LHRH) analogues and antiandrogens (AAs), a resurgence in enthusiasm for NAD therapy has occurred. LHRH agonists exert their effects by initial stimulation of the production of luteinizing hormone (LH) at the pituitary, followed by suppression of LH and testosterone to castration levels after approximately 2 weeks. AAs counteract the effects of adrenal androgen at the target cell by interfering with binding at the receptor in a competitive manner. Together, these agents provide powerful androgen blockade (see Table 1).

Table 1. Agents of NAD Therapy

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*Liver function tests
† Deep venous thrombosis

Medication

The goals of pharmacotherapy are to induce remission, to reduce morbidity, and to prevent complications.

Androgen deprivation agents

These are androgen antagonists used to induce tumor regression.

Leuprolide (Lupron, Viadur, Eligard)

LHRH agonists. Initial stimulation of LHRH production (flare) followed by depletion of LHRH production. Results in castrate levels of testosterone and LH.

Triptorelin pamoate (Trelstar Depot)

Decreases LH and FSH secretion when administered long-term, which causes a subsequent decrease in testosterone and estrogen levels.

Histrelin (Vantas)

LHRH agonist. Causes initial stimulation of LHRH production (flare) followed by depletion of LHRH production. Results in castrate levels of testosterone and LH. Decrease in testosterone levels is observed within 2-4 wk following initiation of treatment. Implant can provide continuous subcutaneous release of histrelin at nominal rate of 50-60 mcg/d over 12 mo.

Goserelin (Zoladex)

LHRH agonists. Initial stimulation of LHRH production (flare) followed by depletion of LHRH production. Results in castrate levels of testosterone and LH.

Flutamide (Eulexin)

Nonsteroidal AA. Direct blockade of androgen receptor. Maintains serum testosterone, libido, and potency.

Nilutamide (Nilandron)

Nonsteroidal AA. Direct blockade of androgen receptor. Maintains serum testosterone levels.

Bicalutamide (Casodex)

Nonsteroidal AA. Maintains serum testosterone levels.

Cyproterone (Androcur, Cyproterone)

Steroidal AA. Progestational activity inhibits LH release. Also blocks androgen receptor. Prevents flare and hot flashes, and lowers testosterone. Not available in United States.

Abarelix (Plenaxis)

Synthetic decapeptide with potent antagonistic activity against naturally occurring GnRHs. Competitively blocks GnRH receptors in pituitary gland. Antagonistic effect suppresses LH and FSH hormones, causing serum testosterone level to decrease, which in turn slows prostate cancer growth. Indicated for advanced prostate cancer in men who cannot take other hormone therapies and who either refuse surgery or are not surgical candidates.

Diethylstilbestrol (Stilphostrol)

Used in advanced prostatic carcinoma. Decreases secretion of LH by inhibiting hypothalamic-pituitary axis. Castrate levels of testosterone may decrease tumor growth.

Rationale for Neoadjuvant Androgen Deprivation Therapy

RP is most likely to cure patients with organ-confined disease. However, owing to the inaccuracy of clinical staging, approximately 50% of men with clinical stage T1 or T2 prostate cancer have tumor extension outside of the prostate capsule, and 5%-40% have positive margins. Approximately 20%-30% of these men with one or more positive margins experience relapse, depending on the site of the positive margin, preoperative PSA level, Gleason score, and presence of seminal vesical invasion. The rationale for the use of neoadjuvant androgen deprivation (NAD) prior to RP is to eradicate malignant androgen-dependent cells in the hope that sufficient tumor regression will permit complete resection of residual prostate cancer, improving pathologic outcome and survival.

Selection of candidates for neoadjuvant androgen therapy

High-risk patients (ie, those with a high T classification, Gleason score, or PSA level) with localized prostate carcinoma are likely to benefit most from effective neoadjuvant therapy. However, heterogeneous definitions of high-risk disease render trial-to-trial comparisons difficult.

The use of preoperative nomograms that incorporate clinical T classification, serum PSA level, and biopsy Gleason grade can enhance prediction of the risk of PSA recurrence and selection of a relatively homogeneous population. The percentage of cancer in biopsy cores and the number of positive biopsy cores, as well as the incorporation of biomarkers (serum interleukin 6 [IL-6]–soluble receptor and transforming growth factor beta-1), may further improve its predictive accuracy. Although a relatively high threshold of PSA recurrence to determine eligibility is reasonable, it may negatively affect accrual. In addition, investigators may determine that radiotherapy instead of prostatectomy is the optimal treatment in such high-risk patients. Conversely, setting a lower threshold of recurrence may result in unnecessary treatment, a reduction in the event rate, and an increase in the number of patients required.

It may be reasonable to hypothesize that patients with a relatively high risk of recurrence may be optimal candidates for cytotoxic chemotherapy, whereas those with a lower risk of recurrence may be optimal candidates for more tolerable biologic agents and immunotherapy.

Clinical Trials

Nonrandomized trials (stage T1-T3)

Many nonrandomized trials of neoadjuvant androgen deprivation (NAD) therapy have been conducted on patients with clinical stage T1-T3 disease. Fair et al (1993) reported a nonrandomized study of 3 months of NAD therapy in 69 patients with T1-T3 prostate cancer, using 72 stage-matched controls.⁴ Androgen deprivation consisted of 3 months of an LHRH agonist and flutamide. A pathologic organ-confined rate of 74% was observed in the treatment arm, compared with 48% in the nonpretreated group. The margin-positive rate was 10% in the NAD group versus 33% in patients without induction of androgen deprivation. The PSA disease-free rate at a mean follow-up of 28.6 months was 89% in pretreated patients and 84% in controls. No significant difference occurred with respect to biochemical failure.

Meyer et al (1999) from Laval University in Quebec, Canada, published their report of 38 months of follow-up of 680 patients, 292 of whom received NAD prior to radical retropubic prostatectomy.⁵ Surgical margins were positive less often in the NAD group (25%) than in the prostatectomy-alone group (47%). PSA failure (>0.3 ng/mL) was observed in 163 patients, and the 5-year failure rate was 33%. Patients treated with neoadjuvant hormonal therapy had significantly lower hemoglobin and hematocrit levels before surgery and, therefore, required blood transfusion more often. No difference in risk of PSA failure was observed overall between the hormonal therapy and prostatectomy groups. However, patients receiving combined therapy for more than 3 months had a significantly lower risk of PSA failure than those treated with RP alone, suggesting a possible benefit in terms of disease-free survival.

The University of Miami conducted one of the largest nonrandomized retrospective reviews. Of 546 consecutive patients undergoing RP, 135 received NAD for a median duration of 3 months prior to surgery. In an effort to create 2 comparable groups among those who did and did not receive NAD therapy, only patients with a PSA value greater than 10 ng/mL and/or biopsy Gleason score greater than 7 and/or stage greater than cT2b were included in the analysis.

The impact of NAD on pathological outcome and disease recurrence was assessed for a mean follow-up of 26 months. Patients with NAD were found to be less likely to have positive margins (28% vs 38%, P = .10). However, the incidence of extracapsular extension, seminal vesicle invasion, and lymph node metastasis was not different between the 2 groups. The recurrence rate was 17% in nontreated patients and 25% in NAD-treated patients (P = .07). Even though a decrease in the incidence of positive surgical margins was observed, the difference did not translate into improved disease-free survival at 26 months of follow-up.

In 2009, Gao et al conducted a retrospective study evaluating 31 patients with local prostate carcinoma who underwent RP.⁶ Of these patients, 12 underwent preoperative hormonal deprivation with a combination of goserelin and flutamide for 5.6 months. A total of 31 patients received pelvic lymph node clearance, and the rate of positive lymph nodes was 12.9% (4 of 31 patients). Serum PSA values were 8.9 ± 1.2 mg/L after neoadjuvant therapy and 0.4 ± 0.3 mg/L one month after RP. The incidence of positive surgical margins, seminal vesicle invasion, and lymph node metastasis was lower in the neoadjuvant therapy group (n = 12) than in the RP group (n = 19, P <0.01).

Table 2. Nonrandomized Trials of NAD Therapy

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*Total androgen blockade
†Diethylstilbestrol

Randomized clinical trials

Labrie et al published the first prospective randomized trial in 1993.¹⁷ One hundred sixty-one men with stage B0-C2 cancer were randomized to surgery alone or 3 months of NAD (LHRH and flutamide) therapy followed by RP. They reported significant clinical and pathologic down-staging and a decreased incidence of positive margins, seminal vesicle invasion, and lymph node metastasis in the NAD group. No follow-up was reported (see Table 3).

Table 3. Randomized Clinical Trials of NAD Therapy

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Soloway et al conducted a randomized multicenter T2bN0M0 trial (1995). Three hundred and three patients were enrolled in the study and randomized to RP plus NAD with an LHRH agonist and flutamide (149 patients) or surgery alone. Patients who received androgen deprivation preoperatively had a significantly lower rate of capsule penetration (47% vs 78%, P <.001), positive surgical margins (18% vs 48%, P <.001), and tumor at the urethral margin (6% vs 17%, P <.01). Androgen deprivation did not affect seminal vesicle invasion or lymph node metastasis. Prostate volume decreased by 30%, and the PSA level decreased to less that 1 ng/mL in 88% of patients and to less than 2 ng/mL overall. Upon pathologic examination, no evidence of tumor (pT0) was found in 6 (4%) patients treated with NAD. At 42 months of follow-up, no significant difference in recurrence (25%) was noted between the 2 groups.¹⁹

In 1996, the Canadian Urologic Oncology Group (CUOG) published the results of a randomized study on 213 patients, of whom 112 were treated with 12 weeks of cyproterone acetate at 300 mg/d prior to surgical therapy. Both groups were well balanced at baseline in terms of demographics, clinical stage, Gleason score, PSA value, and prostate size. The volume of the prostate gland determined by TRUS findings decreased by 20%. The incidence of positive margins was also decreased in the NAD-treated group (27.7% vs 64.8%). No tumors were down-staged to pT0. Goldenberg et al concluded that NAD therapy significantly decreased the incidence of positive margins; however, at 36 months of follow-up, no difference was noted in the biochemical recurrence rate.²⁰

In 1997, Witjes et al (European Study Group on Neoadjuvant Treatment of Prostate Cancer) published a large randomized trial that included 354 patients, of whom 164 were treated with NAD (goserelin acetate plus flutamide) for 3 months. Serum PSA levels decreased by more than 90% in the NAD-pretreated group. Pathologic down-staging was observed in 16% of the NAD group and 6% in the surgery-alone group (P <.001). In patients with clinical T2 tumors, a significant difference in positive margins was demonstrated in favor of patients receiving neoadjuvant therapy. In patients with clinical T3 tumors, no significant difference in margin status occurred. At 15 months of follow-up of 215 patients, the progression-free survival rate did not differ between the 2 groups. Researchers concluded that neoadjuvant therapy was investigational and not advised outside of randomized clinical trials.²²

In 2004, Prezioso et al randomized 167 patients with localized prostate cancer to receive either (1) leuprolide acetate depot 3.75 mg once a month for 3 months and cyproterone acetate 300 mg once a week for 3 weeks prior to surgery (group A) or (2) no pretreatment before surgery (group B). In group A, tumor/prostate volume was reduced in 31% of patients following hormone therapy, and PSA and testosterone levels were significantly reduced (P = 0.0001) compared to basal values. Positive surgical margins (60% vs 39%) and lymph node involvement (11% vs 3%) were more common in group B than in group A.²⁴

In 2007, Gravina et al conducted a randomized, prospective, controlled, intention-to-treat study to determine the usefulness of bicalutamide as a neoadjuvant hormonal therapy regimen to surgery in reducing positive surgical margins and modulating epidermal growth factor receptor (EGFR) members in men with prostate cancer.²⁵

• They evaluated 119 patients with prostate cancer, clinical stage T2-T3a. Of the 119 men, 61 were assigned to receive bicalutamide 150 mg/day for 120 days before RP and 58 to RP alone. Patients treated with bicalutamide had a 3.5-fold increase in negative surgical margins (odds ratio [OR] 3.5; 95% confidence interval [CI], 1.4-8.74; P = 0.011). In particular, in stage pT3a tumors, bicalutamide treatment was associated with a 5-fold increase in negative surgical margins (OR 5.4; 95% CI, 1.9-15.5; P = 0.002). In those with stage pT2, no difference for this surgical outcome was noted.
• Immunohistochemical analysis revealed that bicalutamide increased EGFR levels 2.8-fold (OR 2.8; 95% CI, 1.3-6.2; P = 0.014) and of 2.7-fold Her2/neu (OR 2.7; 95% CI, 1.2-5.8; P = 0.022). The up-regulation of Her2/neu and EGFR and their phosphorylated forms was an early event after bicalutamide treatment.

Systematic Review and Meta-analysis

Kumar et al (2006) conducted a systematic review and a meta-analysis of neoadjuvant hormone therapy in localized or locally advanced prostate cancer (Cochrane review, prepared and maintained by The Cochrane Collaboration). The authors searched MEDLINE (1966-2006), EMBASE, The Cochrane Library, Science Citation Index, LILACS, and SIGLE for relevant randomized trials. Randomized or quasi-randomized controlled trials of patients with localized or locally advanced prostate cancer (stages T1 to T4, any N, M0), comparing neoadjuvant hormonal deprivation in combination with RP versus RP alone were included in the review. Comparable data were pooled together for meta-analysis with intention-to treat principle.²⁶

The meta-analysis showed a significant reduction in the positive surgical margin rate (OR 0.34; 95% CI, 0.27-0.42; P <0.00001) and a significant improvement in other pathological variables such as lymph node involvement, pathological staging, and organ-confined rates with neoadjuvant hormonal therapy prior to prostatectomy. There was a borderline significant reduction of disease recurrence rates (OR 0.74; 95% CI, 0.55-1.0; P = 0.05). Although these latter outcomes were of secondary importance to overall survival, the significant benefit achieved with these pathological variables suggests that neoadjuvant therapy may be useful in attaining local control in nonmetastatic prostate cancer. However, this systematic review did not show any improvement in overall survival with neoadjuvant hormonal therapy prior to prostatectomy (pooled OR 1.11; 95% CI, 0.67-1.85; P = 0.69).

Three studies provided information on overall survival. With a 4-year follow-up period, Schulman et al (2000) reported no difference in the overall survival rates comparing neoadjuvant hormonal therapy plus RP to RP alone (93% vs. 95% of patients alive in the treatment and control groups, respectively; P = 0.64).²⁷ Similarly, Klotz et al (2003) reported no difference in overall survival rates after RP preceded or not by hormonal therapy (88.4% vs 93.9% of patients alive in the treatment and control groups, respectively; P = 0.38).²⁸ Finally, Aus et al (2002) evaluated 126 patients (randomized to receive neoadjuvant hormonal therapy or not) and found no significant difference in the overall survival rates after 7 years of follow-up (P = 0.513).²⁹ These three studies showed that neoadjuvant hormone therapy before prostatectomy does not provide a significant survival advantage over prostatectomy alone.

Five studies that analyzed disease-free survival (defined by either biochemical or clinical progression) were included in the meta-analysis. The follow-up period varied from approximately 6 months²⁴ to 7 years²⁹ .

• The study with the longest follow-up, conducted by Aus et al (2002), showed no significant difference in PSA progression-free survival rates (49.8% in the neoadjuvant arm and 51.5% in the prostatectomy arm; P = 0.588).²⁹
• Similarly, Klotz et al (2003) showed no difference in 5-year biochemical free survival between the treatment arms (60.2% and 68.2%, respectively, for the hormonal and surgery only arms; P = 0.73).²⁸
• In another study, Soloway et al (2002) recruited patients with clinical stage T2 and also reported a 5-year biochemical-free survival that did not differ significantly between the treatment arms (64.8% for the hormonal arm vs 67.6% for the surgery only arm; P = 0.663).¹⁶
• Likewise, Schulman et al (2000) evaluated the 4-year PSA progression rate of patients with T2 to T3,NO,MO disease and showed no difference in disease-free survival (26% vs 33%, respectively; P = 0.18).²⁷
• Finally, Prezioso et al (2004) also evaluated the effect of neoadjuvant hormone therapy on pathological variables and PSA relapse. However, the median follow-up period was less than 7 months, and the data were considered too immature to be analyzed (90% in the treatment group vs 84% in the surgery group; no P value given).²⁴

None of the above studies showed a statistical significant difference in disease-free survival between the neoadjuvant hormone therapy and control (surgery only) arms.

Pathologic Changes of Neoadjuvant Androgen Deprivation

Androgen deprivation therapy (ADT) produces distinct histopathologic changes in both neoplastic and nonneoplastic prostate tissue. A pathologist not familiar with these alterations may misinterpret the specimen, resulting in inappropriate tumor grading or missed tumor foci; thus, the urologist should convey to the pathologist any information regarding therapy that might cause histopathologic changes.

Civantos et al published the largest series in 1995. They reviewed a series of 173 patients who were treated with an LHRH analogue and an AA prior to RP. Atrophy was observed in both benign and malignant tissue. Examination of noncancerous tissue revealed atrophy of secretory cells, with cytoplasmic clearing and vacuolization. Atrophy and disappearance of luminal cells resulted in basal cell prominence. Morphologic alterations induced by treatment were patchy; the entire neoplastic tissue was affected in only 57% of the specimens. The poorly differentiated areas of tumors were affected less frequently.³⁰

Three types of changes in neoplastic tissue were reported. In the most common pattern (90%), the size of the neoplastic glands was reduced. An increase in stroma with a resultant relative decrease in gland density accompanied the size reduction.

Branching empty spaces lined by a few remaining cancer cells with pyknotic nuclei and foamy vacuolated cytoplasm characterized the second pattern (20%). The third pattern (10%) consisted of large, clear, or vacuolated tumor cells within an inflammatory background. The incidence of high-grade prostatic intraepithelial neoplasia was less common in the prostate specimens from patients treated with neoadjuvant therapy.

Pathologic implications of neoadjuvant androgen deprivation therapy

With regard to surgical margins, clinical trials have demonstrated that neoadjuvant androgen deprivation (NAD) significantly reduces the rate of positive margins (overall OR 0.34; 95% CI, 0.27-0.42; P < 0.00001) owing to either tumor regression or the improved ability to resect the prostate with wider surgical margins. The interpretation of margin status on RP specimens after NAD has been the source of much debate. However, with the use of consistent step-sectioning and special stains, the authors believe that an experienced uropathologist can differentiate a true positive margin accurately. The effectiveness of NAD in reducing positive surgical margins depends on clinical tumor stage and the biopsy Gleason score. NAD has been demonstrated to decrease positive margins significantly in clinical stage T1 and T2 prostate cancer. Men with cT3 disease or Gleason score greater than 7 have a less dramatic reduction in positive margins, implying that higher-grade tumors may be less responsive to ADT.

Treatment with neoadjuvant hormones was shown to substantially improve local pathological variables such as organ-confined rates (overall OR 2.30; 95% CI, 1.72-3.08; P < 0.00001), pathological down-staging (overall OR 2.42; 95% CI, 1.50-3.90; P = 0.0003), and rate of lymph node involvement (overall OR 0.63; 95% CI, 0.42-0.93; P = 0.02).

With regard to seminal vesical invasion, one study reported a decrease in seminal vesicle invasion rate with neoadjuvant therapy,¹⁶ whereas another study showed no difference.²⁸

Two of the Gleason criteria are altered by neoadjuvant therapy. A decrease in gland size and an increase in stroma between glands occur. These findings can lead to a false upgrade of the Gleason score. The use of a modified Gleason system has been proposed to evaluate prostatectomy specimens from patients who have received NAD; some physicians have suggested that no Gleason score should be allocated.

Surgical Implications of Neoadjuvant Therapy

Neoadjuvant androgen deprivation (NAD) has been demonstrated to decrease prostate volume by 20%-50%. The initial hope was that shrinking the gland would make RP technically easier, with less blood loss. The findings have been inconsistent.

In the multicenter randomized T2bN0M0 trial, the surgeons rated the difficulty of dissection, presence of seminal vesicle adherence, and extent of blood loss. They also recorded the operating time and amount of blood transfused. Seminal vesicle adherence to the periprostatic tissues was more common in patients pretreated with NAD (37%) compared with those treated with surgery alone (21%). Surgical dissection was more difficult in pretreated patients. No significant difference in operating time, blood loss, or transfusion requirement occurred. Although more dissections that were difficult were reported with NAD therapy, no operative complications occurred in the NAD-treated group, whereas 6 intraoperative injuries were reported in patients undergoing surgery alone.

In cases of patients with large prostates, NAD therapy may facilitate resection by reducing prostate volume, creating more space for the surgeon to operate. However, in patients with smaller prostates, NAD may have a less-desirable effect by allowing the prostate to recede farther under the pubic bone, complicating exposure during the apical dissection. The periprostatic fibrous reaction is variable and may increase the difficulty of surgery, particularly at the apex and seminal vesicles. The authors believe that apical dissection is potentially the most difficult problem caused by NAD. Of serious concern is the fact that NAD-induced fibrosis can make intraoperative evaluation of the extent of the tumor more difficult, which can possibly compromise the extent of resection if the surgeon relies on intraoperative findings to determine performance of a nerve-sparing operation.

Duration of neoadjuvant androgen deprivation treatment

The optimal duration of NAD prior to RP is unknown. Most trials have arbitrarily used 3 months of therapy. However, some evidence indicates that a longer duration of neoadjuvant therapy prior to RP could provide greater surgical downstaging.

Gleave et al (2001) showed a significant improvement with 8-month neoadjuvant therapy over 3 months. They attribute the initial dramatic fall in PSA values caused by androgen ablation to the cessation of androgen-regulated PSA gene expression, whereas a continuing gradual decline represents the actual decrease in tumor volume. They treated patients for 8 months. The mean PSA level decreased 84% after 1 month, and a further decrease of 52% was observed from 3-8 months. Twenty-two percent of patients reached their PSA nadir at 3 months and 84% after 8 months. Therefore, these authors advocate 8 months as the optimal duration of treatment.³¹

Two other studies have compared 3 versus 6 months of neoadjuvant therapy, showing a trend toward an improvement in positive surgical margin rates with 6-month therapy.^32,33 A meta-analysis of these 3 comparative studies showed a significant improvement in the positive surgical margin rates in favor of the longer treatment duration (6 or 8 months).²⁶

In contrast, Pu et al (2007) compared the effect of 3- versus 8-month neoadjuvant hormonal therapy on laparoscopic RP and showed similar positive margin rates between the two groups. They evaluated 55 patients with clinically localized prostate cancer treated with 3-month neoadjuvant hormonal therapy (25 patients [group 1]), 8-month neoadjuvant hormonal therapy (19 patients [group 2]), or nonneoadjuvant therapy (11 patients [group 3]) before laparoscopic RP. Positive surgical margin was demonstrated in 3 (12%), 2 (10.5%), and 5 (45.5%) patients in the 3 groups, respectively.

There was no significant difference in the positive margin rates between groups 1 and 2 (P >0.05); however, the positive margin rate was significantly lower in the 3- or 8-month neoadjuvant hormonal therapy groups than in the nonadjuvant group (group 3) (P = 0.032, respectively). There were no significant differences in the 3 groups with respect to mean operative time, mean blood loss, transfusion rate, operative difficulty, catheterization time, hospital time, and complication rate (P >0.05, respectively). The mean prostate volume was significantly smaller after 8-month than 3-month neoadjuvant hormonal therapy in group 2 (P <0.05). The mean serum PSA level decreased 97.8% in group 1 and 98.1% in group 2 after 3-month neoadjuvant hormonal therapy. A further 72.9% PSA value decrease was determined after 8-month neoadjuvant hormonal therapy in group 2.³⁴

Disadvantages of neoadjuvant androgen deprivation prior to RP

• Clinical trials have not demonstrated unequivocal improvement in disease-free survival rates.
• NAD has an unknown therapeutic effect on microscopic local or metastatic disease.
• Poorly differentiated areas of tumor are altered minimally.
• Tumor is rarely completely eradicated (pT0).
• Risk of androgen-independent clonal proliferation exists with prolonged NAD therapy.
• Compromising the evaluation of extent of the tumor at surgical resection is possible.
• Pathologic interpretation may be obscured.
• Increased difficulty occurs at surgery due to periprostatic fibrosis.
• Cost of therapy is a disadvantage.
• Adverse effects are a potential disadvantage.
• Treatment of the tumor is delayed.
• Chance of blood transfusion during surgery is increased.

Advantages of neoadjuvant androgen deprivation prior to RP

• Rate of positive margins is reduced.
• Organ-confined disease is increased.
• Serum PSA level is reduced.
• Prostate size is reduced.

Neoadjuvant Combination Hormone Therapy and Chemotherapy

No data have emerged that definitively support the use of neoadjuvant chemo-hormonal therapy. Some studies have shown declines in tumor volume and have provided evidence of feasibility, reinforcing the need for new agents to treat prostatic carcinoma.

Optimal sequencing of chemotherapy and hormone therapy for prostatic carcinoma is unclear. Pettaway et al (2000) recruited 33 high-risk patients in a phase II trial and administered 12 weeks of ketoconazole plus doxorubicin alternating with vinblastine, estramustine, and combination androgen deprivation therapy (ADT) followed by prostatectomy. Manageable postoperative complications occurred in 33% of patients. Of 30 patients, 33% had organ-confined disease, 70% had extraprostatic extension, 37% had positive lymph nodes, and 17% exhibited positive surgical margins. All patients achieved an undetectable PSA value postoperatively, and 20 of 29 patients were free of recurrence after a median follow-up of 13 months.³⁵

Konety et al (2004) reported similar results in a study of 36 patients who received 4 cycles of paclitaxel, carboplatin, and estramustine plus goserelin acetate before RP. Clinical stage was reduced in 39% of patients. DVT occurred in 22% of patients. The positive margin rate was 22%, and 45% of the patients remained free from PSA recurrence after a median follow-up of 29 months.³⁶

In 2007, Prayer-Galetti et al evaluated 22 patients with high-risk prostate cancer who underwent neoadjuvant treatment combining a LHRH analogue, estramustine, and docetaxel before undergoing radical retropubic prostatectomy. The neoadjuvant treatment was well tolerated, with only one case of grade 2 toxicity (Eastern Cooperative Oncology Group grading). After chemotherapy, all patients had a PSA level of 0.6 ng/mL or less (mean, 0.17 ng/mL), and the reduction from before to after chemotherapy was statistically significant (Wilcoxon test; P = 0.001). Three patients (14%) had a clinical complete response and 17 (81%) a partial response; one patient with sarcomatoid tumor had local progression after chemotherapy.

Of the 19 patients who underwent radical retropubic prostatectomy, the pathological organ-confined disease rate was 58%. The mean predicted likelihood of organ-confined disease in these patients, according to the Kattan nomogram, was 8%. One (5%) patient had a pathological complete response (pT0), and, in 6 patients, the residual tumor was confined to small foci (<10% of the prostate volume) and comprised single cells or small groups of tumor glands. Comparing pathological and clinical stages, the downstaging rate was 42% (8 patients). Five patients (26%) had positive surgical margins, and 4 (21%) had positive lymph nodes. At a median (range) follow-up of 53 months (range, 30–64 mo), 8 patients (42%) remained disease-free, 9 (47%) had biochemical recurrence, and 2 (11%) had local recurrence.³⁷

Likewise, Sella et al published a trial of neoadjuvant chemohormonal therapy and RP in patients with poor-prognosis localized prostate cancer (PSA level ≥20 ng/mL, Gleason score ≥8, clinical stage ≥T2c).

Viable disease was detected in all patients. The pathologic organ-confined disease rate was 63.6% (14 patients). The specimen-confined disease rate was 72.7% (16 patients). In 9 (40.9%), the tumor involved the seminal vesicles. In 4 (18.1%), the disease disseminated to the pelvic nodes, and, in 9 (40%), the tumor invaded the perineural area. At a median follow-up of 23.6 months (range, 12.1-54.7 mo), 10 patients (45.4%) relapsed. The surgical specimens in relapse cases revealed positive surgical margins in 5 (50%), capsular invasion in 6 (60%), and both in 8 (80%). No correlation was found between nerve sparing (one or two nerves) or specimen/organ-confined status and relapse, showing that a neoadjuvant chemohormonal approach with nerve-preservation surgery is feasible in patients with poor-prognosis localized prostate cancer.³⁸

Recently, Chi et al (CUOG) conducted a phase II multicenter study of newly diagnosed patients with untreated clinically localized prostate cancer and high-risk features. Seventy-two patients received ADT (6.3 mg buserelin acetate every 8 wk for 3 doses and AA for 4 wk) with docetaxel (at 35 mg/m² intravenously, weekly for 6 consecutive weeks followed by a 2-week rest for 3 cycles). Four patients discontinued therapy because of toxicity, 2 because of severe hypersensitivity reactions and 2 because of pneumonitis (grades 3 and 4). Two patients (3%) had a pathologic complete response, and 18 patients (28%) had 5% tumor volume in the prostatectomy specimen. Seventeen patients (27%) had positive margins, and 4 were found to have involvement of regional lymph nodes. After a median follow-up of 42.7 months, 19 recurrences (30%) occurred.

This study compared favorably to the results from the CUOG randomized study comparing 3 months versus 8 months of neoadjuvant hormonal therapy. In that study, PSA recurrence occurred in 52.6% after a mean follow-up of 37.7 months.³⁹

Because estramustine phosphate (EMP) induces biochemical castration caused by its estrogenic activity, it may be appropriate to consider estramustine-containing chemotherapy as a subcategory of chemohormonal therapy. Neoadjuvant EMP resulted in a significant decrease in positive surgical margins in patients with T2b disease in a randomized trial.

Hussain et al (2003) treated 21 patients with 3-6 cycles of docetaxel plus EMP followed by radiation or prostatectomy. In that study, 10 patients underwent prostatectomy, and 11 patients underwent radiotherapy. Of the 10 patients who underwent prostatectomy, 7 patients achieved negative surgical margins. Of the 11 patients who received radiation, 2 patients displayed negative preradiotherapy biopsy results. At a median follow-up of 13.1 months, 71% of all patients showed no evidence of disease.⁴⁰

Likewise, Clark et al (2001) evaluated 3 cycles of EMP plus etoposide before RP in 18 patients with locally advanced disease. Five patients (28%) experienced grade 3 toxicity (two with DVT, two with neutropenia, and one with diarrhea) and one (6%) experienced grade 4 toxicity (pulmonary embolus) before surgery. Organ-confined disease was observed in 31% of patients, and residual carcinoma with androgen-deprivation effect was observed universally. Nine patients (56%) had specimen-confined disease. All patients achieved an undetectable PSA level postoperatively.⁴¹

Generally, EMP-based chemotherapy has been abandoned because of toxicities, especially thromboembolism.

Conclusion

Surgical cure for prostate cancer can be expected only if the entire tumor is excised. Of men with clinical stage T1 or T2 prostate cancer, 50% have tumor extension outside the prostatic capsule and 5%-40% have positive margins. Some of these patients have incompletely resected cancer and, therefore, are at an increased risk for local recurrence and progression. In addition, despite considerable advances in prostate cancer research, high-risk localized prostate cancer remains an extremely refractory disease. Single-modality treatment offers a 5-year biochemical disease-free survival rate of no better than 50%. These concerns over cancer progression have led to a renewed interest in the use of neoadjuvant androgen deprivation (NAD) therapy prior to RP.

Most trials have used 3 months of neoadjuvant therapy and have demonstrated a significant decrease in prostate volume by 20%-50% and serum PSA levels by more than 90%. Studies have also reported a significant increase in organ-confined disease and a decrease in the incidence of positive margins. However, no randomized or nonrandomized study using 3 months of neoadjuvant therapy has shown any statistically significant benefit in terms of overall and disease-free survival. Some preliminary results show that increasing the duration of therapy to 6 or 8 months further reduces tumor volume and PSA nadir levels and decreases the likelihood of positive margins. The authors believe that a subset of patients is likely to benefit from neoadjuvant therapy; however, this population of patients is yet to be defined and may become clearer as the optimal duration and form of NAD therapy is defined.

Many unanswered questions exist regarding the benefit of NAD therapy. Currently, data are insufficient to support the routine recommendation of NAD therapy. Until this ambiguity is clarified, the utility of NAD prior to RP will remain controversial. The ultimate benefit of any therapy will be determined only through properly designed trials with long-term follow-up. Also, the hormone therapy is associated with significant side effects, such as hot flushes and gynecomastia, as well as cost implications. The decision to use hormone therapy should, therefore, be taken at a local level, between the patient, clinician, and policy maker, taking into account the clinical benefits, toxicity, and cost. More research is needed to guide the choice, the duration, and the schedule of hormonal deprivation therapy and the impact of long-term hormone therapy with regard to toxicity and the patient’s quality of life.

However, neoadjuvant therapy may provide an important paradigm for the discovery of active agents for the therapy of prostate carcinoma, in addition to improving clinical outcomes for men with early, high-risk disease. The availability of pretherapy and posttherapy tumor specimens enables the determination of biologic and pathologic antitumor activity with a relatively small number of patients. A multidisciplinary approach with a team of oncologists and urologists will be critical to making advances in the arena of neoadjuvant therapy for prostate carcinoma and aiding in the efficient evaluation of new therapies.

Keywords

neoadjuvant androgen deprivation therapy, ADT, NAD, complete androgen deprivation therapy, combined androgen deprivation hormone therapy, PSA, prostate-specific antigen, prostate specific antigen, adjuvant prostate treatment, prostate carcinoma, prostate downstaging, prostate down-staging, leuprolide, flutamide, nilutamide, bicalutamide, cyproterone acetate, CPA, radical prostatectomy, RP, luteinizing hormone-releasing hormone, LHRH, periprostatic fibrosis, prostate fibrosis

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