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 Management of High-Risk Populations with Locally Advanced Prostate Cancer
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The Oncologist, Vol. 8, No. 3, 259–269, June 2003
© 2003 AlphaMed Press

ORIGINAL PAPER
Genitourinary Cancer

Management of High-Risk Populations with Locally Advanced Prostate Cancer

Masood A. Khan, Alan W. Partin

James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Alan W. Partin, M.D., Ph.D., James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Jefferson Building Room 157, 600 North Wolfe Street, Baltimore, Maryland 21287-2101, USA. Telephone: 410-614-4876; Fax: 410-614-8096; e-mail: apartin{at}jhmi.edu


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Clinical Staging of Locally...
 Factors Predicting High-Risk...
 Novel Markers for the...
 Management of High-Risk...
 Primary Hormone Therapy
 Conclusion
 References
 
After completing this course, the reader will be able to:

  1. Recognize the clinical and pathological characteristics of a prostate tumor that is at high risk of having spread beyond the gland.
  2. Be familiar with novel markers for detection of high-risk prostate cancers.
  3. Explain the management strategy for high-risk prostate cancer.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Clinical Staging of Locally...
 Factors Predicting High-Risk...
 Novel Markers for the...
 Management of High-Risk...
 Primary Hormone Therapy
 Conclusion
 References
 
Prostate cancer that extends beyond the confines of the prostatic gland on clinical and/or radiographic assessment, without evidence of lymph node or distant metastases, is regarded as locally advanced. The locally advanced prostate cancer patient population consists of a heterogeneous group of men, some of whom have tumors that may be amenable to primary curative intent with local definitive therapy associated with acceptable long-term cancer control rates. In order to optimally manage this group of patients, it is important to be able to recognize who is at a high risk of tumor recurrence after primary local therapy. In this brief review, we discuss the factors that contribute to the prediction of high risk in populations with locally advanced disease and the treatment options available.

Key Words. Locally advanced prostate cancer • Risk factors • Management


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Clinical Staging of Locally...
 Factors Predicting High-Risk...
 Novel Markers for the...
 Management of High-Risk...
 Primary Hormone Therapy
 Conclusion
 References
 
Prostate cancer represents a major health problem, as it is the most common cancer and the second most common cause of cancer-related mortality in U.S. men [1]. In 2001, approximately 198,000 men were newly diagnosed and 32,000 men died with prostate cancer in the U.S. [1]. The widespread use of the measurement serum prostate-specific antigen (PSA) level as a diagnostic tool has resulted in a 20% increase in the detection of clinically localized prostate cancer. Despite this, approximately one-third of newly diagnosed cases are regarded as locally advanced at the time of diagnosis [2, 3]. Locally advanced prostate cancer is a clinical diagnosis in which it is felt that the tumor has extended beyond the prostatic capsule without evidence of nodal or distant metastatic spread [4]. Some patients presenting with these tumors may be suitable for primary definitive local treatment modalities such as radical prostatectomy, radiation therapy, or cryoablation. However, locally advanced prostate cancer encompasses a wide spectrum of tumor phenotypes with differing prognoses and more than 50% of these men are at risk of experiencing tumor recurrence after local therapy. It is, therefore, important to be able to recognize those patients that are at high risk so that appropriate primary and/or adjuvant management can be instigated. In this brief review, we discuss the factors that contribute to the prediction of high risk for tumor recurrence in patients with locally advanced prostate cancer and the management options available.


   CLINICAL STAGING OF LOCALLY ADVANCED PROSTATE CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Staging of Locally...
Factors Predicting High-Risk...
 Novel Markers for the...
 Management of High-Risk...
 Primary Hormone Therapy
 Conclusion
 References
 
Earlier staging systems relied primarily on digital rectal examinations (DREs). However, DRE is limited by its relative lack of sensitivity. This point was elegantly demonstrated by Partin et al. [5] who evaluated the sensitivity and specificity of DRE in determining organ-confined status in a large series of patients in which all DREs and radical prostatectomies were performed by one urologist, with pathologic evaluations completed by a single pathologist. In that series, of the 565 men in whom DRE suggested organ-confined disease (T2), 52% actually had organ-confined disease, 31% had capsular penetration, and the remaining 17% exhibited seminal vesicle or lymph node involvement. In that same series, of the 36 men in whom extraprostatic disease was suspected on DRE (T3a), 19% had organ-confined disease, 36% had capsular penetration, and 45% had involvement of either seminal vesicles or lymph nodes. This represents a sensitivity of 52% and a specificity of 81% for the prediction of organ-confined disease by DRE alone.

The introduction of radiographic modalities, such as transrectal ultrasound, has been reported to predict local extent of disease in up to 84% of patients [6]. A more accurate tumor, node, metastases (TNM) staging system was adopted by the American Joint Committee on Cancer and the International Union Against Cancer (Table 1Go) [7]. This system is widely used to report clinical stage, and T3 disease with no evidence of nodal involvement or distant metastases is regarded as locally advanced.


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  		Table 1. The 1997 TNM clinical staging of prostate cancer [7]
 

   FACTORS PREDICTING HIGH-RISK POPULATIONS WITH LOCALLY ADVANCED DISEASE
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Staging of Locally...
 Factors Predicting High-Risk...
Novel Markers for the...
 Management of High-Risk...
 Primary Hormone Therapy
 Conclusion
 References
 
Serum PSA
PSA is recognized as the most useful tumor marker available in clinical practice for the diagnosis, staging, and monitoring of prostate cancer [8]. Although serum PSA is not specific for prostate cancer, the concentration of serum PSA does correlate with pathologic stage and tumor volume [9, 10]. Numerous studies have demonstrated that, in groups of men with prostate cancer, serum PSA correlates directly with advancing clinical and pathologic stage [5, 11–13]. However, in most cases, serum PSA measurement alone does not provide accurate enough staging information for individual patients due to its overlap between stages (Fig. 1Go) [14]. Furthermore, although serum PSA is directly related to the volume of cancer present, other factors can also influence the overall serum PSA level [15]. As such, preoperative interpretation of serum PSA in men with prostate cancer in relation to tumor extent is confounded by the volume of benign prostatic hypertrophic tissue present and also by the tumor grade, as both of these factors can influence serum PSA levels [16]. Nonetheless, 80% and 67% of men with PSA values <4 ng/ml and from 4–10 ng/ml have pathologically organ-confined disease, respectively [17, 18]. On the other hand, >50% of men with PSA values >10 ng/ml have disease beyond the prostate [17, 18]. Moreover, pelvic lymph node involvement is found in nearly 20% and 75% of men with PSA levels >20 ng/ml and >50 ng/ml, respectively [5, 16]. Therefore, patients presenting with a serum PSA level >10 ng/ml are at an intermediate risk for tumor recurrence, and those with a serum PSA level >20 ng/ml represent high-risk populations, as they have a high likelihood of micrometastatic dissemination at the time of diagnosis. These patients are likely to experience poor prognoses with primary local therapy alone (Fig. 2Go). Recently, there has been growing evidence to support that percent-free PSA might also be associated with more extensive disease, but its role in staging needs to be further elucidated [19–21].



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  		Figure 1. Distribution of pathologic (prostatectomy) stages after anatomic radical prostatectomy by preoperative serum PSA. Data were derived from the series of Patrick C. Walsh, The Johns Hopkins Hospital, 1982–2001. Abbreviations: OC = organ confined; EPE = extraprostatic extension; SV = seminal vesicle; LN = lymph node.

 


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  		Figure 2. Kaplan-Meier actuarial likelihood of biochemical recurrence (rising PSA) after anatomic radical prostatectomy in patients with pathological stage T3a disease and varying preoperative PSA levels. Data were derived from the series of Patrick C. Walsh, The Johns Hopkins Hospital, 1982–2001.

 
Histologic Grade and Locally Advanced Prostate Cancer
Of the many histologic grading systems introduced to help predict pathologic stage and prognosis for prostate cancer [22–25], the most commonly used is the Gleason system [24], which correlates directly with pathologic extent of disease. The Gleason grading system is based on a low-power microscopic description of the histologic architecture of the cancer [24, 26]. A Gleason grade of 1 to 5 is assigned as a primary grade (pattern occupying the largest area of the specimen) and as a secondary grade (pattern occupying the second-largest area). A Gleason score (2–10) is determined by adding the primary and the secondary grades.

Figure 3Go illustrates the distribution of Gleason scores determined on pretreatment prostate biopsy as a function of final pathologic stage for 2,897 men who underwent surgery for clinically localized prostate cancer (Johns Hopkins series from 1982–2001). The general trend in these data is that higher biopsy scores tended to have worse pathologic stages; however, on an individual basis, Gleason score alone is insufficient to accurately predict pathologic stage, especially due to the phenomenon of histologic upgrading from biopsy to prostatectomy specimens. As such, D’Amico et al. [27] investigated clinical factors that may predict high-grade disease (i.e., Gleason grade >=4) at radical prostatectomy in 420 patients diagnosed with clinically localized (T1c/2) and low-grade disease (i.e., Gleason grade <=3) at biopsy and found that 40% of those men were found to have high-grade disease at surgery. Those authors also determined that men who had a >=50% chance of being upgraded included those with prostate gland volumes <=75 cm3 and serum PSA levels >20 ng/ml and those with serum PSA levels from 10–20 ng/ml and clinical stage T2b/c. For men with prostate gland volumes >75 cm3, only those with both serum PSA levels >20 ng/ml and clinical stage T2b/c were at significant risk for upgrading.



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  		Figure 3. The distribution of Gleason scores determined on pretreatment prostate biopsy as a function of final pathologic stage for men (n = 2,897) who underwent surgery for clinically localized prostate cancer. Data were derived from the series of Patrick C. Walsh, The Johns Hopkins Hospital, 1982–2001. Abbreviations: OC = organ confined; EPE = extraprostatic extension; SV = seminal vesicle; LN = lymph node; SM = surgical margin status.

 
The importance of histologic grading in men with clinically localized disease is supported by numerous multivariate analyses of prognostic criteria, which have demonstrated that Gleason score (or grade) is a strong predictor of disease extent [5, 28–32]. Han et al. [33] recently demonstrated that, if patients with Gleason score 7 disease on biopsy were subdivided into two groups on the basis of predominant Gleason pattern (3 or 4), the actuarial progression-free probabilities after radical prostatectomy for Gleason score 3 + 4 versus 4 + 3 tumors were significantly different. Therefore, the presence of a Gleason grade >=4 or a Gleason score >7 is predictive of a poor prognosis [28, 29, 34, 35]. To further improve the cancer control predictability of biopsy Gleason grade, Kestin et al. [36] recently performed a detailed analysis of all pretreatment biopsy specimens in patients (n = 160) prospectively treated with external beam radiation therapy and high-dose brachytherapy. The results demonstrated that patients with <33% positive cores had a 5-year biochemical recurrence-free rate of 83%, whereas this value was only 57% in patients with >67% positive cores.

Figure 4Go illustrates the influence of preoperative and pathologic Gleason scores in locally advanced prostate cancer in determining biochemical recurrence after radical prostatectomy. The data demonstrate that Gleason scores of 7 and 8–10 confer an intermediate and a high-risk status for recurrence, respectively. Therefore, Gleason score in combination with percent positive biopsy core and gland volume information may enable us to more accurately predict the high-risk populations.



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  		Figure 4. Kaplan-Meier actuarial likelihood of PSA recurrence by preoperative biopsy Gleason score (A) and by pathologic Gleason score (B) in men with clinically locally advanced prostate cancer. Data were derived from the series of Patrick C. Walsh, The Johns Hopkins Hospital, 1982–2001. Insufficient data for Gleason score <6.

 
Combined Use of Clinical Data to Predict High-Risk Populations with Locally Advanced Prostate Cancer
The prognostic value of any clinical criterion when used alone to predict tumor extent is limited for an individual patient. However, staging accuracy is substantially enhanced by using the combination of local disease extent on DRE (T stage), serum PSA level, and Gleason score from prostate biopsy specimen [5, 37, 38]. To this end, a nomogram (namely, the Partin Tables) based on these preoperative parameters has been constructed [5, 38]. The Partin Tables, which are the result of a single-institutional study of men undergoing radical prostatectomy relating pathologic stage to clinical stage, demonstrate that PSA and biopsy Gleason score exhibit independent predictive significance in multivariate analysis [5, 39]. The wider application of this nomogram was subsequently validated in a multi-institutional study [38]. Therefore, using the Partin Tables, it is possible to accurately predict, among men with locally advanced disease, those that are likely to be at a high risk for disease recurrence (i.e., Gleason score 8–10 and serum PSA >20 ng/ml).

Pathologic Stage and Locally Advanced Prostate Cancer
Transrectal ultrasound is unreliable for the detection of extraprostatic or seminal vesicle invasion [40, 41]. Cross-sectional images provided by computerized tomography (CT) and magnetic resonance imaging (MRI) for the detection of local extension of disease and/or the presence of lymph node metastases have likewise not been found to be routinely useful due to their low sensitivities [42, 43]. Endorectal MRI represents a significant advantage over body coil imaging with respect to the resolution of the prostate and the periprostatic organs. To this end, D’Amico et al. [44] recently demonstrated that endorectal MRI increased the accuracy (to 84%) of staging T1 and T2 disease and also predicted that patients with confirmed pathologic organ-confined disease would also increase from 32% to 61%. However, on further investigation, D’Amico et al. [45] concluded that endorectal MRI provided additional clinically meaningful information in only 20% of patients after accounting for the prognostic values of PSA, biopsy Gleason score, clinical stage, and percent positive biopsies. As a result, the routine use of endorectal MRI could not be justified. Therefore, despite advancements in imaging techniques, pathologic upstaging at the time of radical prostatectomy is still well described for all stages of localized prostate cancer [4]. In the U.S., CT scanning of the abdomen and pelvis as an imaging modality for investigating men with locally advanced disease is often performed by the primary care physician prior to referral for definitive therapy. When surgery is opted for, the CT scan provides little clinically useful information. However, for either external beam radiotherapy or brachytherapy it can contribute to treatment planning.

Pathologic staging, which involves histologic examination of the pelvic lymph nodes and prostate after removal, provides a more accurate representation of extent of disease within and beyond the prostate. Hence, pathologic staging is more valuable than clinical staging in the prediction of prognosis since tumor volume, surgical margin status, extent of extraprostatic extension, and involvement of seminal vesicles and pelvic lymph nodes can all be determined. Most cancer control data, after radical prostatectomy, are substratified based on the presence or absence of cancer within periprostatic tissue (margin, fat, or nerves) and the presence or absence of seminal vesicle or pelvic lymph node involvement as follows: organ-confined disease (confined within the prostatic capsule); capsular penetration (disease extends into the periprostatic tissue); seminal vesicle involvement (disease extends into the muscular wall of the seminal vesicles); and pelvic lymph node involvement [8].

The likelihood of biochemical recurrence-free survival (undetectable PSA) is inversely related to the pathologic stage of disease (Fig. 5Go). The most important pathologic criteria that are predictive of prognosis after radical prostatectomy are tumor grade, seminal vesicle invasion, and involvement of pelvic lymph nodes [8]. In addition, the presence of a positive surgical margin or a high-grade tumor (Gleason grade >=7) in the setting of extraprostatic disease is associated with a higher likelihood of residual disease after radical prostatectomy [29, 35, 46–49]. Furthermore, Gleason score has an independent prognostic significance for men with extracapsular disease [28, 29]. To this end, Epstein et al. [28, 29] demonstrated, in men with extraprostatic disease and negative seminal vesicles and lymph nodes on radical prostatectomy, that high-grade tumors had a significantly higher risk of progression than lower grade tumors. Therefore, extraprostatic disease alone in the absence of other unfavorable factors (e.g., serum PSA, surgical margin status, and Gleason score) does not infer high risk for disease recurrence requiring early adjuvant therapy.



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  		Figure 5. Kaplan-Meier actuarial likelihood of PSA recurrence by pathologic stage and surgical margin status after anatomic radical prostatectomy. Data were derived from the series of Patrick C. Walsh, The Johns Hopkins Hospital, 1982–2001. Abbreviations: OC = organ confined; EPE = extraprostatic extension; SV = seminal vesicle; LN = lymph node; SM = surgical margin status.

 
Seminal vesicle invasion and/or lymph node metastases on pathologic evaluation after radical prostatectomy convey a high risk of distant failure [33, 35, 50, 51]. Hence, not only is pathologic evaluation frequently associated with upstaging of clinical disease, but also clinical outcomes vary greatly among different patients with pathologic stage T3 disease. This is exemplified by the demonstration that extraprostatic extension of prostate cancer is associated with a progression rate that is not very different from organ-confined disease, whereas patients with seminal vesicle and/or lymph node involvement experience tumor recurrence almost universally after surgery [33, 35, 50, 51]. These patients represent high-risk populations and require additional treatment.


   NOVEL MARKERS FOR THE DETECTION OF HIGH-RISK POPULATIONS WITH LOCALLY ADVANCED PROSTATE CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Staging of Locally...
 Factors Predicting High-Risk...
 Novel Markers for the...
Management of High-Risk...
 Primary Hormone Therapy
 Conclusion
 References
 
Monoclonal Antibody Nuclear Scanning
Monoclonal antibody radioimmunoscintigraphy (radiolabeled monoclonal antibody scan) is a promising approach for the detection of microscopic cancer deposits in regional and distant sites. Indium-111 (111In)-capromab pendetide (ProstaScint®; Cytogen; Princeton, NJ) is a radiolabeled monoclonal antibody that targets prostate-specific membrane antigen (PSMA), which is more highly expressed in malignant cells (especially metastatic lesions) [52]. The ProstaScint® scan was approved by the U.S. Food and Drug Administration in 1997 for the staging evaluation of men with a high risk of disease spread beyond the prostate. Manyak et al. [53] recently demonstrated, in men who underwent pelvic lymphadenectomy for high-risk nodal disease based on serum PSA level, Gleason score, and advanced clinical stage, that the ProstaScint® scan was associated with a sensitivity and specificity of 62% and 72% for nodal disease, respectively. In comparison, the sensitivities of CT and MRI were 4% and 15%, respectively, and the specificities for both were 100%. Therefore, use of ProstaScint®, together with serum PSA, histologic grade, and clinical stage, appears to provide additional predictive information. To further improve monoclonal antibody radioimmunoscintigraphy, monoclonal antibodies that bind the extracellular domain of PSMA have been radiolabeled [54] and are currently being studied as possible second-generation scans for the identification of microscopic extraprostatic disease [55].

Telomerase Activity
Telomerase is a ribonucleoprotein enzyme that adds telomeric repeats onto chromosomal ends using a segment of its own RNA component as a template [56]. Telomerase activity is directly involved in telomeric maintenance, and its activation plays a role in cell immortality [56]. Approximately 90% of cancer tissue from prostatectomy specimens exhibits telomerase activity [57], and the level of telomerase activity has been shown to correlate with pathologic grade, suggesting that telomerase activity may be a marker for malignant potential [58]. Furthermore, telomerase activity has been shown to be more commonly detected in surgical margins of patients with locally advanced disease than those with organ-confined disease (14.9% versus 10.4%) [56]. Whether this translates to greater risk for local recurrence needs further evaluation.

{alpha}-Catenin
Normally functioning cell-cell adhesion plays a central role in the maintenance of tissue architecture and cell cohesion [59]. E-cadherin is an important transmembrane protein with epithelial cell adhesion properties [60]. In many types of cancer, the expression of E-cadherin is reduced, leading to a greater risk of disease progression [60, 61]. {alpha}-catenin is one of the intracellular components of the E-cadherin-catenin complex, and abnormalities in its expression appear to be associated with malignant cellular features and disease progression in prostate cancer [61, 62]. As such, Aaltomaa et al. [59] recently demonstrated, in a single institutional study, that abnormal {alpha}-catenin expression was significantly linked with locally advanced disease, metastatic disease, and high Gleason score. Therefore, {alpha}-catenin may provide useful information in the determination of high-risk patients with locally advanced disease. However, larger multicenter studies are needed before this can be confirmed.


   MANAGEMENT OF HIGH-RISK POPULATIONS WITH LOCALLY ADVANCED PROSTATE CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Staging of Locally...
 Factors Predicting High-Risk...
 Novel Markers for the...
 Management of High-Risk...
Primary Hormone Therapy
 Conclusion
 References
 
Primary Curative Local Therapy
Radical prostatectomy alone does not cure most men with locally advanced disease. As such, Bosch et al. [63] reported that surgical cure rates were <30%, which is partly related to the high incidence of pelvic lymph node metastases (up to 50%) in these patients. However, advocates of radical surgery argue that, in selected patients (e.g., with low volume disease), both local control as well as disease-specific survival may be improved with radical prostatectomy [64]. Despite the lack of randomized data to support the concept that higher survival rates are achieved after surgery, some younger and healthier men with less extensive disease do proceed to surgery and appear to experience extended survival [64].

A number of studies investigating the impact of external beam radiation therapy in locally advanced disease have been conducted [65–68]. These studies report that good local control, low morbidity, and overall survival rates comparable to those seen with other modes of treatment can be achieved. However, it should be noted that most of those studies were conducted prior to the PSA era, when local disease control was defined by inaccurate clinical parameters, such as a normal DRE finding. Hence, not surprisingly, in the PSA era much higher recurrent or persistent disease rates have been detected [69]. Zietman and Shipley [69] reported, using PSA >1 ng/ml as a definition of treatment failure, that at 10-years postirradiation, the actuarial disease-free survival was only 21%. In addition, postirradiation prostate biopsies demonstrated persistent disease in up to 50% of patients with locally advanced disease. The poor results associated with radiation therapy may, at least in part, have been due to the administration of inadequate doses of radiation, which was implemented in order to reduce complications. To improve radiation therapy results, especially as the presence of residual cancer is significantly associated with subsequent local and distant failure [70], conformal 3-dimensional radiation therapy, which allows higher doses of radiation to be delivered to the prostate with less exposure to neighboring organs (bladder and rectum), has recently gained popularity with some evidence of improved biochemical outcomes [71]. Despite this, radiation therapy alone is unable to effectively eradicate most locally advanced prostate cancer.

Although cryosurgical ablation of the prostate has been available since the 1970s, recent improvements in the technology, allowing a greater controlled freezing of the prostate, have resulted in its increased popularity. Bahn et al. [72] recently conducted a retrospective study evaluating the efficacy of cryosurgical ablation in patients with locally advanced disease. Taking a serum PSA value of 0.5 ng/ml as evidence of biochemical failure, they reported that the 7-year actuarial biochemical disease-free survival was 61% and that 13% had evidence of residual cancer. Therefore, those authors concluded that cryoablation surgery is as good as, if not better than, radiation therapy for the management of locally advanced prostate cancer. Despite these promising results, longer follow-up data are required before the role of cryosurgical ablation in locally advanced disease can be fully evaluated.

Adjuvant and Neoadjuvant Hormone Therapy
See et al. [73] recently published the preliminary results of a large trial evaluating the efficacy and tolerability of bicalutamide (150 mg daily) as adjuvant therapy after radical prostatectomy or radiation therapy in patients with locally advanced prostate cancer. A total of 8,113 patients was recruited for this placebo-controlled, double-blinded, randomized study. At a median follow-up of 3 years, bicalutamide significantly reduced the risk of objective disease progression by 42% compared with placebo. Unfortunately, this decrease in risk only represented a 4.8% decrease in the actuarial risk of progression, suggesting little clinical significance in the long term. Furthermore, overall survival data are currently immature and longer follow-up is needed to determine if there is an overall survival benefit associated with bicalutamide. Despite the clear demonstration that bicalutamide reduces disease progression by only 4.8% actuarially, this may suffice to warrant its routine administration as an adjuvant therapy in patients with locally advanced prostate cancer.

Due to the high association between extraprostatic disease spread and clinically locally advanced prostate cancer, neoadjuvant hormone therapy has been extensively evaluated in this group of patients [74–76]. Although neoadjuvant hormone therapy has been shown to be associated with a decrease in the rate of positive surgical margin status, no improvements in either disease-free or overall survival have been demonstrated [74–76]. Hence, neoadjuvant hormone therapy prior to radical prostatectomy is not justified. However, neoadjuvant hormone therapy prior to radiation therapy is a different matter. The Radiation Therapy Oncology Group (RTOG) 86-10 trial, a prospective, randomized study comparing 4 months of neoadjuvant and concurrent hormonal therapy plus radiation therapy with radiation therapy alone in patients with locally advanced disease, demonstrated a significant improvement in local control and the incidence of distant metastases at 5 years in the combined group [77].

Adjuvant hormone therapy after radiation therapy has also been extensively investigated [78–80]. The RTOG 85-31 [78] and the European Organization for Research and Treatment of Cancer (EORTC) 22863 [79] trials compared combined therapy with radiation therapy alone in patients with either locally advanced or node-positive disease. Androgen suppression with goserelin was used indefinitely or until progression became evident in the RTOG trial [78] and for 3 years in the EORTC trial [79]. Combined therapy was associated with significantly longer disease-free survival in both trials, and the EORTC trial also demonstrated improved overall survival in the combined therapy arm. In addition, patients with Gleason scores of 8–10 who received combined therapy exhibited significantly greater actuarial 5-year survival probabilities [78].

The question of optimal duration of adjuvant hormone therapy after radiation therapy was addressed by the RTOG 92-02 trial, which compared long-term (28 months) with short-duration (4 months) administration [80]. The results showed that long-term hormone therapy was associated with a significantly improved disease-free survival, without any difference in the overall survival, at 5 years. These studies support the long-term use of adjuvant hormone therapy after radiation therapy in patients with poorly differentiated, locally advanced prostate cancer.


   PRIMARY HORMONE THERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Staging of Locally...
 Factors Predicting High-Risk...
 Novel Markers for the...
 Management of High-Risk...
 Primary Hormone Therapy
Conclusion
 References
 
An alternative approach to the management of locally advanced prostate cancer is that of primary hormone therapy alone. This approach was investigated by Fowler et al. [81], who treated 208 men with locally advanced disease with either gonadal androgen ablation or gonadal androgen ablation and an antiandrogen at a single institution. The actuarial cause-specific survival rates at 5 and 8 years were 92% and 80%, respectively. In addition, the actuarial all-cause survival rates at 5 and 8 years were 59% and 41%, respectively. Those authors concluded that primary hormone therapy for locally advanced disease was associated with all-cause and cause-specific survival rates that paralleled those of integrated hormone and radiation therapy. Although this study suggests that primary hormone therapy is a reasonable option in the management of locally advanced prostate cancer, prospective randomized trials are needed to confirm this.

Adjuvant and Neoadjuvant Chemotherapy
The role of chemotherapy in high-risk patients with locally advanced prostate cancer is slowly evolving. A number of studies are currently investigating the impact of single-agent docetaxel (a microtubule inhibitor) [82] as a neoadjuvant therapy in this group of patients [83, 84]. Preliminary results indicate that the majority of patients experienced an improvement in serum PSA level. However, it is too early to determine whether any survival benefit can be achieved.

Hussain et al. [85] recently performed a pilot study evaluating the adjuvant role of docetaxel in patients with biochemical recurrence after initial definitive treatment (radical prostatectomy or radiation therapy) of locally advanced prostate cancer. The preliminary results showed that the majority of patients exhibited >=40% reductions in serum PSA levels. The impact of docetaxel at an even earlier setting is currently being evaluated in a multi-institutional trial, in which high-risk patients with locally advanced disease are being given weekly docetaxel for up to 6 months after radical prostatectomy.

The concept of chemohormonal therapy (i.e., the use of both hormone therapy and chemotherapy) has recently gained a great deal of interest [86]. To this end, combined neoadjuvant chemotherapy with hormonal therapy, prior to radical prostatectomy or radiation therapy, is currently being evaluated [86]. A phase III RTOG trial of androgen suppression and radiation therapy with or without subsequent taxane-based combination chemotherapy is currently under way in high-risk patients with locally advanced disease [86]. Furthermore, the Southwest Oncology Group is currently comparing adjuvant hormonal therapy with chemohormonal therapy in surgically treated high-risk patients [86]. Figure 6Go summarizes the treatment options available for the management of high-risk patients with locally advanced prostate cancer.



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  		Figure 6. Possible management options for high-risk patients with locally advanced prostate cancer.

 

   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Staging of Locally...
 Factors Predicting High-Risk...
 Novel Markers for the...
 Management of High-Risk...
 Primary Hormone Therapy
 Conclusion
References
 
Locally advanced prostate cancer encompasses a heterogeneous group of patients. Using serum PSA values and biopsy Gleason scores, it is possible to predict those patients that have a high risk of advanced local disease and who are at risk of tumor recurrence after primary local therapy. However, pathologic staging is more accurate than clinical staging in the prediction of prognosis. Although primary curative local therapy may be attempted in high-risk patients with locally advanced disease, in the majority of cases, it is inadequate to prevent disease recurrence. Hence, these patients should also be considered for neoadjuvant and/or adjuvant hormonal therapy (and possibly chemotherapy).


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Staging of Locally...
 Factors Predicting High-Risk...
 Novel Markers for the...
 Management of High-Risk...
 Primary Hormone Therapy
 Conclusion
 References
 

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Received December 10, 2002; accepted for publication March 3, 2003.




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