Neoadjuvant Androgen Deprivation Therapy in Prostate Cancer

Updated: Nov 03, 2016
  • Author: Vipul R Patel, MD; Chief Editor: Edward David Kim, MD, FACS  more...
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Overview

Overview

Current concerns regarding prostate cancer progression have led to a renewed interest in the use of neoadjuvant androgen deprivation (NAD) therapy prior to radical prostatectomy (RP). Surgical cure for prostate cancer can be expected only if the entire tumor is excised, and in men with clinical stage T1 or T2 prostate cancer, 50% have tumor extension outside the prostatic capsule and 40% have positive surgical 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%.

Most trials have used 3 months of NAD therapy and have demonstrated a significant decrease in prostate volume by 20-50% and in serum prostate-specific antigen (PSA) levels by more than 90%. A significant increase in organ-confined disease and a decrease in the incidence of positive margins have also been reported.

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. Moreover, it is possible that a subset of patients is likely to benefit from neoadjuvant therapy; this population of patients has yet to be defined, but its parameters may become clearer as the optimal duration and form of NAD therapy is defined.

Treatment and research considerations

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.

In patients with clinically localized prostate cancer, the National Comprehensive Cancer Network (NCCN) strongly discourages the use of NAD before RP outside of a clinical trial. However, the NCCN notes that androgen deprivation therapy before, during, and/or after radiation prolongs survival in selected radiation-managed patients. [1]

As with any therapy, the ultimate benefit of neoadjuvant NAD in prostate cancer will be determined only through properly designed trials with long-term follow-up. Also, hormone therapy is associated with significant side effects, such as hot flushes and gynecomastia, as well as financial costs. [2]

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 hormone 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 treatment 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 to aiding in the efficient evaluation of new therapies.

There is a particularly strong need for neoadjuvant chemotherapy trials that will allow the more rapid and less costly efficacy screening of new drugs and drug regimens. Unfortunately, use of the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate has proved ineffective against prostate cancer, in both the neoadjuvant and the adjuvant setting; indeed, PDGFR inhibition may accelerate advanced forms of prostate cancer. [3]

A study of the multikinase inhibitor sunitinib in patients with newly diagnosed prostate cancer prior to prostatectomy concluded that sunitinib appears safe and tolerable, with a toxicity profile similar to that seen in patients with advanced cancer. Changes in proliferation and apoptosis in treated patients suggest a treatment effect. [4]

Custirsen (OGX-011) is an experimental agent that inhibits expression of clusterin, a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum resistance in cancer cell lines. The combination of custirsen with chemotherapy is currently being examined in phase III trials. [5]

A phase II study of neoadjuvant chemohormonal therapy with docetaxel and complete androgen blockade in patients with locally advanced and high-risk prostate cancer undergoing RP found that the therapy is feasible despite high hematotoxicity, with excellent functional results. [6] However,the efficacy of neoadjuvant chemohormonal therapieshas not yet been demonstrated. [7]

Fracture

In September 2011, denosumab (Prolia) gained US Food and Drug Administration (FDA) approval for use in increasing bone mass in men at high risk for fracture who are receiving androgen-deprivation therapy for nonmetastatic prostate cancer. Denosumab is a fully human monoclonal antibody that targets the receptor activator of the nuclear factor-kappa-B ligand (RANKL) protein, which acts as the primary signal to promote bone removal. By inhibiting the development and activity of osteoclasts, denosumab decreases bone resorption and increases bone density. A subcutaneous (SC) dose of 60mg is administered once every 6 months.

FDA approval was based on a 3-year, randomized, double-blind, placebo-controlled study of 1468 men with nonmetastatic prostate cancer undergoing androgen-deprivation therapy. Bone mineral density (BMD) was significantly higher in the lumbar spine in patients treated with denosumab (+5.6%) for 2 years compared with those treated with placebo (-1.0%). The treatment difference was 6.7%.

After 3 years, the differences in BMD favoring denosumab were 7.9% at the lumbar spine, 5.7% at the (total) hip, and 4.9% at the femoral neck. Also at 3 years, the incidence of new vertebral fractures was 3.9% in the placebo group versus 1.5% in the denosumab group, yielding a relative risk reduction of 62%. [8]

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Androgen Deprivation

In 1941, Huggins and Hodges won the Nobel Prize for first demonstrating the effect of androgen withdrawal on benign and malignant prostate tissue. [9] Androgen deprivation induces programmed cell death (apoptosis) and inhibits cell proliferation in malignant prostate tissue. This technique has since become an established part of the management of advanced prostatic carcinoma. The role of preoperative androgen deprivation remains controversial, however.

Neoadjuvant androgen deprivation (NAD) is systemic therapy administered after the diagnosis of prostate cancer but before locoregional therapy such as radical prostatectomy (RP) or radiation. Its use arose in response to the limitations of RP.

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 men with 1 or more positive margins experience relapse, depending on the site of the positive margin, preoperative prostate-specific antigen (PSA) level, Gleason score, and presence of seminal vesical invasion.

The rationale for the use of 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.

NAD is not a new concept; it was introduced more than a half a century ago by Vallet et al. Subsequently, others have studied this concept in more depth. In addition to shrinking tumor, 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. [10, 11]

The advent of safe and reversible forms of androgen deprivation such as luteinizing hormone–releasing hormone (LHRH) analogues and antiandrogens (AAs) has spurred a resurgence in enthusiasm for NAD therapy. 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, below).

Table 1. Agents of Neoadjuvant Androgen Deprivation Therapy (Open Table in a new window)

Agent Mechanism Advantages Adverse Effects
Leuprolide



(Lupron)



22.5 mg SC q3mo



OR



Goserelin



(Zoladex)



10.8 mg SC q3mo



LHRH agonists: Initial stimulation of LHRH production (flare) followed by depletion of LHRH production Castration levels of testosterone and LH Flare phenomenon, hot flashes, decreased libido, decreased potency,



weakness, emotional changes



Flutamide



(Eulexin)



250 mg PO tid



Nonsteroidal AA: Direct blockade of androgen receptor Maintains serum testosterone level, libido, and potency Diarrhea, changes in LFT results, gynecomastia, breast tenderness
Nilutamide



(Nilandron)



150 mg PO qd



Nonsteroidal AA: direct blockade of androgen receptor Maintains serum testosterone levels (once-daily dosing) Alcohol intolerance,



abnormal light-to-dark adaptation,



interstitial pneumonitis



Bicalutamide



(Casodex)



50 mg PO qd



Nonsteroidal AA Maintains serum testosterone levels (once-daily dosing) Breast tenderness,



gynecomastia, hot flashes, elevated LFT results



Enzalutamide



(Xtandi)



160 mg PO qd



Nonsteroidal AA Maintains serum testosterone levels (once-daily dosing)



 



TERRAIN study supports use over bicalutamide in asymptomatic or mildly symptomatic metastatic CRPC [12]



Fatigue, back pain, hot flashes, risk of seizures



 



CYP2C8 substrate; avoid coadministration with strong CYP2C8 inhibitors



 



Strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer



 



Posterior reversible encephalopathy syndrome (PRES) reported



Cyproterone acetate



100 mg PO tid



Steroidal AA: Progestational activity inhibits LH release; also blocks androgen receptor Prevents flare and hot flashes,



Lowers testosterone levels



Loss of libido and potency, possible cardiovascular toxicity,



risk of DVT,changes in LFT results



Abarelix



(Plenaxis)



100 mg deep IM on days 1, 15, and 29, then q4wk for a total duration of 12wk



Gonadotropin-releasing hormone (GnRH) antagonist Prevents flare,



Lowers testosterone levels



Potential immediate-onset, life-threatening allergic reaction;



 



Possible cardiovascular toxicity



Diethylstilbestrol



(Stilphostrol)



1-5 mg PO qd



Hypothalamic/pituitary axis inhibitor Castration levels of testosterone Cardiovascular toxicity,



DVT, hot flashes, gynecomastia



AA=antiandrogen; CRPC=castration-resistant prostate cancer; DVT=deep venous thrombosis; LFT=liver function tests; LH=luteinizing hormone; LHRH=luteinizing hormone–releasing hormone

 

In May 2010, the US Food and Drug Administration (FDA) stated that a preliminary and ongoing analysis found that men receiving gonadotropin-releasing hormone (GnRH) agonists were at a small, increased risk for diabetes, heart attack, stroke, and sudden death. On October 20, 2010, the FDA announced that prescribing information for GnRH agonists would include new warnings describing a small, increased risk for heart disease and diabetes. [13]

GnRH agonists approved in the United States include leuprolide (Eligard, Lupron, Viadur), nafarelin (Synarel), triptorelin (Trelstar), histrelin (Vantas), and goserelin (Zoladex).

Some GnRH agonists are also used in women to help manage endometriosis pain, to improve anemia associated with uterine fibroids prior to hysterectomy, and, in some cases, for palliative treatment of advanced breast cancer. Use of these products should not exceed 1 year in women except when treating breast cancer. There are no known comparable studies that have evaluated the risk of diabetes and heart disease in women taking GnRH agonists.

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Selection of Candidates for NAD

High-risk patients (ie, those with a high T classification, Gleason score, or prostate-specific antigen [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. [10]

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 (eg, serum interleukin 6 [IL-6]–soluble receptor and transforming growth factor beta-1), may further improve 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.

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Clinical Trials of NAD

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 (see Table 2, below). Fair et al reported a nonrandomized study of 3 months of NAD therapy in 69 patients with T1-T3 prostate cancer, using 72 stage-matched controls, [14] with the following results:

  • A pathologic organ-confined rate of 74% was observed in the treatment arm, compared with 48% in the non-pretreated group
  • The margin-positive rate was 10% in the NAD group versus 33% in patients without induction of androgen deprivation
  • The prostate-specific antigen (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. Androgen deprivation consisted of 3 months of a luteinizing hormone–releasing hormone (LHRH) agonist and flutamide.

Meyer et al reported on 38 months of follow-up in 680 patients, 292 of whom received NAD prior to radical retropubic prostatectomy, [15] and the rates of positive surgical margins were lower in the NAD group than in the prostatectomy-only group (25% vs 47%, respectively). Patients treated with neoadjuvant hormone therapy had significantly lower hemoglobin and hematocrit levels before surgery and, therefore, required blood transfusion more often. No difference in risk of PSA failure (>0.3ng/mL) was observed overall between the hormone-therapy and prostatectomy-only groups. However, patients receiving combined therapy for more than 3 months had a significantly lower risk of PSA failure than those treated with radical prostatectomy (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 patients who underwent RP and received NAD and found that patients who received NAD were less likely to have positive margins (28% vs 38%). In the study, 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 or did not receive NAD therapy, only patients with a PSA value of greater than 10ng/mL and/or a biopsy Gleason score of greater than 7 and/or a stage greater than cT2b were included in the analysis.

The impact of NAD on pathologic outcome and disease recurrence was assessed for a mean follow-up of 26 months. 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. 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 and found that the incidence of positive surgical margins, seminal vesicle invasion, and lymph node metastasis was lower in the group who underwent preoperative neoadjuvant therapy (n = 12) than in the RP-only group (n = 19). Hormonal deprivation was carried out using a combination of goserelin and flutamide for 5.6 months. [16]

Table 2. Nonrandomized Trials of NAD Therapy (Open Table in a new window)

Author Patients Clinical Stage NAD Therapy and Duration,



mo



PSA Reduction,



%



Positive Margin,



%



Seminal Vesicle Invasion,



%



Lymph Node Metastasis,



%



Follow-up,



mo



Soloway et al, 1994 [17] 37 T2b-T3 TAB*, 3-16 90 41 30 14 33
Fair et al, 1993 [14] 69 T2b-T3 DES, 2-8 99 10 28
Solomon et al [18] 16 T2-T3 TAB, 3-6 12 None
Schulman and Sassine [19] 40 T2-T3 TAB, 2-12 32 None
Pummer et al [20] 34 T2b-T3 TAB, 3-6 98 24 18 15 None
Haggman et al [21] 40 T1b-T3 TAB, 3 86 31 25 3
Oesterling, Andrews,



Suman et al [22]



22 T2c-T3 TAB, 1-4 99 86 60 29 None
Macfarlane et al [23] 22 T2b-T3 TAB, 3 98 86 60 29 None
Abbas et al [24] 40 T1-T3 TAB, 3-20 98 23 23 3 30
Gleave et al [25] 50 T1-T3 TAB, 8 92 4 4 None
Meyer et al [15] 680 T1-T3 TAB, 3 25 17 14 38
Soloway et al, 2002 [26] 546 T1-T3 TAB, 3 28 17 10 26
Gao et al [16] 31 T1c-T3b TAB, 5.6 (3-8) ... NAD 25



RP 43



NAD 8.3 RP 21 NAD 8.3



RP 15.8



1
*Total androgen blockade



†Diethylstilbestrol



Randomized trials

LHRH agonist and flutamide

In the first prospective, randomized trial of NAD, Labrie et al randomized 161 men with stage B0-C2 cancer to surgery alone or to 3 months of NAD (LHRH agonist and flutamide) therapy followed by RP and 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, below). [27]

Table 3. Randomized Clinical Trials of NAD Therapy (Open Table in a new window)

Author Patients Clinical Stage NAD Therapy and Duration, mo Organ Confined, % Positive Margins, % Seminal Vesicle Invasion, % Lymph Node Metastasis, % Mean Follow-Up, mo
Labrie et al [27] 142 B0-C LHRH agonist and flutamide, 3 77 NAD



34 RP



13 NAD



38 RP



12 NAD



34 RP



3 NAD



6 RP



None
Debruyne et al [28] 125 T2-T3, N0M0 LHRH agonist and flutamide, 3 27 NAD



39 RP



None
Soloway et al, 1995 [29] 303 T2b, N0M0 LHRH agonist and flutamide, 3 53 NAD



22 RP



18 NAD



48 RP



15 NAD



22 RP



6 NAD



6 RP



42
Goldenberg et al [30] 213 T1b-T2b Cyproterone acetate, 3 34 NAD



64 RP



36
Van Poppel et al [31] 130 T2-T3 Estramustine, 6 72 NAD



63 RP



58 NAD



53 RP



6
Witjes et al [32] 354 T1-T3 LHRH agonist and flutamide, 3 71 NAD



51 RP



27 NAD



46 RP



2 NAD



3 RP



15
Aus et al [33] 122 T1-T3a LHRH agonist and cyproterone acetate, 3 24 NAD



45 RP



14 NAD



22 RP



5 NAD



14 RP



38
Prezioso et al [34] 167 T1a-T2b LHRH agonist and cyproterone, 3 39 NAD



60 RP



3 NAD



11 RP



In a multicenter trial by Soloway et al, patients with T2bN0M0 prostate cancer were randomized to RP plus NAD with an LHRH agonist and flutamide (149 patients) or surgery alone (154 patients), and patients who received androgen deprivation preoperatively were found to have significantly lower rates of capsule penetration (47% vs 78%), positive surgical margins (18% vs 48%), and tumor at the urethral margin (6% vs 17%).

In the study, 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 1ng/mL in 88% of patients and to less than 2ng/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. [29]

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, and serum PSA levels decreased by more than 90% in the NAD group. Pathologic down-staging was observed in 16% of the NAD group and 6% in the surgery-alone group. Positive margins were significantly less frequent in NAD patients with clinical T2 tumors, but there was no difference in those with clinical T3 tumors. At 15 months of follow-up of 215 patients, the progression-free survival rate did not differ between the 2 groups. The researchers concluded that neoadjuvant therapy was investigational and not advised outside of randomized clinical trials. [32]

Enzalutamide and bicalutamide

Enzalutamide proved superior to bicalutamide in the TERRAIN clinical trial, a double-blind, randomized phase II study in 375 asymptomatic or minimally symptomatic men with prostate cancer progression on ADT. Patients in the group had Median progression-free survival was significantly longer with enzalutamide than bicalutamide (15.7 versus 5.8 months; HR, 0.44; P<0.0001). However, 68% of patients in the enzalutamide group and 88% of those in the bicalutamide group discontinued their assigned treatment before study end, mainly due to progressive disease. [12]

Cyproterone acetate

The Canadian Urologic Oncology Group published the results of a randomized study on 213 patients, of whom 112 were treated with 12 weeks of cyproterone acetate at 300mg daily prior to surgical therapy, and reported that in the NAD-treated group, the volume of the prostate gland, determined by transrectal ultrasonography, decreased by 20% and the incidence of positive margins was lower than in the surgery-only group (27.7% vs 64.8%).

Both groups were well balanced at baseline in terms of demographics, clinical stage, Gleason score, PSA value, and prostate size. No tumors were down-staged to pT0. However, at 36 months of follow-up, no difference was noted in the biochemical recurrence rate. [30]

Prezioso et al, who randomized 167 patients with localized prostate cancer to receive either leuprolide acetate depot 3.75mg once a month for 3 months and cyproterone acetate 300mg once a week for 3 weeks prior to surgery (group A) or no pretreatment before surgery (group B), found that in group A, tumor/prostate volume decreased in 31% of patients after hormone therapy and that PSA and testosterone levels fell significantly from 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. [34]

Epidermal growth factor receptor

Epidermal growth factor receptor (EGFR) has been implicated in prostate cancer growth. In a randomized, prospective, controlled, intention-to-treat study in 119 patients with clinical stage T2-T3 prostate cancer, Gravina et al investigated the ability of NAD with bicalutamide to reduce positive surgical margins and modulate EGFR, and discovered that the 61 men who received bicalutamide, 150mg daily for 120 days before RP, had a 3.5-fold increase in negative surgical margins. [35]

In the study, Gravina and colleagues also found that in stage pT3a tumors, negative surgical margins increased 5-fold in patients who underwent bicalutamide treatment. In patients with stage pT2 tumors, the investigators found no difference for this surgical outcome. However, immunohistochemical analysis revealed that early after bicalutamide treatment, EGFR levels increased 2.8-fold and levels of the Her2/neu oncogene were upregulated 2.7-fold. The investigators speculated that the capacity of the residual tumor to acquire compensatory survival pathways may overwhelm the benefits of NAD. [35]

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Overall and Disease-Free Survival

A systematic review and meta-analysis of neoadjuvant androgen deprivatin (NAD) therapy in localized or locally advanced prostate cancer (stages T1-T4, any N, M0) by Kumar et al showed that NAD did not improve overall survival. [36]

However, NAD did produce a significant reduction in the positive surgical margin rate and a significant improvement in other pathologic variables, such as lymph node involvement, pathologic staging, and organ-confined rates. There was a borderline significant reduction of disease recurrence rates. Although these latter outcomes were of secondary importance to overall survival, the significant benefit achieved with these pathologic variables suggests that NAD may be useful in attaining local control in nonmetastatic prostate cancer. [36]

Three other studies also provided information on overall survival. With a 4-year follow-up period, Schulman et al reported no difference in overall survival rates with NAD plus RP compared with RP alone (93% vs 95% of patients alive in the treatment and control groups, respectively). [37]

Similarly, Klotz et al reported no difference in overall survival with NAD (88.4% vs 93.9% of patients alive in the treatment and control groups, respectively). [38] Finally, Aus et al found no significant difference in overall survival with NAD after 7 years of follow-up. [39]

These 3 studies showed that neoadjuvant hormone therapy before prostatectomy does not provide a significant survival advantage over prostatectomy alone. Studies that have analyzed disease-free survival (defined by either biochemical or clinical progression) have also shown no statistically significant difference with NAD. In the study with the longest follow-up, conducted by Aus et al, PSA progression–free survival over 7 years was 49.8% in the neoadjuvant arm and 51.5% in the prostatectomy arm. [39]

Similarly, Klotz et al found that 5-year biochemical disease-free survival was 60.2% and 68.2%, respectively, for the NAD and surgery-only arms. [38] Soloway et al reported a 5-year biochemical-free survival of 64.8% for the hormonal arm, versus 67.6% for the surgery-only arm, in patients with clinical stage T2 disease. [26] Schulman et al found that the 4-year PSA progression rates of patients with T2-T3, NO, MO disease in the NAD and the surgery-only arms were 26% and 33%, respectively. [37]

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Histopathologic Changes in NAD

Androgen deprivation therapy produces distinct histopathologic changes in neoplastic and nonneoplastic prostate tissue. A pathologist who is 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 on the pathology of androgen deprivation therapy for prostate cancer, and in the series of 173 patients who were treated with a luteinizing hormone-releasing hormone (LHRH) analogue and an antiandrogen (AA) prior to radical prostatectomy (RP), atrophy was observed in 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. [40]

Three types of changes in neoplastic tissue were reported in the Civantos study [40] :

  • 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.
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Pathologic Implications of NAD Therapy

Reduction in positive-margin rate

Clinical trials have demonstrated that neoadjuvant androgen deprivation (NAD) therapy significantly reduces the rate of positive surgical margins owing to either tumor regression or the improved ability to resect the prostate with wider surgical margins.

The interpretation of margin status on radical prostatectomy (RP) specimens after NAD therapy 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 identify 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 a Gleason score greater than 7 have a less dramatic reduction in positive margins, implying that higher-grade tumors may be less responsive to NAD therapy.

Improvement in pathologic variables

Treatment with neoadjuvant hormones has been shown to substantially improve local pathologic variables, such as organ-confined rates, pathologic down-staging, and rate of lymph node involvement. With regard to seminal vesical invasion, one study reported a decrease in seminal vesicle invasion rate with neoadjuvant therapy, [26] whereas another study showed no difference. [38]

Changes in Gleason criteria

Two of the Gleason criteria are altered by NAD 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.

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Surgical Implications of NAD

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

In the multicenter, randomized T2bN0M0 trial, surgeons rated the difficulty of dissection, presence of seminal vesicle adherence, and extent of blood loss and found that seminal vesicle adherence to the periprostatic tissues was more common in patients pretreated with NAD (37%) than in those treated with surgery alone (21%). They also recorded the operating time and amount of blood transfused. 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 in this study, no operative complications occurred in the NAD-treated group, whereas 6 intraoperative injuries were reported in patients who underwent surgery alone.

In 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 interference with apical dissection is potentially the most difficult problem caused by NAD. Also of serious concern is the fact that NAD-induced fibrosis can make intraoperative evaluation of the extent of the tumor more difficult, which in turn may compromise the extent of resection if the surgeon relies on intraoperative findings to determine performance of a nerve-sparing operation.

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Duration of NAD Treatment

The optimal duration of neoadjuvant androgen deprivation (NAD) therapy prior to radical prostatectomy (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 down staging.

Gleave et al showed a significant improvement with 8-month neoadjuvant therapy compared with 3 months. They attributed the initial dramatic fall in prostate-specific – antigen (PSA) values caused by androgen ablation to the cessation of androgen-regulated PSA gene expression, whereas a continuing gradual decline represented the actual decrease in tumor volume. The mean PSA level in study patients decreased 84% after 1 month, with a further decrease of 52% from 3-8 months. In 22% of patients, the PSA reached its nadir at 3 months; in 84% of patients, after 8 months. Therefore, these authors advocated 8 months as the optimal duration of treatment. [41]

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. [42, 43]

A meta-analysis of the 3 comparative studies showed a significant improvement in the positive surgical margin rates in favor of the longer treatment duration (6 or 8 months). [36]

In contrast, Pu et al found no significant difference in rates of positive surgical margin between men treated with 3 months of NAD therapy and those treated with 8 months of therapy. However, the positive margin rate was significantly lower in men who received either 3 or 8 months of NAD therapy than in a third group, who did not receive NAD therapy.

In the study, 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. In the patients who received 8 months of NAD therapy, the mean prostate volume was significantly smaller after 8 months than after 3 months; serum PSA values decreased by 98.1% after 3 months and showed a further 72.9% decline after 8 months. [44]

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Advantages and Disadvantages of NAD

Advantages

NAD therapy offers the following potential advantages:

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

Disadvantages

The following disadvantages of neoadjuvant androgen deprivation (NAD) therapy have been identified:

  • 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
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Combining NAD Therapy and Chemotherapy

No data have emerged that definitively support the use of neoadjuvant chemohormonal 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.

Pettaway et al

Optimal sequencing of chemotherapy and hormone therapy for prostatic carcinoma is unclear. Pettaway et al 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 followed by prostatectomy, and all patients achieved an undetectable PSA value postoperatively. Moreover, 20 of 29 patients were free of recurrence after a median follow-up of 13 months.

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. [45]

Konety et al

Konety et al reported similar results in a study of 36 patients who received 4 cycles of paclitaxel, carboplatin, and estramustine plus goserelin acetate before radical prostatectomy (RP), with the clinical stage being reduced in 39% of patients. Deep venous thrombosis (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. [46]

Prayer-Galetti et al

Prayer-Galetti et al, in evaluating 22 patients with high-risk prostate cancer who underwent neoadjuvant treatment combining a luteinizing hormone–releasing hormone (LHRH) analogue, estramustine, and docetaxel before undergoing radical retropubic prostatectomy, found that 3 patients (14%) had a clinical complete response and that 17 (81%) a partial response. One patient with sarcomatoid tumor had local progression after chemotherapy 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 0.6ng/mL or less (mean, 0.17 ng/mL), and the reduction from before to after chemotherapy was statistically significant. [47]

Of the 19 patients who underwent radical retropubic prostatectomy, the pathologic 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 pathologic complete response (pT0), and in 6 patients, the residual tumor was confined to small foci (< 10% of the prostate volume) and was composed of single cells or small groups of tumor glands. Comparing pathologic and clinical stages, the down-staging rate was 42% (8 patients).

Five patients (26%) had positive surgical margins, and 4 (21%) had positive lymph nodes. At a median 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. [47]

Sella et al

Likewise, Sella et al, in a published a trial of neoadjuvant chemohormonal therapy and RP in patients with poor-prognosis, localized prostate cancer (PSA level ≥20ng/mL, Gleason score ≥8, clinical stage ≥T2c), found that at a median follow-up of 23.6 months (range, 12.1-54.7mo), disease relapsed in 10 patients (45.4%). [48]

The surgical specimens in relapse cases revealed positive surgical margins in 5 (50%), capsular invasion in 6 (60%), and both in 8 (80%). 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 patients (40.9%), the tumor involved the seminal vesicles. In 4 patients (18.1%), the disease disseminated to the pelvic nodes, and in 9 patients (40%), the tumor invaded the perineural area.

No correlation in the study was found between nerve sparing (1 or 2 nerves) or specimen/organ-confined status and relapse, showing that a neoadjuvant chemohormonal approach with nerve-preservation surgery is feasible inpatients with poor-prognosis, localized prostate cancer.

Chi et al

Chi et al, in a phase II, multicenter study of NAD therapy (6.3mg buserelin acetate every 8wk for 3 doses and antiandrogen for 4wk) with docetaxel (35mg/m2 intravenously, weekly for 6 consecutive weeks, followed by a 2-week rest for 3 cycles) in newly diagnosed patients with untreated, clinically localized prostate cancer and high-risk features, found that 2 patients (3%) had a pathologic complete response and that 18 patients (28%) had 5% tumor volume in the prostatectomy specimen. [49]

Four patients in the study discontinued therapy because of toxicity, including 2 who suffered severe hypersensitivity reactions and 2 who developed pneumonitis (grades 3 and 4). 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.

Canadian Urologic Oncology Group

The results of this study compared favorably with those of the Canadian Urologic Oncology Group randomized study comparing 3 months and 8 months of neoadjuvant hormonal therapy. In that study, PSA recurred in 52.6% of patients after a mean follow-up of 37.7 months.

Hussain et al

Because estramustine phosphate (EMP) induces biochemical castration through its estrogenic activity, it may be appropriate to consider estramustine-containing chemotherapy as a subcategory of chemohormonal therapy. Generally, EMP-based chemotherapy has been abandoned because of toxicities, especially thromboembolism.

Neoadjuvant EMP resulted in a significant decrease in positive surgical margins in patients with T2b disease in a randomized trial. Hussain et al treated 21 patients with 3-6 cycles of docetaxel plus EMP followed by radiation or prostatectomy (10 patients underwent prostatectomy, and 11 patients underwent radiotherapy). Of the 10 patients who underwent prostatectomy, 7 patients had negative surgical margins, while 2 of the 11 patients who received radiation displayed negative preradiotherapy biopsy results. At a median follow-up of 13.1 months, 71% of all patients showed no evidence of disease. [50]

Clark et al

Clark et al evaluated 3 cycles of EMP plus etoposide before RP in 18 patients with locally advanced disease, and all patients achieved an undetectable PSA level postoperatively. Five patients (28%) experienced grade 3 toxicity (2 with DVT, 2 with neutropenia, and 1 with diarrhea), and 1 patient (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. [51]

Bolla et al

Bolla et al compared the use of combination radiotherapy plus long-term androgen suppressive therapy with radiotherapy plus short-term androgen suppressive therapy in patients with locally advanced prostate cancer, and it was determined that the addition of short-term androgen suppression provided inferior survival compared with long-term androgen suppression when combined with radiotherapy. Patients who had received external beam radiotherapy plus 6-months of androgen suppression were randomly assigned to receive an additional 2.5 years of androgen suppressive therapy or no further androgen suppressive therapy. Study enrollment proceeded slowly, and because of this, an interim analysis was completed and released at median follow-up of 5.2 years. [52, 53]

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