Recent Advances in Hormonal Therapy for Advanced Prostate Cancer

ABSTRACT: Hormonal treatment of advanced prostate cancer should be consideredfor patients who have stages C and D1 disease, a high risk of recurrenceafter local therapy, or prostate-specific antigen–measured recurrenceafter local treatment. This approach is dependent on most prostatecancer cells being androgen-dependent, but androgen-independentcells may arise after several years of hormonal therapy. Options forandrogen blockade primarily include orchiectomy, luteinizing hormone–releasing agonists and antagonists, and nonsteroidal antiandrogens.There is some controversy regarding combined androgen blockade,intermittent androgen blockade, and the question of whether earlyandrogen blockade is superior to delayed therapy. Convincing data doexist for the use of adjuvant/neoadjuvant hormonal therapy with external-beam radiation therapy. Although hormonal therapy is an importanttreatment modality for advanced prostate cancer, long-termtreatment carries significant side effects that need to be considered.

More than 60 years haveelapsed since Huggins andHodges[1] first recognizedthe hormonal dependence of prostatecancer. The mainstay of endocrinemanipulation for metastatic adenocarcinomaof the prostate is either orchiectomyor medical hormonetherapy. Although the traditional definitionof "advanced" prostate cancerencompasses patients with widespreadosteoblastic or soft-tissue metastases,this nomenclature for advanced diseaseshould be challenged. A morecontemporary definition needs to beconsidered in order to maximize treatmentoptions. This would include notonly stage D2 patients, but also menwith stages C and D1 (T3, T4, andany T, N1) disease, a high risk of diseaserecurrence after local therapy, andprostate-specific antigen (PSA) recurrenceafter local therapy.[2]The premise of androgen ablationrelies on growth of most prostate carcinomacells being androgen-dependent.The androgen receptor expressedby these cells binds dihydrotestosterone,which is then transported intothe nucleus, leading to a cascade ofevents that induces cellular growth. Ifandrogen is removed, cellular deathensues via apoptosis of the androgensensitivecells. An androgen-independentphenotype can occur by wayof androgen-resistant clones that surviveand proliferate, their growth beingstimulated by mitogenic growthfactors. The predomination of an androgen-independent phenotype canoccur approximately 1 to 2 years afterthe initiation of androgen deprivation.Multiple strategies have been usedto induce serum levels of testosteronesimilar to those following castration.Traditional treatment options for androgenblockade include orchiectomy,luteinizing hormone-releasing hormone(LHRH) agonists and antagonists,nonsteroidal antiandrogens, andestrogens. Estrogens are rarely used atthis time, owing to their potentially lifethreateningcardiovascular toxicity andlack of availability.[3] In the early1980s, LHRH agonists and antiandrogenswere introduced. However, controversiesexist concerning the use ofLHRH agonists and antiandrogens,such as the utility of combined or totalandrogen blockade (ie, using anLHRH agonist plus an antiandrogenor orchiectomy plus an antiandrogen),early vs delayed hormonal therapy,and intermittent vs continuous therapy.Risk of Disease Progressionand DeathA large percentage of men withadvanced prostate cancer have nonmetastaticextracapsular disease (stageT3). These individuals are at an increasedrisk of dying when comparedto those with localized, organ-confineddisease.[4] A great majority ofmen with T3 disease are otherwisehealthy, with minimal comorbid factors.Most are asymptomatic but havea substantial risk of disease progressionand death; therefore, they shouldbe treated in a manner similar to menwith metastatic disease. A larger subgroupof patients would then be included,that is, men with clinical T2cancers would be pathologically upstagedto T3 disease; this is appropriategiven that between 30% and 50%of patients with clinical T2 diseasehave pathologic T3 cancers.[5] A dilemmamight arise over patient selectionfor treatment, but it is hard todeny treatment to the T3 cohort, whoare at a significantly increased risk ofdeveloping metastatic disease. Anothersubgroup of patients-those with apersistent elevation of PSA after localizedtreatment by external-beamradiation or radical prostatectomy-also should be considered as havingadvanced disease.Recurrence Modeling
Moul[6] described the use of a recurrencemodel for men treated afterradical prostatectomy, which wasbased on a model by Bauer et al.[7]Recurrence modeling appears to behelpful in identifying men at a highrisk of disease recurrence. The Departmentof Defense Center for ProstateDisease Research model includedfour prognostic factors-PSA, Gleasonsum, pathologic stage, and race-to derive a risk of recurrence. In thisstudy, men in the high-risk category(relative risk > 30) had a 55.5% chanceof recurrence at 3 years and an 84.8%chance at 5 years.[6]When Partin et al[8] conducted studiesin patients with stage B2 disease,they identified a select group of patientswith a high risk of disease recurrenceafter radical prostatectomy. Ourown group has developed artificial neuralnetworks, including the prostate calculator,to assist with predictingrecurrence after radical prostatectomy(www.prostatecalculator.org).[9] Althoughno model can be 100% predictive,individuals who are at a high riskof disease recurrence may benefit fromearly treatment with hormone therapy.In the future, new and innovative biochemicaltools (eg, proteomics, proteinscreening) will yield new markers thatwill help clinicians not only to diagnoseprostate cancer but also to identifypatients at risk for progression andrecurrence.Orchiectomy vs LHRH AgonistsAlthough orchiectomy is an excellentmodality for producing castratelevels of testosterone, it is an underusedform of hormonal treatment. The procedureitself is straightforward: It canbe performed in an outpatient settingand it produces an immediate reductionin levels of circulating testosteronewithin a few hours.[10]The first Veterans AdministrationCooperative Urological ResearchGroup study in 1967 illustrated thatorchiectomy was associated with a1-year survival rate of 73% and a5-year survival rate of 35% amongstage IV patients, vs 66% and 2%,respectively, among patients receivingplacebo.[11] Over a longer follow-up period, however, hormonetreatment did not have an impact onthe development or course of androgen-independent disease.[12] Orchiectomydid result in subjectiveimprovement in pain symptoms andperformance status, compared withplacebo.Although orchiectomy and LHRHagonists have equivalent outcomes,most patients prefer LHRH agonistsbecause of the psychological problemsassociated with the removal ofthe testicles.[13] Another issue withorchiectomy is the irreversible natureof the procedure and the fact that itcan limit future therapeutic options;for example, intermittent hormonalablation therapy, hypothesized to delaythe development of the androgeninsensitivephenotype, obviously is notpossible in the setting of orchiectomy.Data from the Prostate Cancer OutcomesStudy provided an update onquality-of-life issues for patients receivinghormonal therapy.[14] Thosewho chose LHRH-agonist treatmentreported more sexual dysfunctionthan patients who had undergone orchiectomy;both groups had equalbaseline sexual function prior to treatment.Again, however, the psychologicalimplications of loss of thetesticles may lead men to continuechoosing LHRH-agonist therapy overorchiectomy.LHRH AgonistsCurrently, LHRH agonists seem tobe the preferred method of hormonetherapy. Since Schally et al[15] identifiedthe structure of gonadotropinreleasinghormone (GnRH) in 1971,this molecule has been of utmost importancein the treatment of prostatecancer. GnRH, also called LHRH, isreleased from the hypothalamus in apulsatile fashion and exerts its effectsby stimulating the anterior pituitaryto synthesize and release luteinizinghormone and follicle-stimulating hormone.Luteinizing hormone attachesto receptors on the Leydig cells of thetestes, promoting testosterone production.Continuous exposure to LHRHagonists eventually causes downregulationof receptors in the pituitary,inhibiting release of both folliclestimulatinghormone and luteinizinghormone and diminishing testosteroneproduction.The main drawback of LHRH agonistsis the initial hormonal flare,during which the stimulation of pituitaryGnRH receptors results in aninitial surge of gonadotropins (luteinizinghormone, follicle-stimulatinghormone) and androgens (testosterone,dihydrotestosterone ). This flarecan result in an exacerbation of symptoms,including increased bone pain,urinary retention, neurologic deficitsfrom worsening spinal cord compression, and ureteral obstruction.The two most common LHRH agonistsare leuprolide (Lupron) andgoserelin acetate (Zoladex). In theirdepot formulations, LHRH analogs areeasily administered, produce castrateserum levels of testosterone withinabout 1 month, and are not associatedwith increased cardiovascular toxicity.Phase III studies of LHRH agonistsvs surgical castration demonstrated nodifferences in survival between thetwo therapies.[16] Multiple trials withsymptomatic stage D patients haveshown improvement in or stabilizationof both local disease status andoverall performance status in nearlyall patients treated with LHRH agonisttherapy.[17,18]LHRH AntagonistsNewer LHRH (GnRH) antagonistsunder study (eg, abarelix, cetrorelix[Cetrotide]) directly block the centralGnRH receptors in the pituitary. Thismechanism completely avoids the initialgonadotropin and androgen surges,ultimately producing immediatecastration with no exacerbation ofsymptoms. Abarelix was comparedwith leuprolide acetate in a phase IIIrandomized trial.[19] By day 15, medicalcastrate levels of testosterone wereachieved for 75% of patients who receivedabarelix, compared with 10%of patients in the leuprolide group.By day 29, both groups had attainedsimilar PSA levels.In addition to their antagonistic effectson the pituitary, GnRH antagonistsmay exhibit direct inhibition ofandrogen-independent cells in theprostate.[20] GnRH agonists cause aprogressive rise in follicle-stimulatinghormone until it reaches baseline;this rise in follicle-stimulating hormonedoes not occur with GnRH antagonists.It has not been clinicallyestablished whether this follicle-stimulatinghormone-mediated role preventsor delays the occurrence ofhormone-refractory prostate cancer,but it offers a new possibility for treatmentmodalities for hormone-refractorydisease.Abarelix produces a rapid and largereduction in prostate volume (30%within 2 months) in patients receivingthe compound as neoadjuvant therapyprior to brachytherapy or radiotherapy.In addition, GnRH antagonistshave a reversible mode of action,which makes them applicable for neoadjuvanttherapy or short treatmentoptions such as intermittent therapy.Time and experience will be requiredin order for clinicians to fully evaluatethe benefits of GnRH antagonistsvs agonists in the treatment of prostatecancer.Nonsteroidal AntiandrogensAbout 5% to 10% of androgensare synthesized by the adrenal glands,which potentially can continue to stimulateandrogen-sensitive cells. The useof nonsteroidal antiandrogens (ie, bicalutamide[Casodex], nilutamide [Nilandron],flutamide), which interferewith the binding of testosterone anddihydrotestosterone to the androgenreceptor, may offer an advantage overmonotherapy.In a multicenter randomized trialof 486 men with metastatic prostatecancer, bicalutamide (50 mg/d) wascompared with hormone ablationeither by LHRH-agonist therapy ororchiectomy.[21] The overall conclusionwas that 50 mg of bicalutamidewas not as effective as hormonal ablationby LHRH-agonist therapy ororchiectomy. Conventional doses ofantiandrogens are not sufficient to produceadequate androgen deprivationand should not be utilized as singleagents for the treatment of advancedprostate cancer.Combined Androgen BlockadeBased on the facts that low levelsof androgens are produced by the adrenalglands and that monotherapy(orchiectomy or LHRH-agonist treatment)results in a 90% decrease incirculating testosterone, the use ofcombined androgen blockade theoreticallyshould be superior. Althoughthis topic is controversial, there is someevidence that combination therapy improvesresponse and survival rates.In 1989, the Southwest OncologyGroup (SWOG) published the firsttrial showing a potential advantage ofcombined androgen blockade overmonotherapy.[22] This randomized,double-blind, placebo-controlled studyevaluated leuprolide as a single agentvs leuprolide/flutamide in 603 men withpreviously untreated, metastatic prostatecancer. Compared with leuprolidemonotherapy, combined androgenblockade was associated with improvementin both median progression-freesurvival (16.5 vs 13.9 months) andmedian overall survival (35.6 vs 28.3months). In addition, the use of combinedandrogen blockade as initial therapydecreased the flare phenomenon.Other studies seem to validate thesepositive findings regarding combinedandrogen blockade, including the NationalCancer Institute (NCI) study0036, European Organization forResearch and Treatment of Cancer(EORTC) study 30853, the CanadianAnandron Study, and the MultinationalNilutamide Study, all of whichshowed a survival benefit of 7 to 15months with combination hormonaltherapy.[23]Not all research findings are inagreement about the value of combinedandrogen blockade, however.SWOG published another study (NCIIntergroup trial 0105)[24] of 1,387patients who were randomized to orchiectomyplus flutamide or orchiectomyplus placebo. They found nosurvival benefit from the addition ofan antiandrogen to orchiectomy. Inaddition, the Prostate Cancer Trialists'Cooperative Group[25] publisheda meta-analysis of trials using combinedandrogen blockade vs monotherapy.The analysis evaluated 27trials and included 8,275 men. The5-year survival rate for all patientsreceiving monotherapy was 23.6%,compared with 25.4% for combinedandrogen blockade; this overall survivaldifference was not statisticallysignificant. Studies to date have notresulted in a consensus regarding theclinical utility of combined androgenblockade.Early vs Delayed TherapyAnother topic of debate is the timingof hormonal ablation. Does earlyintervention improve survival vs delayedintervention? Although thequestion of when to initiate therapyremains difficult, data from severalstudies may assist the practitioner andpatient in making this decision.In 1997, the Medical ResearchCouncil (MRC)[26] of Great Britainfound that early hormonal ablationmay prolong survival, compared withdelayed treatment. This large study,which included 938 men with locallyadvanced or asymptomatic metastaticprostate cancer, had well-matchedtreatment groups: 469 men receivedhormonal therapy immediately and465 men were given hormones onlywhen they became symptomatic.The MRC study demonstrated anincrease in disease-specific and overallsurvival in patients treated withimmediate androgen deprivation. Theimpact of immediate vs delayed hormonaltherapy on overall mortality(including M0, MX, M1) was 62%for the immediate treatment arm and71% for the delayed-treatment group(P = .02). In addition, men whosetherapy was deferred suffered significantlymore comorbid events associatedwith their disease.The Eastern Cooperative OncologyGroup[27] examined the impact ofimmediate hormonal therapy on patientswith node-positive disease whounderwent radical prostatectomy andpelvic lymphadenectomy. The menwere randomized to one of two treatmentarms (immediate androgen deprivation,achieved by goserelin ororchiectomy) or were followed untildisease progression.After a median follow-up periodof 7.1 years, prostate cancer-specificsurvival, progression-free survival,and overall survival were significantlybetter in the group receiving immediatehormone therapy than in thecontrol group. After 10 years, the actuarialsurvival of patients treated withimmediate therapy was approximately80%, compared with 55% in thedeferred-treatment group. Thus, althoughthese patients were in a highriskcategory owing to their nodepositivedisease, early androgen deprivationimproved survival.Available information suggests thatearly androgen suppression for thetreatment of advanced prostate cancerreduces disease progression andits associated complications. Earlyandrogen suppression may provide asmall but statistically significant improvementin overall survival at10 years. Additional studies are requiredto evaluate more definitivelythe efficacy and adverse effects ofearly vs delayed androgen suppressionin men with prostate cancer. Patientswith high-risk profiles (ie,advanced disease) should have theopportunity to discuss hormone-treatmentoptions, and treatment shouldbe implemented if possible.Intermittent Androgen BlockadeIntermittent androgen blockade hasreceived close attention over the pastfew years. The primary driving forcebehind this strategy is the avoidance ofpotential side effects associated withlong-term use of hormone therapy, butintermittent androgen blockade mayalso prolong the development of anandrogen-independent phenotype.Klotz et al[28] published a studyof 20 patients with advanced prostatecancer who were treated with intermittentandrogen blockade in the formof diethylstilbestrol or flutamide.Treatment was continued until a clinicalresponse was seen (median treatmenttime: 10 months), at which pointtherapy was discontinued and then restartedafter evidence of disease recurrence.The median relapse period was8 months after treatment interruption.After recurrence, all patients respondedto reinitiation of hormonal ablation.Although no large randomizedclinical trial of LHRH agonists areavailable, animal and in vitro cell linestudies suggest that intermittent androgenblockade is beneficial.[29]Currently, the Southwest OncologyGroup, the National Cancer Institute ofCanada, the German Cancer Society,and the South European Uro-Oncological Group are studying the effectsof intermittent androgen blockade.External-Beam Irradiation andNeoadjuvant Hormonal AblationMultiple studies evaluating the efficacyof adding androgen-deprivationtherapy to external-beam radiationtherapy have illustrated improved outcomesin patients with localized or locallyadvanced prostate cancer. TheRadiation Therapy Oncology Group(RTOG)[30,31] evaluated androgendeprivation as adjunctive therapy followingstandard external-beam radiationtherapy in patients with locallyadvanced prostate cancer. Patientswith clinical stage C (T3, N0, M0) orD1 (any T, N1-3, M0) prostate cancerwere randomized to radiation plusadjuvant LHRH agent therapy, whichwas begun immediately and continuedindefinitely, or to radiation andobservation, with LHRH therapy givenonly at the time of relapse.RTOG 8531
In the RTOG 8531 trial, 977 patientswere randomized to receiveradiation only (androgen deprivationstarted at disease relapse) or radiationplus adjuvant goserelin.[30] The localfailure rate at 8 years was 23% for thecombination-therapy arm and 37% forthe radiation-alone arm (P < .0001).Disease-free survival results favoredthe immediate-androgen-deprivationarm (P < .0001), but overall survivalwas not statistically different betweenthe two groups (49% vs 47% at 8years). Given that only one-fourth ofthe patients have died thus far, however,it may be too early to assess theimpact of immediate LHRH therapyon overall survival, because there hasbeen insufficient time for evidence ofany survival advantage to emerge.RTOG 8610
It is still unclear what duration ofandrogen-deprivation therapy is necessaryfor patients to obtain the maximalbenefit. RTOG 8610, conductedfrom 1987 to 1991, randomized 471patients with T2 to T4 tumors, withor without pelvic lymph node involvement,to receive radiation plus combinedandrogen blockade with goserelinand flutamide vs radiation therapyalone.[31] Analysis at 8 years demonstratedthat patients treated withcombination therapy had improvementsin local control (12% advantage,P = .016) and disease-freesurvival (12% advantage, P = .004),as well as reductions in the incidenceof distant metastases (11% advantage,P = .04), and disease-specific mortality(8% advantage, P = .05).EORTC Trial
In 1997, the EORTC published arandomized, prospective trial of 415men (< 80 years of age) with locallyadvanced disease and no previoustreatment of prostate cancer; data from401 of those patients were availablefor analysis.[32] The study, conductedfrom 1987 to 1995, evaluatedexternal-beam radiation vs externalbeamradiation/goserelin. The overall5-year survival rate for men treatedwith an adjuvant LHRH agonist inaddition to radiotherapy was 79%, comparedwith 62% in the radiation-onlygroup (P = .001). At 5 years, 85% ofsurviving patients in the combinedtreatmentgroup and 48% of the groupwho received external-beam treatmentalone were free of disease (P < .001).Evaluating Studies of AdjuvantHormonal Treatment
The data from the aforementionedRTOG and EORTC trials stronglysuggest that adjuvant hormonal treatmentin patients with locally advancedprostate cancer improves both localcontrol and survival. Further evaluationwill be necessary to elucidate theoptimum duration of neoadjuvant andadjuvant hormonal therapy, the valueof such therapy in earlier-stage (T1c,T2) disease, and the value and durationof antiandrogens (combined androgenblockade) in this setting.All of these studies can be criticallychallenged because they comparedradiation therapy vs radiation therapy/androgen deprivation for a significantperiod of time. No study had acohort receiving androgen-deprivationmonotherapy alone, however, and hormonaltherapy without radiation mayproduce results similar to those seenwith combination radiation/hormonaltherapy. Furthermore, although thesestudies with external-beam radiationappear to be attractive, the value ofneoadjuvant and adjuvant hormonaltherapy in patients treated with surgery,brachytherapy, or cryotherapyremains unknown.Quality-of-Life IssuesAlthough the efficacy of hormonalablation is becoming increasinglyclear, there is concern about the unknowneffects associated with yearsof hormonal therapy. The most commonside effect is loss of libido, butseveral other toxicities exist, includingosteopenia, hot flashes, gynecomastia,loss of cognitive function,fatigue/malaise, depression, and lossof muscle mass.[33] If severe symptomspersist, discontinuation of therapymay be warranted.A recent study by Herr andO'Sullivan[33] assessed the quality oflife of asymptomatic men with nonmetastaticprostate cancer who receivedandrogen-deprivation therapy. Of 144men evaluated, 79 received androgendeprivation and 65 did not. Androgendeprivation consisted of orchiectomy,leuprolide alone, or leuprolide/flutamide(combined androgen blockade).Fatigue, emotional distress, decreasedphysical functioning, and impairedquality of life were observed amongmen who received androgen-deprivationtherapy; however, a greater adverseeffect was seen in the combinedandrogen blockade group.One recent concern is thatlong-term treatment with androgendeprivation may result in osteoporosis.[34,35] Although one study hassuggested that osteoporosis does resultfrom long-term hormonal ablation,[36] multiple groups argue thatmen receiving hormonal therapy donot have significantly lower bone mineraldensities than age-matched controls.[37] The precise incidence ofrelevant bone fractures remains unclear,especially in regard to the potentialof osteopenia/osteoporosisfrom hormonal ablation.ConclusionsWith ongoing studies, the advantagesof hormonal management foradvanced prostate cancer are becomingevident. The traditional definitionof advanced disease should includenot only those men with widely metastaticdisease but also those with asignificant chance of progression andrisk of death from prostate cancer:patients with stages C and D1 (T3,T4, and any T, N1) disease, those athigh risk of disease recurrence afterlocal therapy, or those with PSA recurrenceafter local treatment.As new molecular markers areidentified, and with the use of relative-risk modeling tools (eg, artificialneural networks), an increasing numberof men can begin treatment beforemetastatic disease develops. It is hopedthat earlier initiation of therapy willreduce overall morbidity and mortalityfor these patients, thereby allowingthem to have a longer symptom-freeinterval and better quality of life.Surgical castration and medicalmanagement with GnRH analogs havebeen shown to be equally effective.Although both forms of treatmenthave psychological implications, ultimatelythe form of therapy selectedwill be the patient's decision. Controversywill continue regarding the clinicalutility of combination hormonaltherapy. Existing data do not uniformlysupport the value of combinationtherapy in improving morbidity andsurvival. Currently, combined androgenblockade and treatment with monotherapyseem to be equally efficacious.The optimal timing of hormonalablation represents another area ofcontroversy. Does early interventionprevail over delayed therapy? Evidencesuggests that early androgensuppression does reduce disease progressionand complications resultingfrom progression. When patients havehigh-risk profiles, clinicians shoulddiscuss the options of early hormonalintervention, and treatment should beimplemented if feasible. Concernabout known and unknown effects ofyears of hormonal therapy use,including the potential for osteoporosis,has increased interest in intermittentandrogen blockade; future studieswill reveal the true efficacy of thistreatment modality.The role of adjuvant/neoadjuvanthormonal therapy in the setting ofexternal-beam radiation therapy isbecoming increasingly clear. Futurestudies will need to include a cohortwith hormonal monotherapy alone,and should identify the optimal durationof neoadjuvant/adjuvant hormonaltreatment.Further research will determine themost effective treatment approachesusing hormonal and other therapies.The combination of chemotherapy andhormonal therapy needs to be investigated.The ultimate goal is to identifytherapies that yield the greatest efficacywithout seriously compromisingthe well-being of the patient.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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