Review

© Future Drugs Ltd. All rights reserved. ISSN 1473-7140 37

CONTENTS

Physiology

Monotherapy

Combined androgen blockade

Peripheral androgen blockade as primary therapy

Androgen-independent progression ofprostate cancer

Antiandrogen withdrawal

Novel strategies for delaying androgen resistance

Timing of hormonal therapy

Expert opinion

Five-year view

Key issues

References

Affiliations

www.future-drugs.com

Hormonal therapy for prostate cancer: past, present and futureBasil F El-Rayes and Maha H Hussain†

Prostate cancer is the second leading cause of cancer mortality in men in the USA. For the past six decades, hormonal therapy has been the main treatment of advanced prostate cancer. Hormonal therapy has developed from a surgical procedure to a complex pharmacological treatment. Trials comparing the efficacy of different monotherapies have demonstrated the equivalence of DES, LHRH agonists and orchiectomy. Combined androgen blockade has been compared with monotherapy. However, the results of the different trials have been conflicting. Novel hormonal therapy schedules involving intermittent treatment and peripheral androgen blockade are currently in clinical trials. The role of hormonal therapy in locally advanced disease as part of a multimodality therapy is a new and rapidly developing aspect of hormonal therapy. The mechanism of hormone refractoriness in prostate cancer is an active area of basic science and translational research.

Expert Rev. Anticancer Ther. 2(1), 37–47 (2002)

†Author for correspondenceDivision of Hematology/Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, 4100 John R Street, Detroit, MI 48201, USAhussainm@karmanos.org

KEYWORDS:hormones, prostate cancer

In the year 2001, 198,100 American men willbe diagnosed with prostate cancer [1].Although prostate cancer mortality hasdecreased in the past several years, it is stillthe second most common cause of cancermortality in men [1]. Low-risk patients (withearly-stage and low-grade tumors) are mostlycurable with local therapy. Treatment ofpatients with high-grade tumors or locallyadvanced disease is suboptimal. Metastaticdisease remains largely an incurable diseasewith significant morbidity [2].

Since the pioneering work of Huggins andHodges in 1941 on hormonal dependence ofprostate cancer [3], androgen ablation has beenthe initial therapy of advanced prostate cancer.The past six decades have witnessed the evolu-tion of the pharmacology and indications ofhormonal therapy. The introduction of hor-monal therapy in the locally advanced diseasehas improved local control and delayed pro-gression and may have increased survival.Nevertheless, several issues pertaining to hor-monal therapy remain unanswered, includingthe timing, duration of treatment, role innon-metastatic biochemical relapse and early-stage high-risk disease. These are areas ofactive clinical research.

PhysiologyThe testis and adrenals are the only source ofandrogens. In the testis, the Leydig cells synthe-size and secrete 90% of the testosterone. Thisprocess is under the control of the pituitarygland via the luteinizing hormone (LH). LHsecretion is in turn dependent on the pulsatilestimulation by the hypothalamic hormoneLHRH. This complex hypothalamic–pituitaryaxis is inhibited by either androgens or estrogens;thus, maintaining a steady state of androgens.The adrenal cortex synthesizes the second majorandrogen, dihydroepiandrosterone sulfate(DHEAS) that is regulated by the pituitary hor-mone adrenocorticotropin-releasing hormone(ACTH). Corticosteriods but not androgensinhibit ACTH secretion. In the prostate tissuetestosterone is metabolized into dihydrotesto-sterone (DHT) by the enzyme 5-α-reductase [4].The DHT affinity for the androgen receptor ismuch higher than testosterone [5].

The androgen receptor (AR) belongs to thesuperfamily of steroid/nuclear receptors thatact as transcription factors. Androgen bindingstabilizes the AR–DNA complex against rapiddegradation [6]. This interaction results intranscription of genes that influence tumorgrowth, differentiation and apoptosis.

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38 Expert Rev. Anticancer Ther. 2(1), (2002)

MonotherapyOrchiectomyBilateral orchiectomy – the first hormonal therapy for advancedprostate cancer [3] – has been the gold standard to which othertherapies were compared. It offers several advantages includingsafety, low cost and rapid palliative effect. On the other hand, it isirreversible and is associated with psychological trauma of castra-tion, decreased libido, impotence, hot flashes, loss of muscle mass,anemia, osteoporosis, inability to concentrate and weight gain.

EstrogensDiethylstilbestrol (DES) – a synthetic estrogen – inhibits LHRHthrough negative feedback on the hypothalamic–pituitary axis.Initially, DES was introduced as a means of performing a phar-macological orchiectomy. DES has been shown to have directinhibitory effects on prostate cancer [7–9]. These effects includeincreasing the level of sex hormone binding globulin and block-ing 5-α-reductase activity. The side effects of DES includedgynecomastia, nausea, vomiting and most seriously thromboem-bolic complications. Earlier trials conducted by the VeteransAdministration Co-operative Urological Research Group(VACURG) underscored the importance of these side effects. Inthe first study, orchiectomy was compared with 5 mg/day ofDES [10]. Although the cancer-specific mortality was lower in theDES group, the increased rate of cardiovascular complications inthe DES arm resulted in a similar survival to the orchiectomygroup. A dose finding study was subsequently conducted by theVACURG. Treatment arms included placebo, 0.2, 1 and 5 mg ofDES daily. The 1 mg/day dose was as effective as the 5 mg/day indelaying progression. However, the effects on survival were mod-est as compared to placebo. The 5 mg/day dose resulted in anunacceptably high rate of complications and was therefore aban-doned [11]. Similarly, the 1 mg/day of DES was equivalent toorchiectomy in the European Organization for the Research andTreatment of Cancer (EORTC) trial [12]. However, with the evo-lution of the pharmacology of hormonal therapy DES has beenessentially abandoned as first-line therapy for metastatic prostatecancer in this country.

Steriodal antiandrogensSteroidal antiandrogens include cyproterone acetate (CPA) ormegestrol acetate. Their main mechanism of action is androgenreceptor antagonistic action. Other effects include inhibition ofLHRH release. Furthermore, steroidal antiandrogens functionas ligands for several receptors including the androgen, gluco-corticoid and progestin receptors. CPA at a dose of 200 mg/daywas compared with orchiectomy and has shown similar regres-sion of prostate cancer [13]. As monotherapy, however, neitherof these agents is capable of suppressing androgens to castratelevels and therefore are not usually used as monotherapy [14].

Nonsteriodal antiandrogensNonsteriodal antiandrogens are selective antagonists to theandrogen receptors and therefore, do not result in a castratelevel of androgens [15]. Consequently, this group of drugs was

thought to have a lesser effect on potency. Schroder et al.reported a prospective randomized study comparing potency in310 patients treated with either flutamide or CPA [16]. At 2-year follow-up, loss of spontaneous erections and sexual func-tion occurred in 80 vs. 92% and 78 vs. 88% in the flutamideversus CPA groups, respectively. This group of agents includesflutamide, nilutamide and bicalutamide (TABLE 1). Monotherapywith flutamide was compared in a randomized study to DES (1mg t.i.d.) in 92 patients with D2 disease. Median survival was43 months in the DES group and 28 months in the flutamidegroup [17]. Similarly, the survival after orchiectomy was superiorto bicalutamide (50 mg/day) in patients with metastatic pros-tate cancer [18]. Both bicalutamide at a dose of 150 mg/day andflutamide at 750 mg/day in separate studies have been shownequivalent to orchiectomy in M0 disease [19,20]. Both thesestudies had relatively small numbers and short follow-up.

LHRH agonistsA substitution of glycine at position 6 with D-leucine in theLHRH molecule results in a more potent and longer half-lifeagonist [21]. LHRH analogs through the nonpulsatile stimula-tion of the pituitary downregulate their receptors and conse-quently suppress LH/FSH release. LHRH agonists result inelimination of testicular androgen secretion with no effect onthe adrenal androgens. Goserelin and leuprolide are the com-mercially available agents in this class. In several randomizedstudies, LHRH agonists produced equal response rates and 1-year survival to either DES or orchiectomy [22–24]. The sideeffects of LHRH agonists are similar to orchiectomy includinghot flashes, decreased libido, impotence and weight gain.

Upon initiation of LHRH agonists, a stimulation of andro-gen synthesis and secretion occurs prior to the downregulationof the pituitary receptors. This increase in testosterone levelsmay result in a flare of prostate cancer symptoms. In patientswith impending cord compression, pain or urinary outflowobstruction the flare phenomena may result in devastating clin-ical consequences. Combination therapy with a lead in antian-drogen is recommended to prevent these flare phenomena insymptomatic patients [25].

LHRH antagonistsThe potential advantage of the LHRH antagonist over LHRHagonist is in avoiding the testosterone surge, thus resulting inrapid achievement of castrate level testosterone. Furthermore,FSH receptors are expressed on prostate cancer cells and mayplay a role in the regulation of the growth of hormone-refrac-tory prostate cancer [26]. Abarelix, a LHRH antagonist, is avail-able in depot injectable formulation. Clinical trials comparingtestosterone and FSH levels in patients treated with abarelix toLHRH agonist demonstrate a rapid suppression of testosteroneand FSH levels in the patients on abarelix and maintenance ofFSH levels until the end of the study [27–29]. None of thepatients on the abarelix had a testosterone or FSH-surge com-pared to 70% of the patients treated with leuprolide and bical-utamide [27]. Abarelix was also evaluated in patients with

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advanced symptomatic prostate cancer in a Phase II trialinvolving 48 patients with bladder neck obstruction, impend-ing neurologic compromise or symptomatic skeletal metastasisfrom prostate cancer. Rapid medical castration was achievedwith no flare with an overall objective response rate of 90% anda complete response rate of 10% [30].

The Phase II/III studies of abarelix have not focused on thelong-term outcome end-points, such as progression-free sur-vival or overall survival. At this point, abarelix appears to be asafe and effective alternative treatment for patients with pros-tate cancer and a risk of a flare on LHRH agonists. Overall, itrepresents modest progress in the treatment of this disease andit is not clear if it will impact outcome significantly.

Monotherapy overviewPrimary gonadal suppression is associated with a response rateof 60–85% with a median and progression-free survival of24–30 and 12–18 months, respectively.

A meta-analysis of ten trials on monotherapy in advancedprostate cancer including more than 1900 patients concludedequivalent survival with either LHRH agonists or orchiectomy[31]. Antiandrogens are less effective as monotherapy especiallyin patients with M1 disease [31], while DES may be equivalentto orchiectomy.

Combined androgen blockadeSince the adrenals and the testis produce androgens, completeandrogen blockade requires blocking adrenal androgens withantiandrogens and testicular androgens with LHRH agonists ororchiectomy. Labrie et al. reported a 40% DHT activity in theprostate of castrated men [32], thus providing the basis for aclinical trial with reported overall and complete response ratesof 96 and 29%, respectively [33]. Subsequently, this concept wasvery actively investigated with several randomized trials con-ducted in the 1980s and early part of the 1990s comparing pri-mary gonadal suppression to CAB. The results of these trialswere inconsistent (TABLE 2).

A meta-analysis was conducted on these trials in an attemptto resolve this controversy. The first meta-analysis used datafrom seven trials comparing orchiectomy with either placebo ornilutamide, 1056 patients were treated. A reduction in disease

progression was noticed but without a significant effect on sur-vival [34]. In a second meta-analysis, a benefit for CAB wasnoticed [35]. This meta-analysis included only published trialswith long-term follow-up and survival data. The most recentmeta-analysis conducted by the Prostate Cancer Trialists’ Col-laborative Group [36]. This meta-analysis included 27 trials anda total of 5932 patients. Different agents were included in thesetrials. The 5-year survival was 25.4 and 23.6% in the CAB andthe monotherapy groups, respectively. The difference was notstatistically significant. CPA resulted in an inferior outcome ascompared with CAB. With the inability of meta-analysis toresolve this controversy, evaluation of each of these Phase IIIstudies with attention to the study design, sample size andmethods of hormonal therapy used is still necessary. The largestof these trials is Intergroup study 0105, comparing orchiec-tomy plus placebo with orchiectomy plus flutamide. This trialrevealed no advantage to CAB in the setting of surgical castra-tion [37]. The studies comparing CAB to a LHRH agonist havecontradictory results. The study by Boccardo et al. had a shortmedian follow-up of 18 months, which might be inadequategiven the long natural history of prostate cancer [38]. The Inter-national Prostate Study Group failed to show superiority ofCAB in a Phase III study involving 560 patients and a medianfollow-up of 57 months [39]. Intergroup study 0036 enrolled606 patients with a median follow-up of 48 months, superiorprogression-free and overall survival for the CAB arm wasobserved [40]. A similar finding was reported on the EORTCtrial [41]. Although controversial, the possibility of a small butsignificant improvement in median survival with LHRH ago-nist-based CAB still exists. However, in considering this treat-ment several things must be taken into consideration, includingtreatment objective, cost of care and quality of life issues.

Peripheral androgen blockade as primary therapyAndrogen ablation in advanced prostate cancer has produced sig-nificant palliation of symptoms. The side effects of androgenablation, however, affect the quality of life since it causes loss oflibido, impotence, gynecomastia, hot flashes, edema and moodchanges. Moreover, physiologic effects of androgen withdrawalare increasingly recognized, such as decreased muscle mass, ane-mia and decreased bone mineral density [42] with a possibleincreased risk of osteoporosis. An alternative strategy aimed atimproving the quality of life of patients with prostate cancer isperipheral androgen blockade by combining a 5-α-reductaseinhibitor (finasteride) with an antiandrogen. Finasteride as a sin-gle agent has no effect on the progression of prostate cancer [43].Animal studies show that the finasteride/flutamide combinationis superior to monotherapy with either agent [44]. Nonrand-omized small studies have demonstrated the activity of this com-bination. Fleshner et al. treated 22 patients with stage C or D1disease with the finasteride and flutamide combination. SerumPSA was decreased from a mean of 42 to 2 ng/dl at 6 months andpersisted for 24 months [45]. In a randomized Phase II study, thiscombination resulted in an equal decrease in PSA as comparedwith fenasteride and gosorelin [46]. The finasteride and flutamide

Table 1. Pharmacological properties of the nonsteroidal antiandrogens.

Agent Dose Side effectFlutamide 250 mg every 8 h Nausea, anorexia,

diarrhea hepatic toxicity, gynecomastia

Nilutamide 150 mg once daily Visual disturbances (in 30%), gynecomastia, alcohol intolerance

Bicalutamide 50–150 mg once daily Hepatic toxicity, gynecomastia

El-Rayes & Hussain

40 Expert Rev. Anticancer Ther. 2(1), (2002)

combination did not affect potency in over 80% of patients. Thiscombination has not been incorporated into a large randomizedPhase III study with either medical or surgical castration andtherefore at this time is still considered investigational.

Androgen-independent progression of prostate cancerProstate cancer cells are heterogeneous in their hormonal sensi-tivity. In vitro assays demonstrate that certain clones grow andsurvive in the absence of androgens (androgen-independent),others require androgens for growth (androgen-sensitive) andsome clones require androgens for growth and survival (andro-gen-dependent). This heterogeneity translates clinically intothe regression but incurability of prostate cancer after androgendeprivation [47]. Understanding the androgen-independentgrowth and survival mechanisms of prostate cancer could leadto the identification of targets for future therapy. While thesequence of events leading to the development of androgenindependence and hormone-refractory status is not yet known,several potential mechanisms have been postulated.

With castrate-level testosterone, increased androgen sensitivitymight result in growth and survival of prostate cancer cells in thislow androgen milieu. Mechanisms of increased androgen sensitiv-ity include increased expression of the AR [48,49], upregulation ofthe AR target genes [50,51], increased stability of the AR [52] andimproved growth signalling of the AR [53]. Alternatively, othergrowth factors, such as insulin-like growth factor-1 (IGF) [54], epi-dermal growth factors (EGF) [55] and platelet-derived growth fac-tors (PDGF) [56] have been shown to stimulate growth and sur-vival of prostate cancer cells in the absence of androgens.Activation of the EGFR receptors results in a complex intracellularsignalling pathway involving the cell survival mechanisms, such asphosphoinositide 3-kinase (PI 3) and the mitogen activated pro-tein (MAP) kinase. PTEN dephosphorylates the substrates of PI 3including Akt [57]. In prostate cancer, PTEN mutations are fre-quent [59]. The increased growth factor receptors and the low

PTEN might act together to activate androgen-independent cellsurvival pathways. Inhibitors of EGFR whether of the monoclonalantibody type (C225) or of the small molecule type (Irressa™) arecurrently in clinical trials in prostate cancer and inhibitors of thePI 3 are currently in preclinical trials.

Activation of antiapoptotic genes is another mechanism forandrogen resistance. The over expression of bcl-2 has beendemonstrated in hormone-refractory prostate cancer cell lines[59]. Mutations in several tumor suppressor genes including,p53 [58], ANX7 [61] and NXK3.1 [62] have been demonstrated inhormone-refractory prostate cancer.

Antiandrogen withdrawalFailure of hormonal therapy is detected by a rising PSA thatusually precedes radiological or clinical progression by6 months [63]. This failure could be attributed to either andro-gen-independent growth or inadequate suppression of testo-sterone. A noncastrate level of testosterone after medical ther-apy is an indication for alternative mode for gonadalsuppression including surgical castration. Therefore, initialwork up at the time of progression usually includes measuringserum testosterone levels.

Scher et al. reported a PSA decrease after flutamide withdrawalin ten of 27 patients on CAB [64]. Similar responses were reportedwith bicalutamide [65], DES [66], nilutamide [67] and megace [68].The response rate and duration of response to antiandrogen with-drawal is approximately 25% and 4 months, respectively. Responseto antiandrogen withdrawal usually occurs within a few weeks.The molecular bases of this phenomenon are currently being inves-tigated. Several mutations in the AR have been identified [69].Three of these mutations can change flutamide and nilutamidefrom an antagonist to an agonist of the receptor. Interestingly,bicalutamide maintained its antagonistic effect to these mutatedAR. This may explain the response to antiandrogen withdrawal orto the second-line antiandrogen therapy [70].

Table 2. Trials comparing CAB and monotherapy.

Study group Study arm N Results Ref.NCI INT Leu

Leu + Flu300303

Improved PFS (16.5 vs.13.9) and overall survival (35.6 vs. 28.5) in the CAB arm

[40]

EORTC OrchGos + Flu

163164

Improved PFS (30.7 vs. 19.6) and overall survival (34.4 vs. 27.1) in the CAB arm

[41]

Janknegt et al. OrchOrch + Nilu

232225

Improved PFS (19 vs. 14.9) in the CAB arm [93]

Boccardo et al. Gos + FluGos

152152

Nonsignificant difference in PFS or OS [38]

Tyrrel et al. GosGos + Flu

284287

Nonsignificant difference in PFS or OSFlutamide dose was 250 mg b.i.d.

[39]

Iverson et al. OrcGos + Flu

133129

Nonsignificant difference in PFS or OS9% had local disease

[94]

NCI INT OrchOrch + Flu

681690

Nonsignificant difference in PFS or OS [37]

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Novel strategies for delaying androgen resistanceSince progression of prostate cancer on hormonal therapy to anandrogen-resistant state is inevitable, several strategies are cur-rently being investigated to delay this phenomenon, includingintermittent hormonal therapy and the use of chemotherapy incombination with hormonal therapy.

Intermittent hormonal therapyNormal maturation of the prostate under the influence ofandrogens results in androgen-sensitive cells. In animal models,when malignant prostate cells surviving androgen withdrawalwere reintroduced into an androgen-rich medium, these cellscould mature and regain the androgen-sensitive phenotype [71],thus, setting the stage for a second response to androgen with-drawal. Several pilot clinical trials of intermittent androgenblockade have been conducted. In general, patients are treatedwith hormonal therapy until the PSA reaches a nadir. Subse-quently, the therapy is withheld until the PSA starts rising to apredetermined level. During the period when therapy is with-held, the serum testosterone increases to normal level and withthis potency may be regained and hot flashes resolved. One ofthe earlier trials was reported by Klotz et al. on 20 patientstreated intermittently with either DES or flutamide [72]. Theduration off-therapy was 2–70 months and reinstitution ofhormonal therapy resulted in a rapid response in all of thepatients. Several other contemporary trials have demonstratedthe feasibility of this approach [73–75]. In addition, observationson other end-points have also been made. Higano et al.reported on the effects of intermittent hormonal therapy onbone mineral density. The absolute value as well as the percent-age of change in the bone mineral density show stabilization orincrease in the off-treatment period [75]. Although there is nocurrent consensus on the duration of induction hormonal ther-apy or the trigger to restart treatment, it is recommended thatandrogen suppression be maintained for a longer period of time(7–9 months) to ensure significant debulking of the tumor. Toaddress the role of intermittent hormone therapy two interna-tional cooperative group randomized trials are being conductedin patients with newly diagnosed metastatic prostate cancer(SWOG 9346, Intergroup trial-0162) and biochemical failurefollowing radiation (JPR07 NCIC CTG PR.7).

Chemotherapy in hormone-sensitive prostate cancerAs prostate cancer cells become androgen-independent, thesecells activate antiapoptitic mechanisms resulting in resistance tochemotherapy [57–62]. Therefore, early introduction of chemo-therapy with hormone therapy in hormone-sensitive prostatecancer may delay or prevent development of progression toandrogen-independent disease. Several Phase II studies are eval-uating different chemotherapeutic regimens in hormone-sensi-tive metastatic prostate cancer. Different approaches to earlyinitiation of chemotherapy in documented untreated metastaticdisease include chemotherapy after maximal reduction of dis-ease with hormonal therapy versus initial chemotherapy withhormonal therapy in an attempt to delay progression. In a Phase

II study paclitaxel, estramustine and etoposide (TEE) weregiven following 6 months of total androgen blockade inpatients with an 80% decrease in their PSA [76]. Of the 13patients who completed chemotherapy, six had progressed witha progression-free survival (PFS) of 14 months and seven hadnot progressed with a PFS of 12 months. Trudeau et al.reported on 15 patients with metastatic disease treated with acombination of estramustine, vinblastine and goserelin. Chem-otherapy was administered every 8 weeks for four cycles and waswell-tolerated. At the time of the report 12 patients were assess-able for response. The overall response rate was 100% with 11/12 patients having a complete response [77]. In a randomizedPhase II design, 25 patients with metastatic prostate cancer weretreated with either goserelin alone or in combination with ralti-trexed. The toxicity was slightly higher in the combined therapyarm. Complete responses were seen in 17 out of 18 patients inthe combined therapy arm versus four out of seven in the goser-elin arm [78]. These studies demonstrate the safety, feasibilityand high response rates of chemohormonal therapy in hor-mone-sensitive prostate cancer. However, the role of chemo-therapy in this setting must be defined in randomized trials.

Timing of hormonal therapyPrimary therapyThe timing of therapy in asymptomatic patients withadvanced prostate cancer was a controversial issue. Historically,hormonal therapy was thought of as a palliative treatment withno effect on survival [10,11]. Therefore, only symptomaticpatients were treated. The observation that 50% of theuntreated patients with stage C progress to stage D in52 months in comparison with 10% of the patients treatedwith DES [79] raised the issue of early initiation of therapy.Recently the Medical Research Council (MRC) conducted theonly randomized study of early versus deferred treatment. Ninehundred and thirty eight asymptomatic patients with stage M0or M1 were randomized to immediate versus treatment at thetime of progression with LHRH agonist or surgical castration[80]. Disease progression, mortality and disease-specific mortal-ity were significantly higher in the deferred treatment arm butonly for patients with M0 disease. Similarly, disease-relatedmorbidities (spinal cord compression, urethral obstruction,fractures and pain) were significantly more frequent in thedeferred treatment arm thus supporting the use of early hor-monal therapy in the asymptomatic metastatic prostate cancerpatients. Criticism of the MRC study includes failure to reachtarget accrual and survival advantage was mainly in the M0group. The patients on the delayed treatment arm werereported on once a year and some patients never receivedandrogen ablation therapy. EORTC study no. 30891 is evalu-ating in a randomized prospective study early versus late treat-ment in non-metastatic (M0) prostate cancer. The primaryoutcome is symptom-free survival. Secondary outcomesinclude overall survival and time to distant progression. Thestudy has accrued 900 patients [101]. Follow-up is short and thefinal results are not published yet.

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42 Expert Rev. Anticancer Ther. 2(1), (2002)

The controversial issue in the timing of hormonal therapy per-tains to the patient with a rising PSA after local therapy in theabsence of radiological evidence of metastatic disease. In theabsence of randomized studies addressing this issue, the timing oftreatment should be individualized reflecting the patient prefer-ence as well as the aggressiveness of the disease and therapy objec-tives and when possible these patients must be enrolled on clinicaltrials. It has been suggested that a high Gleason score, a short pro-gression-free interval after local therapy and a rapidly rising PSAshould prompt consideration of early rather than deferred treat-ment due to the high likelihood of early symptomatic metastaticdisease in this group of patients [2].

Adjuvant/neoadjuvant therapyPre- and post-therapy risk prediction of relapse relies on a com-bination of clinical and pathologic criteria including stage,tumor grade and pretreatment PSA level [2]. High-risk patients(involvement of the seminal vesicles, lymph nodes, surgicalmargins, PSA over 20 and or Gleason score above 7) have a 5-year biochemical failure rate after surgery or radiation of 50%or greater [2]. Systemic failure accounts for the majority of clini-cal relapses. Therefore, a combination of systemic and localtherapies is required in locally advanced prostate cancer. Withthe efficacy of hormonal therapy as the primary treatment foradvanced prostate cancer, several trials examined the combina-tion of hormonal therapy with either surgery or radiation inthis setting.

Surgery & hormonal therapy

Hormonal therapy has been used in the adjuvant and neoadju-vant settings. Messing et al. reported the first randomized studyof surgery with immediate adjuvant hormonal therapy versus hor-monal therapy at progression [81]. Ninety-eight patients withorgan-confined disease except for pelvic lymph node metastasiswere randomized to each arm of the study. The mortality (13 vs.34%), clinical and biochemical progression were significantlylower in the immediate treatment arm at 7 years. Criticism of thisstudy includes failure to accrue its anticipated target populationof 220 and lack of central pathology review of the prostatectomy

specimens. The EORTC study no. 30846 is evaluating early ver-sus late hormonal therapy in pathologic N1-3 disease. The studyhas accrued 320 patients [101]. The follow-up is still short and theresults are not published.

In a different approach, hormonal therapy was introduced inthe neoadjuvant setting as a means to downstage tumors inorder to facilitate resection. The results of the neoadjuvantstudies indicate a significant improvement in margin-free resec-tions but not in survival [82–86]. Possible interpretation of thediscrepancy between downstaging and survival effects includeunderpowered studies that fail to detect small survival differ-ences or ineffectiveness of short-term neoadjuvant treatment incontrolling systemic disease. A third possibility includes a his-tological change in the tumor making the margins falsely freeof disease without altering its stage. Neoadjuvant hormonaltherapy is considered experimental.

Radiation & hormonal therapy

Radiation Therapy Oncology Group (RTOG) conducted severalrandomized trials comparing outcomes of radiation therapy withor without hormonal therapy in locally advanced prostate cancer(TABLE 3) [87–91]. These trials indicate improved local control andprolonged disease-free survival in the hormone therapy group.Furthermore, in an EORTC trial, combined therapy resulted insignificant increase in overall survival as compared to the observa-tion group [89]. Subgroup analysis of RTOG 85-31 indicates thatthe patients with a Gleason of 8–10 showed a significant survivaladvantage with hormonal therapy [88,91].

RTOG 92-02 compared short- (4 months) versus long-(28 months) term androgen deprivation therapy after radiation[90]. As expected the progression-free survival was significantlylonger in the long-term hormonal therapy arm. However, theimpact on overall survival awaits longer follow-up.

Antiandrogen adjuvant therapy

The effects of early single-agent antiandrogen therapy on sur-vival in patients with locally advanced prostate cancer afterdefinitive local treatment were recently explored in a rand-omized trial [92]. Eight thousand one hundred and eighteen

Table 3. Randomized trials of radiation and hormonal therapy in locally advanced prostate cancer.

Study Study arm Local control (%) RFS (%) OS (%) Results Ref.Pilepich RT

HT followed by RT2954

1536

NS Increase in PFS and local control [87]

Pilepich RTRT followed by HT

6985

4462

7175

No increase in overall survival§ [88]

Bolla RTRT followed by HT

8797

4885

6279

Improved local control and OS [89]

Hanks RT + short-term HTRT + long-term HT

8794

3454

7978

Long-term better than short-term in PFS§§ [90]

§Improved survival in patients with Gleason score of 8–10.§§No improvement in overall survival.

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patients with locally advanced prostate cancer were randomizedto either placebo or bicalutamide (150 mg/day) after local treat-ment, which included surgery, radiation or watchful waiting.The bicalutamide group had a 42% reduction in the risk of pro-gression at 3 years. Risk reduction was seen regardless of stage orprimary treatment. However, any conclusion on the role ofantiandrogen therapy in the adjuvant setting is premature andmust await survival outcome.

Expert opinionHormonal therapy has resulted in significant palliation inpatients with prostate cancer and is considered the standardfirst line treatment for metastatic disease. Randomized studieshave failed to show a definitive advantage of CAB over mono-therapy although a trend towards a small benefit in survival wasseen. Early therapy of patients with documented metastatic dis-ease is beneficial in preventing debilitating consequences, suchas cord compression.

In the locally advanced disease combination hormonal ther-apy with local therapy is superior to single modality approachwith respect to disease-free survival and overall survival in cer-tain groups, such as radiation treated locally advanced patientsor N1 surgically treated patients. Thus, such approach is con-sidered standard in these settings. Although the duration ofhormonal therapy is yet to be defined, longer-term therapyappears to be more effective than short-term in this setting.This must be counter balanced by the side effects of protractedandrogen deprivation.

Due to a high relapse rate following local therapy, high-riskprostate cancer due to poor histology or high pretreatment PSA(Gleason score > 7 or PSA > 15–20) is becoming the next frontfor investigating systemic therapy. Early data from severalRTOG trials suggest a potential survival advantage associatedwith the addition of hormonal therapy to radiation therapy inpatients with poorly differentiated tumors. However, optimaltherapy in this setting is yet to be defined.

Five-year viewHistorically, hormones have been used with a palliative intentfor advanced disease with 60 years of experience confirming theincurability of advanced prostate cancer irrespective of modesof androgen suppression. Therefore, progress in outcome willrequire alternative novel approaches.

Resistance to hormonal manipulation remains a majorproblem. Understanding the mechanisms of resistance will

help in identifying targets for therapy. Furthermore, betterdefinition of the mechanism of resistance will help in identi-fying patients that could benefit from second-line hormonetherapy. Biological therapy targeting the EGFR, angiogen-esis and cell signalling pathways and cell cycle modulatorsare currently at different stages of development. The role ofthese novel agents in prostate cancer will be addressed byclinical trials initially in metastatic disease and then in theadjuvant setting.

The timing and modality of treatment in patients with arising PSA and no evidence of metastatic disease needs to beevaluated in randomized studies. These studies should focuson evaluation of prognostic factors characterizing patientsthat could benefit from early intervention. Novel schedules,such as intermittent hormonal therapy or targeted therapiesmay play a role in this setting.

The incorporation of chemotherapy with hormonal therapyis and will be an area of active research in the hormone-sensitivemetastatic as well as the locally advanced disease. Novel chemo-therapeutic agents and combinations with or without androgendeprivation are currently being evaluated in different stages ofprostate cancer including the neoadjuvant setting and risingPSA postlocal therapy.

Key issues

• Hormonal therapy for prostate cancer is currently the established treatment for metastatic disease.

• Intermittent hormonal therapy is a promising new approach that could improve quality of life and possibly delay the emergence of resistance.

• Hormonal therapy combined with surgery or radiation in certain patients with locally advanced or N1 prostate cancer improves local control and possibly survival.

• Understanding the mechanism of emergence of hormone resistance will help in devising strategies to prolong androgen dependence and identifying new therapeutic targets. The combination of chemohormonal therapy in prostate cancer is an area of active research in metastatic and high-risk stage disease.

• The role of targeted therapies in prostate cancer is an area of active basic science and clinical research.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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79 Byar DP, Corle DK. Hormone therapy for prostate cancer: results of the Veterans Administration Co-operative Urological Research Group studies. NCI Mono. 7, 165–170 (1988).

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•• Prospective randomized study of early versus late hormonal therapy in metastatic prostate cancer.

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•• Prospective randomized study of adjuvant hormonal therapy in surgically treated N-1 prostate cancer. Improved PFS and OS in the adjuvant arm of the study.

82 Labrie F, DuPont A, Cusan L et al. Downstaging of localized prostate cancer by neoadjuvant therapy with flutamide and lupron: the first controlled and randomized trial. Clin. Invest. Med. 16(6), 499–509 (1993).

83 Goldenberg SL, Klotz LH, Srigley J et al. Randomized, prospective, controlled study comparing radical prostatectomy alone and neoadjuvant androgen withdrawal in the treatment of localized prostate cancer. Canadian Urologic Oncology Group. J. Urol. 156(3), 873–877 (1996).

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85 Dalkin BL, Ahmann FR, Nagle R, Johnson CS. Randomized study of neoadjuvant testicular androgen ablation therapy before radical prostatectomy in men with clinically localized prostate cancer. J. Urol. 155(4), 1357–1360 (1996).

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•• Randomized prospective study evaluating hormonal therapy in locally advanced prostate cancer with radiation. Improved local control and PFS in hormonal therapy group.

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88 Pilepich MV, Caplan R, Byhardt RW et al. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31. J. Clin. Oncol. 15(3), 1013–1021 (1997).

•• Subgroup analysis demonstrating an improvement in overall survival in the patients with a Gleason score of 8 or above.

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•• Improved survival in patients with locally advanced/high-risk prostate cancer treated with radiation and hormonal therapy over radiation alone.

90 Hanks GE, Lu J, Machtay M et al. RTOG protocol 92-02: A Phase III trial of the use of long-term androgen suppression following neoadjuvant hormonal cytoreduction and radiotherapy in locally

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• Comparison of long-term androgen suppression in the adjuvant setting results in prolonged PFS as compared to short-term.

91 Lawton C, Winter K, Murray K. Updated results of the Phase III radiation therapy oncology group (RTOG) trial 85-31 evaluating the potential benefit of androgen deprivation following standard radiation therapy for unfavourable prognosis carcinoma of the prostate. Proc. Am Soc. Clin. Oncol 18, 311a Abstract 1195, (1999).

92 Wirth M, See W, McLeod D, Iversen P, Persson BE, Carroll K. Bicalutamide (‘Casodex’) 150 mg as immediate or adjuvant therapy in 8113 men with localized or locally advanced prostate cancer. Proc. Am. Soc. Clin. Oncol. Abstract 705, (2001).

93 Janknegt RA, Abbou CC, Bartoletti R et al. Orchiectomy and nilutamide or placebo as

treatment of metastatic prostatic cancer in a multinational double-blind randomized trial. J. Urol. 149(1), 77–82 (1993).

94 Iversen P, Rasmussen F, Klarskov P, Christensen IJ. Long-term results of Danish Prostatic Cancer Group trial 86. Goserelin acetate plus flutamide versus orchiectomy in advanced prostate cancer. Cancer 72(12 Suppl.), 3851–3854 (1993).

Website

101 The European Organization for Research and Treatment of Cancerhttp://www.eortc.be

Affiliations• Basil F El-Rayes• Maha H Hussain, MD

Division of Haematology and OncologyKarmanos Cancer InstituteWayne State University4100 John R StreetDetroit, MI 4820, USAhussainm@Karmanos.org