The Current State of Hormonal Therapy for Prostate Cancer
`
`The Current State of Hormonal
`Therapy for Prostate Cancer
`
`Beth A. Hellerstedt, MD; Kenneth J. Pienta, MD
`
`Dr. Hellerstedt is Fellow, Division
`of Hematology and Oncology,
`University of Michigan Medical
`Center, Ann Arbor, MI.
`
`Dr. Pienta is Professor,
`Internal
`Medicine and Urology and Director,
`Urologic Oncology Program, Uni-
`versity of Michigan Medical Center,
`Ann Arbor, MI.
`
`ABSTRACT Androgen deprivation therapy remains a mainstay of treatment for men with
`prostate cancer. New uses for hormonal therapy, including use in the adjuvant and neoadjuvant
`setting, are being evaluated. Prevention of the side effects of therapy has led to the
`development of alternative schedules and therapeutics. (CA Cancer J Clin 2002;52:154-179.)
`
`INTRODUCTION
`
`This article is also available at
`www.cancer.org.
`
`Hormonal or androgen deprivation therapy is utilized in multiple settings in the
`prostate cancer patient (Figure 1). In general, androgen deprivation induces a
`remission in 80 to 90 percent of men with advanced prostate cancer, and results in
`a median progression-free survival of 12 to 33 months.1 At that time, an androgen-
`independent phenotype usually emerges, leading to a median overall survival of 23
`to 37 months from the time of initiation of androgen deprivation.
`In 1895,White first documented the use of androgen ablation in 111 men with prostate hypertrophy treated by
`castration.2 David and colleagues isolated testosterone in 1935 and in 1941, Huggins and Hodges introduced
`androgen deprivation as therapy for advanced prostate cancer.3,4 In the 1950s, retrospective analyses provided data
`suggesting that patients treated with hormonal therapy in the form of estrogens or orchiectomy enjoyed a survival
`and quality-of-life advantage when compared with patients followed in the pre-therapy era.5,6
`Multiple strategies have been used to induce castrate serum levels of testosterone or interfere with its function
`(Figure 2). In order to rigorously test the previously reported data that androgen deprivation can impact the natural
`history of prostate cancer, the Veterans Administration Cooperative Urological Research Group (VACURG)
`conducted three large, randomized studies regarding the treatment of early stage and advanced prostate cancer from
`1960 to 1975.7,8,9,10 These prospective studies provided data on a large cohort of men, and provided guidelines for the
`use of orchiectomy and estrogens as treatment. In the 1980s, luteinizing hormone-releasing hormone (LHRH)
`agonists and antiandrogens were introduced.These compounds have been evaluated in practically every conceivable
`clinical setting, from the traditional role in advanced disease to use in the adjuvant and neoadjuvant settings.
`Combination treatment with testicular androgen suppression and an antiandrogen (called combined androgen
`blockade or maximal androgen blockade) soon followed. Although an impressive body of knowledge has
`accumulated, the variety of options and occasionally conflicting data has made the use of hormonal therapy all but
`straightforward.
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`CA Cancer J Clin 2002;52:154-179
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`METHODS OF PRIMARY ANDROGEN ABLATION
`
`Orchiectomy
`
`The first VACURG study, published in
`1967, randomized 1,764 Stage III and IV
`patients to one of four treatment options:
`placebo, orchiectomy plus placebo, DES 5 mg
`per day, or orchiectomy plus DES 5 mg per
`day.8 Orchiectomy was associated with a one-
`year survival rate of 73 percent and a five-year
`survival rate of 35 percent in Stage IV patients,
`compared with 66 percent and 20 percent in
`placebo-treated patients. With longer follow-
`up, however, overall survival curves for all four
`arms were equivalent, suggesting that the type
`of hormonal treatment did not influence
`the development or course of androgen-
`independent disease.11 Compared with pla-
`cebo, all treatments were associated with
`subjective
`improvements
`in pain
`and
`performance status.
`its efficacy,
`regarding
`Despite data
`orchiectomy may be an underused form of
`hormonal treatment. Surgical castration is an
`outpatient procedure that results
`in an
`immediate reduction in circulating testos-
`terone over a period of a few hours.12 Although
`data are sparse, some studies suggest that up to
`50 percent of men choose orchiectomy when
`it is offered as an option for reasons of
`convenience and cost.13 The most recent data
`from the Prostate Cancer Outcomes Study
`provided an update on quality-of-life issues for
`patients receiving hormonal therapy.14 Men
`who chose LHRH agonist therapy reported
`greater problems with their overall sexual
`functioning than did orchiectomy patients,
`despite both groups having similar levels of
`function prior to treatment. LHRH agonist
`patients were also less likely to perceive
`themselves as free of cancer, due to the need
`
`for ongoing injections. Another study, how-
`ever, suggested that men who underwent
`orchiectomy were more likely to regret this
`decision as compared with those treated with
`LHRH agonist therapy.15
`
`Diethylstilbestrol
`
`Diethylstilbestrol (DES), a semi-synthetic
`estrogen compound, was one of the first
`nonsurgical options for the treatment of
`prostate cancer. Widespread use has been
`limited, however, by
`the potential
`for
`significant cardiovascular and thromboembolic
`toxicity.
`Initial studies from VACURG and the
`European Organization for Research and
`Treatment of Cancer (EORTC) used 3 to 5
`mg of DES per day, and showed the remission
`rate of DES to be equivalent to orchiectomy.8
`Overall mortality, however, was higher in the
`DES group due to an excess of cardiovascular
`deaths. A more recent study (EORTC 30805)
`demonstrated the equivalence of orchiectomy
`and DES at 1 mg per day.16 In this study, 13
`percent of patients receiving DES had
`treatment discontinued due to cardiovascular
`complications, compared with none in the
`orchiectomy arm. Most of the events were
`venous in nature, including edema and deep
`venous thrombosis. DES at a dose of 3 mg per
`day has also shown equivalence to LHRH
`agonists in patients with locally advanced and
`metastatic disease in terms of overall survival
`and subjective improvement.17-21 DES proved
`to be superior to flutamide alone in the
`treatment of metastatic disease.22 Several
`EORTC
`trials
`(30761
`and
`30762)
`demonstrated DES 3 mg per day to be
`equivalent to estramustine23 and cyproterone.24
`The introduction of the LHRH analogs, with
`no significant cardiovascular toxicity, lack of
`
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`
`The Current State of Hormonal Therapy for Prostate Cancer
`
`FIGURE 1
`Treatment Algorithm After Initial Diagnosis
`
`Diagnosis of Prostate Cancer
`
`Neoadjuvant
`Androgen Deprivation
`
`Watchful Waiting
`
`Primary Therapy
`
`Cured
`
`Adjuvant Androgen Deprivation
`
`Local Salvage
`
`Rising PSA
`
`Progression
`
`Androgen Deprivation Therapy
`
`Progression
`
`Secondary Hormonal Therapy
`
`Androgen Independence
`
`After initial diagnosis, patients have several options regarding treatment. Androgen deprivation therapy is indicated, however, at the time of disease
`progression after definitive and salvage local therapy.
`
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`CA Cancer J Clin 2002;52:154-179
`
`breast enlargement, and significant reim-
`bursement for clinicians, essentially ended the
`use of DES as a first-line hormonal therapy.
`DES is no longer mass produced for human
`use in the United States.
`
`Cyproterone
`
`Cyproterone acetate (CPA) is a steroidal,
`progestational antiandrogen that blocks the
`androgen-receptor interaction and reduces
`serum testosterone through a weak anti-
`gonadotropic action.25 It is commonly used in
`Canada as monotherapy or as an agent to
`prevent disease flare during initiation of LHRH
`agonist therapy. Cyproterone can also suppress
`hot flashes in response to androgen deprivation
`treatment with LHRH agonists or orchiec-
`tomy.26 Although it is generally well tolerated,
`CPA is also associated with a high rate of
`cardiovascular complications,
`and
`is not
`available in the United States.
`
`LHRH Agonists and Antagonists
`
`The introduction of the LHRH agonists, the
`two most common being leuprolide and
`goserelin, revolutionized the treatment of
`advanced prostate cancer. No surgery is
`required—a potentially important physical and
`psychological benefit.
`LHRH is normally released from the
`hypothalamus in pulses. This leads to the
`pulsatile release of FSH (follicle stimulating
`hormone) and LH (luteinizing hormone). LH
`attaches to receptors on the Leydig cells of the
`testes, promoting testosterone production.
`Constant exposure to LHRH after treatment
`with an LHRH agonist, however, eventually
`causes downregulation of receptors in the
`pituitary, inhibition of FSH and LH release,
`and a concomitant decrease in testosterone
`production.
`Initial treatment with LHRH agonists,
`
`however, causes a surge of LH release, with a
`corresponding increase in testosterone levels.
`This testosterone surge can result in a transient
`increase in prostate cancer growth. Some
`patients can experience a worsening of bone
`pain, urinary obstruction, or other symptoms
`attributable to rapid cancer growth, known as
`the flare phenomenon.
`LHRH agonists have different side effect
`profiles than DES and CPA,
`including no
`cardiovascular toxicity. Phase III studies of
`LHRH agonists versus surgical castration
`demonstrated no difference in survival between
`the
`two
`therapies.27 Depot preparations
`(injections lasting three to four months) for
`androgen ablation are now the most common
`treatments for metastatic prostate cancer.
`Multiple Phase III studies have demonstrated
`that all preparations have similar efficacy.28
`Abarelix is one of the new, modified
`gonadotropin-releasing hormone antagonists.
`Unlike the standard LHRH agonists, abarelix is
`a direct LHRH antagonist, and thus avoids the
`flare phenomenon. This compound was
`recently compared with leuprolide acetate in a
`Phase III randomized trial.29 Medical castration,
`as measured by serum testosterone levels, was
`achieved in 75 percent of the abarelix group by
`day 15, compared with 10 percent of patients in
`the leuprolide group. The percentage decrease
`in PSA was significantly greater in the abarelix
`group on day 15 after treatment. At day 29,
`post-treatment and beyond, PSA levels were
`similar between leuprolide and abarelix. As this
`study does not have mature follow-up, it is not
`possible to determine if abarelix and leuprolide
`will provide identical rates of disease control.
`
`PC-SPES
`
`PC-SPES, an herbal supplement, has been
`evaluated in a prospective Phase II trial.30 The
`mechanism behind the efficacy of PC-SPES is
`not well understood. The toxicities and
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`The Current State of Hormonal Therapy for Prostate Cancer
`
`biochemical effects appear to be estrogenic.
`Analysis of the product, however, did not yield
`any known estrogens.As PC-SPES is an herbal
`supplement, no standards exist for ensuring all
`pills have equal amounts of “active” extract.
`Additionally, PC-SPES has been shown to
`decrease PSA production in vitro, a finding that
`may play a role in evaluation of efficacy.
`Recently the California Department of Health
`Services (CDHS) found traces of warfarin
`in PC-SPES during laboratory analysis.31
`Researchers at the University of Cali-
`fornia/San Francisco Medical Center then
`issued a statement indicating that certain lots of
`PC-SPES being used in a clinical trial also
`contained traces of DES.32 The CDHS has
`subsequently recalled all lots of existing drug.33
`
`Nonsteroidal Antiandrogens
`
`The nonsteroidal antiandrogens bicalu-
`tamide,
`flutamide, and nilutamide interfere
`with
`the binding of
`testosterone and
`dihydrotestosterone to the androgen receptor
`(Figure 2). In a randomized, multicenter trial of
`486 patients with previously untreated
`metastatic prostate cancer, bicalutamide 50 mg
`per day was compared with castration with
`either orchiectomy or LHRH agonist
`therapy.34 Bicalutamide was almost as effective
`as orchiectomy; treatment failure occurred in
`53 percent of bicalutamide-treated patients
`compared with 42 percent of castrated patients.
`Survival was not significantly different between
`the two groups.Although PSA progression was
`not considered to be evidence of disease
`progression, PSA normalization occurred in 17
`percent of the bicalutamide group and 47
`percent in the castrated group; this represented
`a median decline of 88 percent and 97 percent
`from baseline,
`respectively. The authors
`concluded that 50 mg of bicalutamide was not
`as effective as castration for the treatment of
`patients with metastatic disease. Given this
`
`at
`antiandrogens, when utilized
`data,
`conventional doses, do not provide adequate
`androgen deprivation. Therefore, they should
`not be used as single agents for the treatment
`of advanced prostate cancer.
`
`Combined Androgen Blockade
`
`Monotherapy with androgen deprivation
`results in a decline of 90 percent of circulating
`testosterone (Figure 2). Ten percent of
`circulating testosterone is still present in
`castrated men due to peripheral conversion of
`circulating adrenal steroids to testosterone.
`Few
`subjects have generated more
`controversy in the field of urologic oncology
`over the last ten years than the question of
`whether patients should be treated with
`monotherapy versus combined androgen
`blockade (CAB). CAB consists of treatment
`with a LHRH agonist or orchiectomy plus a
`nonsteroidal antiandrogen.
`The first trial to show a potential advantage
`to CAB over monotherapy was published in
`1989.This randomized, double blind, placebo-
`controlled study evaluated leuprolide alone
`versus leuprolide and flutamide in 603 men
`with previously untreated, metastatic prostate
`cancer.35 CAB was associated with a significant
`improvement
`in median progression-free
`survival (16.5 months versus 13.9 months) and
`in median overall survival (35.6 months versus
`28.3 months). Men with minimal disease and
`good performance status appeared to benefit
`the most from combined therapy, although
`retrospectively, only 41 men in each group
`qualified for this category. In addition, the use
`of CAB in initial therapy lessened the flare
`phenomenon. It was unclear if the prevention
`of the flare could account for the differences in
`survival.Testosterone levels were elevated for a
`few weeks at most. These results were
`considered to be validated by two other early
`trials: EORTC 3085336 (originally reported in
`
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`

`
`FIGURE 2
`Strategies for Androgen Deprivation
`
`CA Cancer J Clin 2002;52:154-179
`
`Hypothalamus
`
`Estrogen
`
`LHRH
`
`LHRH Analogs (leuprolide, goserelin)
`
`LHRH Antagonists (abarelix)
`
`Anterior Pituitary
`
`LH
`
`Testicles
`
`Adrenal Gland
`
`Steroids
`
`90% T
`
`10% T
`
`Conversion
`
`Surgical Castration
`
`Nonsteroidal antiandrogens
`block binding of T and DHT
`to the androgen receptor.
`(flutamide, bicalutamide,
`nilutamide)
`
`T
`
`AR
`
`T
`5αR
`
`DHT
`
`Finasteride prevents
`T conversion to active metabolite
`dihydrotestosterone.
`
`DNA
`
`Cell Proliferation
`
`LHRH = Luteinizing hormone-releasing hormone.
`LH = Luteinizing hormone.
`T = Testosterone.
`DHT = Dihydrotestosterone.
`
`Prostate Cancer Cell
`
`5αR = 5-alpha reductase.
`AR = Androgen receptor.
`DNA = Deoxyribonucleic acid.
`
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`The Current State of Hormonal Therapy for Prostate Cancer
`
`FIGURE 3
`10-year Survival in the 27 Randomised Trials of MAB Versus Monotherapy
`
`Reprinted with permission from The Lancet.39
`
`1990) and PONCAP37 (the Italian Prostatic
`Cancer Project, reported in 1993).These trials
`also demonstrated a statistically significant
`improvement in survival for patients treated
`with CAB (goserelin and flutamide) versus
`monotherapy (orchiectomy).
`Later studies provided conflicting data. In
`
`1998, Eisenberger and colleagues published a
`study of 1,387 patients (NCI-INT 0105) with
`previously untreated metastatic disease who
`were randomized to bilateral orchiectomy and
`placebo versus bilateral orchiectomy and
`flutamide.38 At the time of progression, the
`study was unblinded and patients receiving
`
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`CA Cancer J Clin 2002;52:154-179
`
`placebo were allowed to cross over to
`flutamide. The data were reported using an
`intention-to-treat analysis. There were no
`differences between the two groups in overall
`survival or progression-free survival. Two
`factors were hypothesized to account for the
`discrepancy between the results of this trial and
`the earlier reports. The first factor was
`noncompliance in the 1989 study to the daily
`regimen of leuprolide injections, which may
`have resulted in incomplete testicular ablation.
`The superiority of flutamide may have been a
`simple reflection of this. Second, the flare
`phenomenon may have played a role in the
`superiority of CAB over monotherapy, as the
`improvements were not seen with bilateral
`orchiectomy. Approximately 20 other studies
`also failed to confirm the survival advantage
`detected in the earlier studies, although many
`were small with flawed statistical analysis and
`immature data.
`In 2000,
`the Prostate Cancer Trialists’
`Cooperative Group published a meta-analysis
`of
`the available
`trials of CAB versus
`monotherapy, in an attempt to summarize the
`available data.39 The analysis included 27 trials,
`which incorporated 8,275 men, representing
`98 percent of men ever randomized in trials of
`CAB versus monotherapy (Figure 3).The five-
`year survival for all patients receiving CAB was
`25.4 percent compared with 23.6 percent for
`patients receiving monotherapy. This 1 to 2%
`absolute difference in survival did not reach
`statistical significance.
`In subset analyses,
`patients treated with cyproterone seemed to
`fare slightly worse than those treated with
`flutamide or nilutamide, mostly secondary to
`non-prostate cancer related death. If the trials
`involving cyproterone were excluded, there
`was a significant improvement in survival with
`CAB including nilutamide or flutamide, but
`with a 95% confidence interval of 0.4 to 5.4
`percent.Taken as a whole, the data suggest that
`there is a small survival advantage to CAB
`
`using flutamide or nilutamide, which does not
`exceed a 5% improvement in five-year survival,
`and is likely closer to a 2 to 3% improvement.
`With these data, the authors did not support
`CAB over monotherapy as the first-line
`hormonal treatment of choice.
`At this juncture, there is no way to predict
`which patients, if any, would benefit from the
`immediate institution of CAB. No molecular
`markers with predictive capacity exist, unlike
`estrogen receptor and progesterone receptor
`positivity in breast cancer patients.Additionally,
`no trials compare CAB with monotherapy
`followed by the institution of CAB at the time
`of progression. A trial of this type may be
`embraced in the current environment, as
`treatment of prostate cancer moves toward
`sequential
`interventions,
`attempting
`to
`maximize the therapeutic effects of each
`maneuver while balancing benefits with side
`effects. As more data are gathered about
`the mechanism of change from hormone-
`dependence to hormone-independence,
`it
`seems unlikely that the simple manipulation of
`the androgen receptor could result in the
`complex array of gene and signal transduction
`activation necessary for this transformation. It
`is unlikely,
`therefore,
`that further trials of
`appropriate size and randomization will be
`undertaken with the primary objective of
`defining the survival advantage of CAB.
`Despite the degree of available data and
`analysis, there is no consensus on the use of
`CAB. The ultimate decision on monotherapy
`versus CAB remains, at this time, in the hands
`of the individual patient and practitioner.
`
`HORMONE THERAPY IN CONJUNCTION WITH
`RADICAL PROSTATECTOMY
`
`Neoadjuvant Therapy
`
`Neoadjuvant hormonal therapy prior to
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`The Current State of Hormonal Therapy for Prostate Cancer
`
`prostatectomy has been investigated in several
`trials.The Lupron Depot Neoadjuvant Prostate
`Cancer Study Group conducted a multi-
`institutional prospective randomized trial for
`patients with Stage cT2b prostate cancer.40 One
`hundred thirty eight men received three
`months of leuprolide plus flutamide prior to
`radical prostatectomy and 144 underwent
`radical prostatectomy alone. Patients were
`followed with PSA measurements every six
`months for five years. Biochemical recurrence
`was defined as PSA greater than 0.4 ng/ml.
`Although patients who received three months
`of androgen deprivation had a significant
`decrease in the positive margin rate at the time
`of surgery, there was no difference in the
`biochemical recurrence rate at five years. PSA
`was less than 0.4 ng/ml in 64.8 percent of the
`patients in the neoadjuvant androgen ablation
`plus prostatectomy and 67.6 percent in the
`prostatectomy-only group (p = 0.663). The
`authors concluded that neoadjuvant androgen
`deprivation before radical prostatectomy was
`not indicated. This conclusion is supported by
`another study of 402 patients, 192 who
`underwent three months of neoadjuvant
`goserelin and
`flutamide and 210 who
`underwent surgery alone.41 These investigators
`similarly reported improved local control rates
`at the time of surgery, but no difference in the
`rate of biochemical recurrence. The overall
`conclusion
`from
`these
`trials was
`that
`neoadjuvant therapy should not be utilized
`outside a clinical research setting.
`It has been suggested that three months of
`neoadjuvant androgen deprivation may not be
`long enough. Gleave and colleagues treated 156
`men with localized prostate cancer with
`neoadjuvant CAB for eight months prior to
`radical prostatectomy.42 The risk of PSA
`recurrence with this regimen was low after five
`years of follow-up in relation to the presence of
`adverse preoperative risk factors. The lack of a
`control group in this study makes it impossible
`
`longer duration of
`say whether a
`to
`neoadjuvant androgen deprivation therapy
`would provide more benefit than shorter
`schedules or no therapy.The Gleave group has
`recently undertaken a randomized trial of three
`versus eight months of neoadjuvant therapy
`prior to prostatectomy.43 A recently published
`interim analysis reports a significantly higher
`percentage of patients with an undetectable
`PSA nadir in the eight-month group compared
`with the three-month group (75 percent versus
`43 percent). Mean PSA levels decreased by 98
`percent (0.12 µg/L) after three months of
`therapy, but continued to decline an additional
`57 percent to 0.052 µg/L after eight months of
`therapy. Similar trends were seen in prostate
`volume. Radical prostatectomy has been
`completed in 500 men, with significantly lower
`rates of positive margins in the eight-month
`group
`(12 percent versus 23 percent).
`Recurrence rates (either biochemical or local)
`post-prostatectomy were not reported, as
`follow-up time was too short. The authors
`caution that these biochemical and pathological
`end points should not be interpreted as
`conclusive.
`
`Adjuvant Therapy
`
`Several nonrandomized, retrospective studies
`have
`suggested
`that adjuvant androgen
`deprivation therapy after radical prostatectomy
`may improve local control and possibly survival.
`In a recent review of adjuvant hormonal
`therapy, Zincke and colleagues systematically
`analyzed retrospective data from the Mayo
`Clinic database in addition to the existing
`prospective and retrospective trials from other
`institutions.44 The retrospective review of the
`Mayo Clinic data included 707 men who
`underwent
`prostatectomy
`for
`Stage
`pT3bN0M0 disease, 147 of whom received
`adjuvant hormonal therapy (orchiectomy or
`oral hormones). Adjuvant
`therapy was
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`CA Cancer J Clin 2002;52:154-179
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`associated with a significant improvement in
`biochemical progression-free survival (67
`percent versus 23 percent at 10 years), systemic
`progression-free survival (90 percent versus 78
`percent) and cause-specific survival (95 percent
`versus 87 percent).
`The Eastern Cooperative Oncology Group
`(ECOG) randomized 98 men with positive
`lymph nodes at the time of surgery to receive
`immediate antiandrogen therapy (with either
`goserelin or orchiectomy) or to be followed
`until disease progression.45 After 7.1 median
`years of follow-up, 7 of 47 men who received
`immediate antiandrogen treatment had died, as
`compared with 18 of 51 men
`in the
`observation group (p = 0.02). In the adjuvant
`group, three men died of prostate cancer,
`compared with 16 men in the observation
`group (p < 0.01).
`Interest has been increasing in the use of
`nonsteroidal antiandrogens as adjuvant therapy
`in patients with localized disease.46 Early results
`of a study of 365 patients with pT3N0 disease
`investigating the efficacy of flutamide (250 mg
`twice daily) given after radical prostatectomy
`demonstrated a 10% clinical recurrence rate at
`four years in the flutamide-treated patients
`compared with a rate of 31 percent for those
`receiving placebo (p = 0.002).47 The patients
`treated with flutamide, however, experienced a
`high
`incidence of
`side effects, with
`approximately 20 percent of the patients
`withdrawing from the study secondary to
`toxicity. The mature results of the study have
`not been reported.Another trial is underway to
`evaluate the effectiveness of adjuvant high-dose
`bicalutamide (150 mg) in patients undergoing
`definitive therapy for localized disease.48
`Timing of the institution of hormonal
`therapy
`for
`prostate
`cancer
`remains
`controversial, but there is a growing consensus
`that men with nodal disease at the time of
`surgery have a survival benefit from immediate
`androgen deprivation. This approach must be
`
`balanced by the toxicity associated with long-
`term adjuvant therapy.49
`
`HORMONE THERAPY IN CONJUNCTION WITH
`EXTERNAL BEAM RADIATION THERAPY
`
`Several studies have addressed whether
`androgen deprivation
`therapy added
`to
`radiation
`therapy
`improves outcomes
`in
`patients with localized or locally advanced
`prostate cancer (Table 1).
`In 1997, the EORTC reported the results of
`415 patients with locally advanced prostate
`cancer treated with external beam radiation
`versus external beam radiation plus goserelin
`for three years.50 At a median follow-up of 45
`months, the Kaplan-Meier estimates of overall
`survival at five years were 79 percent for
`patients who received combined treatment
`versus 62 percent in the group treated with
`external beam
`radiation
`therapy alone
`(p = 0.001). Eighty-five percent of surviving
`patients were free of disease at five years in the
`combined-treatment group and 48 percent in
`the group
`that received external beam
`treatment alone (p < 0.001).These data strongly
`suggested that adjuvant treatment in patients
`with locally advanced prostate cancer improved
`both local control and survival at five years.
`RTOG 85-31 also sought to determine the
`advantage of
`androgen deprivation
`as
`adjunctive therapy following standard external
`beam radiation therapy in patients with locally
`advanced prostate cancer.51 A total of 977
`patients were randomized to receive radiation
`only (androgen deprivation started at disease
`relapse) or radiation plus adjuvant goserelin.
`The local failure rate at eight years was 23
`percent for the combination-therapy arm and
`37 percent for the radiation-alone arm
`(p < 0.0001). The distant metastasis rate in
`the combination arm was 27 percent and
`37 percent
`in
`the radiation-alone arm
`
`Volume 52 • Number 3 • May/June 2002
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`
`The Current State of Hormonal Therapy for Prostate Cancer
`
`TABLE 1
`Trials of XRT and Adjuvant Hormonal Therapy
`
`Study
`
`Eligibility
`
`Intervention
`
`Results
`
`EORTC
`
`RTOG 85-31
`
`T1/T2 high-grade,
`T3/T4 any grade,
`node negative
`disease
`
`Clinical Stage T3
`or node positive
`disease
`
`Definitive XRT versus XRT + goserelin
`beginning day 1 x 3 years.
`
`Improvement in overall survival,
`disease-free survival, and local control.
`
`Definitive XRT or salvage XRT after having
`poor prognostic features at prostatectomy
`versus goserelin beginning the last week
`of XRT.
`
`Improvement in local control, freedom
`from distant mets, and disease-free
`survival. No benefit in overall survival
`except in patients with high-grade
`cancers.
`
`RTOG 86-10
`
`T2-T4, node
`negative or node
`positive disease
`
`Definitive XRT versus XRT + CAB two
`months prior and two months during
`XRT.
`
`Improvement in local control and survival
`in patients with Gleason 2 to 6 disease
`only.
`
`RTOG 92-02
`
`Clinical Stage
`T2-T4
`
`All patients received CAB two months
`prior and during radiation then CAB for an
`additional 24 months versus no additional
`CAB.
`
`Disease-free survival improved in
`24-month group. Overall survival
`improved in 24 month group for Gleason
`8 to 10 disease.
`
`Joint Center for
`Radiation Therapy
`
`Clinical Stage
`T1-T2
`
`All patients received AB, two months prior,
`two months during, and two months after
`XRT, retrospective analysis.
`
`Relative risk of biochemical failure at five
`years was decreased in intermediate-
`and high-risk patients.
`
`(p < 0.0001). The disease-free survival favored
`the immediate androgen deprivation arm
`(p < 0.0001). Overall survival was not
`statistically different between the two groups
`(49 percent versus 47 percent at eight years).
`The length of androgen deprivation therapy
`necessary for the maximum benefit remains
`unknown. RTOG 86-10 randomized 471
`patients with T2 to T4 tumors with or without
`pelvic lymph node involvement to receive
`radiation plus complete androgen blockade
`with goserelin and flutamide versus radiation
`therapy alone.52 Androgen deprivation therapy
`was administered for two months prior to
`radiation therapy and during radiation therapy.
`Analysis at eight years demonstrated that
`patients treated with combination therapy had
`an improvement in local control (30 percent
`
`versus 42 percent, p = 0.016), reduction in the
`incidence of distant metastases (34 percent
`versus 45 percent, p = 0.04), disease-free
`survival (21 percent versus 33 percent, p =
`0.004), and disease-specific mortality (23
`percent versus 31 percent, p = 0.05). However,
`subset analysis indicated that the beneficial
`effect of short-term androgen deprivation was
`only significant in patients with Gleason score
`two to six tumors (survival 70 percent versus
`52 percent, p = 0.015). Patients with Gleason
`seven to ten tumors had no improvement in
`local control or survival.
`RTOG protocol 92-02 treated over 1,500
`patients with locally advanced prostate cancer
`with radiation and differing regimens of
`androgen deprivation therapy.53 All patients
`received two months of neoadjuvant complete
`
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`CA A Cancer Journal for Clinicians
`
`

`
`CA Cancer J Clin 2002;52:154-179
`
`androgen blockade with goserelin and
`flutamide, which was continued for two
`months during radiation. Patients were then
`randomized to receive either no hormones or
`an additional 24 months of complete androgen
`blockade. The patients treated with 24
`additional months of androgen deprivation
`demonstrated significant improvement in
`disease-free survival 54 percent versus 34
`percent (p = 0.0001),
`local progression 6
`percent versus 13 percent (p = 0.0001), distant
`metastasis 11 percent versus 17 percent
`(p = 0.001), and biochemical failure 21 percent
`versus 46 percent (p = 0.0001). At a median
`follow-up of 4.8 years, 54 patients died of
`prostate cancer in the short-term androgen
`deprivation group compared with 33 patients
`in the long-term androgen deprivation group.
`Disease-specific survival showed a trend in
`favor of the 24-month hormone group, 92
`percent versus 87 percent (p = 0.07). In the
`subgroup of patients with Gleason eight to ten
`tumors,
`five-year survival was significantly
`better with long-term therapy, 80 percent
`versus 69 percent (p = 0.02) as was disease-
`specific survival, 90 percent versus 78 percent
`(p = 0.007).
`The Joint Center for Radiation Therapy
`conducted a retrospective analysis of 1,586
`patients with localized prostate cancer treated
`with definitive radiation therapy versus those
`patients treated with radiation therapy plus six
`months of androgen deprivation.54 Complete
`androgen blockade was given two months
`prior, two months during, and two months
`after radiation therapy. Low-risk patients had a
`PSA of 10 µg/L or less, a Gleason score of six
`or less, and a T1c or T2a tumor. Patients
`classified as intermediate-risk had a T2b tumor
`or a PSA of 10.1 to 20 µg/L or a Gleason score
`of seven. High-risk patients had a T2c tumor,
`PSA of more than 20 µg/L or Gleason score of
`eight or higher. The group estimated the
`
`biochemical relapse rate of patients at five
`years, i.e., the proportion of patients that had a
`rising PSA. Overall survival data were not
`described. The relative risks of PSA failure in
`intermediate-risk and high-risk patients
`treated with radiation therapy plus