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Neoadjuvant Hormonal Therapy Prior to Radical Prostatectomy: Promises and Pitfalls

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Neoadjuvant Hormonal Therapy Prior to Radical Prostatectomy: Promises and Pitfalls Prostate Cancer and Prostatic Diseases (2000) 7, 136±144 ß 2000 Macmillan Publishers Ltd All rights reserved 1365±7852/00 $15.00 www.nature.com/pcan Review Neoadjuvant hormonal therapy prior to radical prostatectomy: promises and pitfalls ME Gleave1*, S La Bianca1 & SL Goldenberg1 1Division of Urology, University of British Columbia, Vancouver General Hospital, D-9, 2733 Heather Street, Vancouver, BC, Canada Prostate Cancer and Prostatic Diseases (2000) 3, 136±144. Keywords: prostate cancer; radical prostectomy; neoadjuvant; hormonal therapy Introduction the incidence of positive surgical margins and disease recurrence. The goal of radical prostatectomy is complete removal of The term adjuvant therapy refers to the use of systemic all cancer cells. Unfortunately, even in carefully selected therapy after management of localized disease when risk patients, up to two-thirds of clinically con®ned tumors of recurrence is known to be high. Chemotherapy regi- are understaged, and positive margin rates of 30 ± 60% are mens can cure some patients when used adjuvantly even reported following radical prostatectomy.1±3 Although though the same regimen fails to alter the natural history higher tumor stage, grade and pre-operative serum pros- of established metastatic disease. Experimental animal tate speci®c antigen (PSA) levels correlate with higher model and early clinical trial data suggest that adminis- pathologic stage and risk of disease recurrence, prognos- tration of systemic therapy is more likely to affect cure tic variables are limited in their ability to independently when tumor burden is low.10 Neoadjuvant therapy and individually predict pathologic stage and risk of extends this logic further by applying systemic therapy recurrence.4±6 In order to optimize outcomes from radical earlier in the course of the disease prior to de®nitive prostatectomy, only men with low-risk tumors (T1 or T2a, locoregional therapy. The aim of neoadjuvant hormonal Gleason score < 6, serum PSA < 10 mg/l) have tradition- therapy (NHT) prior to radical prostatectomy is reduction ally been considered ideal for cure by surgical interven- of positive margin rates and ultimately decreased disease tion. Thus, ideal candidates for radical prostatectomy are recurrence. The role of NHT prior to radical prostatec- men with the highest probability of being cured by the tomy is controversial as some clinicians argue that down- operation. Indeed, cure rates following radical prostatec- sizing occurs without down staging and any apparent tomy alone exceed 80% in men with low-risk tumors.7,8 down staging results from dif®culty in pathologic evalua- However, radical therapy may represent overtreatment in tion of the neoadjuvantly treated prostatectomy speci- some of these men because of the indolent natural history men.11,12 Others further argue that short-term follow-up of low-risk disease.9 In contrast, most men with high-risk from randomized studies comparing 3 months of NHT to localized tumors (> T2b, Gleason score 7, PSA > 10 mg/l) surgery alone show no difference in biochemical recur- and life expectancies > 10 y will die of their disease if they rence rates.13 However, NHT has many attractive theore- are not treated with curative intent.9 High-risk tumors tical features and research in this are is justi®ed and exhibit a more aggressive natural history and have important. The purpose of this article is to review the higher positive margin and recurrence rates after radical rationale behind NHT, critique the randomized studies of prostatectomy or radiotherapy alone, where unimodality 3 months of therapy, and examine the optimal duration therapy probably represents undertreatment.4±9 Para- of therapy. doxically, the therapeutic ratio (patients who actually realize a survival bene®t from a therapeutic intervention) may therefore be greater in high-risk disease if its natural history can be altered by multimodality therapy. It is important, therefore, to investigate therapies that opti- Rationale behind neoadjuvant therapy mize complete extirpation of all cancer cells and reduce prior to radical prostatectomy High positive margin rates following radical *Correspondence: M Gleave, D-9, 2733 Heather Street, Vancouver prostatectomy General Hospital, Vancouver, BC, Canada V5Z 3J5. Although higher tumor stage, grade and pre-operative Received 6 March 2000; accepted 31 May 2000 serum PSA levels correlate with higher pathologic stage, Neoadjuvant hormonal therapy ME Gleave et al no prognostic variable exists that can be applied inde- suicide' process that requires activation of a series of 137 pendently and individually to predict pathologic stage.4 genes and is characterized morphologically by shrunken Up to two-thirds of clinically con®ned tumors are under- cells with condensed and fragmented nuclei (apoptotic staged, and positive margin rates of 30 ± 60% are reported bodies). Initiation of apoptosis may, in part, be cell-cycle following radical prostatectomy.1±3 Incomplete excision speci®c or regulated by epigenetic factors and may there- places the patient at higher risk of disease recurrence.5±8 fore begin at different times in different populations of Selection of patients who are most likely to bene®t from cells. Maximal apoptotic regression of ventral rat prostate NHT remains critical; NHT is less likely to alter outcome glands and Shionogi tumors is complete within 1 ± 2 in most low-risk tumors (PSA < 10 mg/l, Gleason score weeks following castration;19 however, timing of apopto- 6, stage T1C, since most of these patients do well with sis has not been well characterized in benign or malignant surgery alone. In contrast, men with high-risk localized human prostate tissue and probably takes place over a tumors (PSA > 10 mg/l, Gleason grade > 7) are at signi®- longer period of time. cant risk of positive margins and PSA recurrence. Patients with positive margins are often offered post-operative radiation therapy to consolidate local therapy, which is Availability of PSA as a marker of tumor regression associated with increased risk of urinary incontinence, importance and anastomotic strictures. It is therefore PSA gene expression is androgen-regulated and serum important to investigate combinations of therapies that PSA levels are dependent on both androgen levels and optimize complete extirpation of all cancer cells and tumor volume.20,21 After institution of androgen ablation reduce the incidence of positive surgical margins. therapy, serum PSA levels decrease rapidly and dramati- cally due to cessation of androgen-regulated PSA gene expression and apoptosis. Although signi®cant downsiz- Reversible androgen suppression therapy ing occurs after 3 months of therapy, serum PSA does not reach undetectable levels after 3 months in most patients, The development of potent, well-tolerated and reversible which suggests that optimal duration of NHT may be agents for androgen ablation therapy provides a safe longer than 3 months. Maximal tumor regression prob- method for inducing prostate cancer cell death and ably occurs when PSA reaches its nadir level. Changes in tumor regression prior to radical prostatectomy. Several serum PSA following NHT provide objective biochemical classes of drugs induce castrate levels of testosterone information that re¯ects tumor response and may identify through suppression of LH release from the pituitary patients not responding favorably. gland, including diethylstilbestrol (DES)14 luteinizing- hormone-releasing hormone (LHRH) agonists include 15,16 goserelin, leuprolide and buserelin. The ¯are reaction Animal model studies can be prevented by cyproterone acetate or DES 1 week prior to the LHRH analog, or blocked by nonsteroidal Androgen withdrawal in the Shionogi tumor model pre- anti-androgens like ¯utamide or bicalutamide. cipitates apoptosis and tumor regression in a highly Prostate tumor cell death, not just tumor shrinkage, reproducible manner with up to a 2-log cell kill, but occurs following medical castration. Apoptosis, or pro- despite undergoing complete regression, androgen-inde- grammed cell death, occurs in normal, benign hyper- pendent tumors recur after one month.19 Conceptually, plastic and malignant prostatic epithelial cells by any the ideal time to implement curative therapy is after procedure that results in castrate levels of testoster- maximal castration-induced tumor involution but before one.17 ± 19 Apoptotic cell death appears to be a `genetic outgrowth of androgen-resistant clones. Experiments Figure 1 Neoadjuvant castration reduces local recurrence rates in the Shionogi tumor model. Tumors were allowed to grow to 1 ± 2 g before mice were randomized to either tumor excision with wide margins and castration upon tumor recurrence (group 1), or neoadjuvant castration for 10 days followed by wide excision of the regressed tumor (group 2). The study endpoint was androgen-independent tumor recurrence which occurred in 80% of Group 1 after a median of 36 days and 44% of mice in Group 2 after a median of 42 days. Prostate Cancer and Prostatic Diseases Neoadjuvant hormonal therapy ME Gleave et al 138 designed to determine whether local recurrence rates after historical controls, but no postoperative follow-up data tumor excision were lower with neoadjuvant compared to has been reported. Investigators at Memorial Sloan Ket- adjuvant androgen ablation demonstrated that tumor-free tering Cancer Center have conducted a series of studies survival was signi®cantly greater in the NHT group (56% beginning with a report
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