SECONDARY HORMONAL THERAPIES IN THE TREATMENT
`OF PROSTATE CANCER
`
`WILLIAM K. OH
`
`ABSTRACT
`Patients with androgen-independent prostate cancer demonstrate progression of disease, despite chemical
`or surgical castration, and have a poor prognosis. Cancer progression may be manifest as an asymptomatic
`increase in serum prostate-specific antigen (PSA) or may be accompanied by symptomatic and/or radio-
`graphic evidence of tumor growth. Observation remains a reasonable choice for asymptomatic patients.
`However, many patients remain anxious about withholding further treatment and, although studies have not
`demonstrated a survival benefit with second-line hormonal therapy, it may be appropriate to consider these
`therapies. In patients who have radiographic and/or symptomatic progression, the use of second-line
`hormonal therapy is more easily justified. Treatment options include: (1) secondary use of antiandrogens (eg,
`high-dose bicalutamide), (2) therapies targeted against adrenal steroid synthesis (eg, ketoconazole, ami-
`noglutethimide, and corticosteroids), and (3) estrogenic therapies (eg, diethylstilbestrol). Symptomatic
`improvement and PSA-level decreases of ⱖ50% have been reported in approximately 20% to 80% of
`patients with androgen-independent prostate cancer who receive such second-line hormone therapies, with
`a typical response duration of 2 to 6 months. Toxicity is generally mild for these oral therapies, although
`serious side effects, including adrenal insufficiency, liver toxicity, and thrombosis, may occur. In conclusion,
`secondary hormonal therapies have a significant role in the treatment of patients with androgen-indepen-
`dent prostate cancer. Further research is needed to understand their optimal use. UROLOGY 60 (Suppl 3A):
`87–93, 2002. © 2002, Elsevier Science Inc.
`
`In 2001, ⬎31,000 men are projected to die of
`
`prostate cancer, the second-leading cause of
`cancer death in men in the United States.1 Al-
`though most of these men respond initially to an-
`drogen deprivation therapies (ADT), such as bilat-
`eral orchiectomy or luteinizing hormone–releasing
`hormone (LHRH) agonists, patients eventually
`progress to an androgen-independent state in
`which the initial ADT regimen is no longer ade-
`quate to control disease.2 The median duration of
`survival of patients with metastatic androgen-inde-
`pendent prostate cancer is approximately 1 year.3
`Although most men with androgen-independent
`prostate cancer eventually develop symptoms re-
`lated to metastases, often, the first indication of
`disease progression is an asymptomatic increase in
`serum prostate-specific antigen (PSA) levels noted
`during routine surveillance. Although there is no
`
`From the Department of Adult Oncology, Lank Center for Geni-
`tourinary Oncology, Dana-Farber Cancer Institute, Harvard
`Medical School, Boston, Massachusetts, USA
`Reprint requests: William K. Oh, MD, Dana-Farber Cancer
`Institute, 44 Binney Street, Boston, Massachusetts 02115. E-mail:
`william_oh@dfci.harvard.edu
`
`© 2002, ELSEVIER SCIENCE INC.
`ALL RIGHTS RESERVED
`
`evidence that secondary hormonal therapies or
`chemotherapy improve survival, patients and phy-
`sicians often pursue treatment, despite a lack of
`symptoms. Physicians and their patients might ini-
`tiate therapy because of concerns over impending
`symptoms, rapidity of increase of PSA levels, pa-
`tient anxiety about observation alone, or the phy-
`sician’s belief that treatment may improve the pa-
`tient’s outcome. An important concern of this
`more aggressive approach is that the treatment
`may have a significant effect on quality of life, and
`therefore simpler treatments with less toxicity
`would be considered preferable in asymptomatic
`patients.4
`In contrast, there is more evidence that treat-
`ment can palliate symptoms for patients with ad-
`vanced disease. Despite this evidence, the lack of a
`documented survival benefit and concerns about
`toxicity leave many unanswered questions. Which
`therapies should be used and when? What is an
`acceptable level of toxicity? What is the psycholog-
`ical impact for patients of waiting without therapy?
`Is there an ability to predict response and to select
`appropriate patients for different approaches? In
`
`0090-4295/02/$22.00
`PII S0090-4295(02)01581-9 87
`ARGENTUM EX1021
`
`Page 1
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`of mutant androgen receptors. Taplin et al.9 re-
`ported mutations in androgen receptors in 5 of 16
`patients receiving combined androgen blockade
`versus only 1 of 17 receiving LHRH monotherapy,
`suggesting a selection for mutant receptors in pa-
`tients exposed to antiandrogens. In addition, it has
`also been demonstrated that antiandrogens may
`activate prostate cancer cells harboring mutant an-
`drogen receptors.10
`The Cancer and Leukemia Group B (CALGB)
`studied this phenomenon in a randomized, pro-
`spective trial (9583) of antiandrogen withdrawal
`alone compared with antiandrogen withdrawal
`plus high-dose ketoconazole.11 In the antiandro-
`gen withdrawal–alone arm, a ⱖ50% PSA response
`was seen in only 13% of patients, with an objective
`response rate of 4% (Table I). In a correlative sci-
`ence companion study (CALGB 9663), 194 bone
`marrow biopsies were performed, 48 (25%) of
`which had evidence of cancer. In a preliminary
`abstract, of 27 patients for whom androgen recep-
`tor messenger RNA (mRNA) and PSA data were
`available, only 6 patients had detectable androgen
`receptor mutations. Of these, 1 (4%) had an anti-
`androgen withdrawal response and 5 (19%) had no
`antiandrogen withdrawal response. The conclu-
`sion of this correlative study was that androgen
`receptor mutations are not, in fact, responsible for
`the antiandrogen withdrawal response.12
`
`SECOND-LINE ANTIANDROGENS
`
`Bicalutamide is a nonsteroidal antiandrogen
`with dose-response effects in normalizing PSA lev-
`els in androgen-dependent prostate cancer. Pa-
`tients with androgen-independent prostate cancer
`treated with high doses (150 to 200 mg) of bicalu-
`tamide have PSA decreases of ⱖ50% in 20% to 24%
`of cases, with most responses seen in those who
`received prior flutamide therapy (Table II).13–15 It
`is not known why patients with prior flutamide
`treatment might have higher response rates to sec-
`ond-line bicalutamide, although it has been theo-
`rized that a mutant androgen receptor induced by
`prior flutamide therapy may mediate a higher re-
`sponse to salvage bicalutamide. The results of the
`study by Kucuk et al.14 suggest, however, that this
`is not the case. Treatment is oral and well tolerated,
`with the most common side effects being hot
`flashes (23%) and nausea (21%). However, treat-
`ment
`is expensive (approximately $1000 per
`month) and is associated with a low response rate.
`Megestrol acetate is a steroidal antiandrogen
`with progestational activity. Its antiandrogenic ef-
`fects are not promising in treating androgen-inde-
`pendent patients, with objective response rates of
`0% to 9%. A recent randomized study of 149 men
`randomized to low or high doses of megestrol ace-
`
`FIGURE 1. A typical treatment strategy for patients
`with androgen-independent prostate cancer.
`
`particular, the timing of cytotoxic chemotherapy
`versus secondary hormonal therapies remains con-
`troversial and poorly studied.2 In our institution,
`our practice is generally to start with secondary
`hormonal therapies in asymptomatic or minimally
`symptomatic patients and to proceed to chemo-
`therapy as such treatments fail. However, there are
`some patients whose androgen-independent dis-
`ease progresses rapidly enough that immediate in-
`stitution of chemotherapy may be appropriate.
`In general, a reasonable stepwise approach is to
`consider the easiest and least toxic interventions
`first, thus reserving chemotherapy for patients who
`have failed secondary hormonal therapies (Figure
`1). Patients who are receiving antiandrogen ther-
`apy at the time of progression are monitored for
`signs of antiandrogen withdrawal syndrome. Sub-
`sequent treatment options may include (1) second-
`line antiandrogens, (2) adrenal androgen inhibi-
`tors, and (3) estrogenic therapies (Figure 2).
`
`ANTIANDROGEN WITHDRAWAL
`SYNDROME
`
`In 1993, clinical and PSA responses were re-
`ported in men who discontinued the antiandrogen
`flutamide upon developing progressive disease.5
`This antiandrogen withdrawal syndrome was an
`important discovery in interpreting clinical trials
`and treating patients. In 3 separate studies of 138
`patients, 29 (21%) had a PSA level decrease of
`ⱖ50% after stopping flutamide.6 Generally, dura-
`tion of response is 3 to 5 months, although re-
`sponses ⬎2 years have been seen. Such withdrawal
`responses also have been reported after treatment
`with bicalutamide and megestrol acetate.7,8 A pro-
`posed mechanism to account for the antiandrogen
`withdrawal syndrome is the paradoxical activation
`
`88
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`UROLOGY 60 (Supplement 3A), September 2002
`
`Page 2
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`

`
`FIGURE 2. Secondary hormonal therapies for androgen-independent prostate cancer. *Prostate-specific antigen
`(PSA) response rate represents reported PSA decreases of ⱖ50% in phase 2 clinical trials. Bars represent range of
`PSA decline rates in different clinical trials using bicalutamide (Casodex; AstraZeneca, Wilmington, DE), PC SPES
`(herbal compound; BotanicLab, Brea, CA), and other drugs.
`
`TABLE I. CALGB 9583: randomized trial of antiandrogen
`withdrawal (AAW) versus antiandrogen withdrawal plus high-dose
`ketoconazole (HDK)11
`AAW
`Alone
`(n ⴝ 132)
`13%
`4%
`16 mo
`4%
`
`ⱖ50% PSA response
`Objective response
`Survival
`Grade 3,4 toxicity
`PSA ⫽ prostate-specific antigen.
`
`AAW ⴙ
`HDK
`(n ⴝ 128)
`27%
`13%
`15 mo
`22%
`
`P-Value
`0.012
`0.016
`0.795
`0.001
`
`tate reported PSA decreases only 8% to 13% of the
`time and rare objective responses.16 Side effects in-
`cluded thrombophlebitis and fluid retention. Based
`on these results, megestrol acetate has limited anti-
`tumor activity in androgen-independent prostate
`cancer and should not be used for this indication.
`
`LOW-DOSE CORTICOSTEROIDS FOR
`PROSTATE CANCER
`
`Low-dose corticosteroids inhibit adrenocortico-
`tropic hormone secretion through a negative feed-
`back loop, which thereby decreases adrenal andro-
`gen production. Tannock et al.4
`reported a
`significant palliative response with 10 mg of pred-
`nisone in a phase 2 trial of 37 patients. In 2 subse-
`quent, large, randomized studies of mitoxantrone
`plus steroids versus steroids alone, the steroid arm
`was associated with more modest palliative bene-
`
`UROLOGY 60 (Supplement 3A), September 2002
`
`fits. In a Canadian randomized trial of prednisone
`10 mg daily versus prednisone plus mitoxantrone,
`a significant pain response was seen in 12% of pa-
`tients, lasting only 18 weeks, in the prednisone
`arm.17 Furthermore, PSA level decreases of ⱖ50%
`were seen in only 18% of these patients. CALGB
`found similar results in 123 patients randomized to
`an arm of daily hydrocortisone 40 mg alone, with a
`significant reduction of pain in only 8% and a PSA
`response rate of 22%.3 Low doses of dexametha-
`sone have also been reported to have significant
`palliative and objective benefit. In a recent study of
`37 men with hormone-refractory disease, 62% had
`a PSA level decrease of ⱖ50%. In addition, im-
`provements in bone scans and symptoms were not-
`ed.18 In summary, low-dose corticosteroids have a
`modest role in the management of androgen-inde-
`pendent prostate cancer. Although orally adminis-
`
`89
`
`Page 3
`
`

`
`TABLE II. High-dose bicalutamide for androgen-independent
`prostate cancer
`
`Study
`Scher et al. (1997)15
`Joyce et al. (1998)13
`Kucuk et al. (2001)14
`PSA ⫽ prostate-specific antigen.
`
`N
`51
`31
`52
`
`Dose (mg)
`200
`150
`150
`
`>50% PSA
`Response
`24%
`23%
`20%
`
`>50% PSA
`Response in Patients
`with No Prior Flutamide
`15%
`6%
`20%
`
`TABLE III. High-dose ketoconazole plus hydrocortisone for
`androgen-independent prostate cancer
`Dose
`(mg tid)
`400
`400
`400
`200
`
`>50% PSA
`Response
`63%
`40%
`27%
`55%
`
`Study
`Small et al. (1997)21
`Millikan et al. (2001)22
`Small et al. (2001)11
`Harris et al. (2001)23
`PSA ⫽ prostate-specific antigen.
`
`N
`48
`45
`128
`22
`
`tered, inexpensive, well-tolerated, and associated
`with objective benefit, the overall response rate is
`low enough and duration of response short enough
`that this therapy might be considered only after
`more effective secondary hormonal therapies have
`been tried.
`
`INHIBITORS OF ADRENAL ANDROGEN
`PRODUCTION
`
`Approximately 10% of circulating androgen in
`humans is secreted by the adrenal glands. In andro-
`gen-independent states, some tumor cells must re-
`tain sensitivity to androgens, because a further de-
`crease in circulating androgen levels by bilateral
`adrenalectomy or by drugs that inhibit adrenal ste-
`roidogenesis can induce a clinical response.19 Ami-
`noglutethimide, ketoconazole, and corticosteroids
`act primarily via this mechanism. In a review of 13
`clinical trials of aminoglutethimide plus hydrocor-
`tisone, there was an overall partial response rate of
`9%.20 Aminoglutethimide toxicity includes fa-
`tigue, nausea, skin rash, orthostatic hypotension,
`and ataxia.
`Ketoconazole is similarly effective in suppress-
`ing testicular and adrenal androgen production. In
`vitro experiments also suggest a possible direct cy-
`totoxic effect of ketoconazole on prostate cancer
`cells.21 A review of 10 older studies in androgen-
`independent prostate cancer using high-dose keto-
`conazole plus replacement hydrocortisone showed
`measurable responses in approximately 15%.20
`There are 3 more recent trials of high-dose keto-
`conazole that demonstrate much higher response
`rates when using PSA endpoints (Table III).11,22,23
`
`Small et al.22 treated 48 patients with 400 mg 3
`times daily in a phase 2 trial and found PSA de-
`creases of ⱖ50% in 63%. In another trial of 45
`patients treated with high-dose ketoconazole, Mil-
`likan et al.23 showed a 40% PSA response rate using
`a similar dose.
`In the previously mentioned
`CALGB trial (9583), the arm that received concur-
`rent antiandrogen withdrawal and high-dose keto-
`conazole demonstrated a 27% PSA response rate
`and a 13% measurable response rate, both signifi-
`cantly greater than the antiandrogen withdrawal–
`alone arm (Table I).11
`Increased gastric pH decreases drug absorption,
`so ketoconazole should be taken on an empty
`stomach and, if possible, in the absence of hista-
`mine-2 blockers or antacids. Although toxicity is
`generally mild or moderate, including nausea, di-
`arrhea, fatigue, and skin changes, some patients
`require discontinuation of the drug because of tox-
`icity. A recent phase 2 study suggests that similar
`response rates may be obtained with half the tradi-
`tional dose (ie, 200 mg 3 times daily), with fewer
`apparent side effects (Table III).24
`
`ESTROGENIC THERAPIES
`
`Estrogenic therapies can induce secondary re-
`sponses in patients with apparent androgen-inde-
`pendent prostate cancer, suggesting an additional
`mechanism of action beyond suppression of the
`pituitary– gonadal axis. Several modern series sug-
`gest that diethylstilbestrol (DES) and other estro-
`gens can produce PSA responses in a significant
`proportion of patients with androgen-independent
`prostate cancer (Table IV).25–28 The mechanism for
`
`90
`
`UROLOGY 60 (Supplement 3A), September 2002
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`

`
`TABLE IV. Estrogenic therapies in androgen-
`independent prostate cancer
`Type
`(Daily
`Dose)
`N
`21 DES
`(1 mg)
`18 DES
`(3 mg)
`127 DES
`(1 mg)
`115 DES
`(3 mg)
`16 PC SPES
`(9 caps)
`22 PC SPES
`(3 caps)
`37 PC SPES
`(9 caps)
`23 PC SPES
`(6 caps)
`
`Study
`Smith et al. (1998)25
`
`Rosenbaum et al.
`(2000)24
`Shahidi et al. (2001)27
`
`Pfeiffer et al. (1999)34
`
`de la Taille et al.
`(2000)31
`Small et al. (2000)35
`
`Oh et al. (2001)33
`
`>50%
`PSA
`Response
`43%
`
`66%
`
`26%
`
`32%
`
`81%
`
`66%
`
`54%
`
`52%
`
`questions remain about the role of PC SPES in the
`management of androgen-independent prostate
`cancer and, perhaps most significantly, the identi-
`fication of the active ingredient(s) of PC SPES.
`
`CONCLUSION
`Secondary hormonal therapy for prostate cancer
`represents an important group of therapies for a
`grop of patients with a limited prognosis. Although
`many important issues remain unanswered about
`the optimal use of these treatments, multiple phase
`2 trials have demonstrated that PSA and clinical
`responses can be seen with these treatments in sig-
`nificant proportions of androgen-independent
`prostate cancer patients. Interpretation of phase 2
`trials must be done carefully in this setting, be-
`cause comparisons between trials may be invalid
`and because objective and PSA responses must be
`kept distinct. Nonetheless, no study has yet dem-
`onstrated a survival benefit with the use of these
`treatments, which can be expensive as well as
`toxic, with a potential negative effect on quality of
`life, particularly in patients who have minimal or
`no symptoms. Cost is especially critical to consider
`when prescribing these oral medications, as many
`elderly patients have inadequate or no prescription
`drug coverage.
`Despite this, patients appear to benefit from ther-
`apy in several ways. Clearly, symptomatic patients
`have had palliative responses to treatment. Other
`patients may have a delay in progression of their
`disease. Patients are also relieved if their increasing
`PSA level is effectively reversed; this important
`psychological effect deserves further study. Fi-
`nally, patients have few good treatment alterna-
`tives to secondary hormonal therapies. Chemo-
`therapy, although active and generally well
`tolerated, has a less favorable side-effect profile in
`general.2 Radiopharmaceuticals or external-beam
`radiotherapy may benefit patients with symptom-
`atic disease, but may have limited efficacy and po-
`tentially serious toxicity.
`Further research needs to continue in defining
`the optimal use of secondary hormonal therapies,
`including the appropriate timing and sequencing
`of treatments. Furthermore, more randomized tri-
`als are needed to compare treatments and to eval-
`uate survival benefits, if any, to these treatments.
`
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`statistics, 2001. CA Cancer J Clin 51: 15–36, 2001.
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`the effect is unclear, but may represent a direct
`cytotoxic effect on the cells, perhaps through an
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`suggested that doses of DES from 1 to 3 mg may
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`PC SPES (BotanicLab, Brea, CA)* is an herbal
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`rates (ranging from 52% to 81%) and toxicities
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`
`* After the time of this writing, in February 2002, the California
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`was voluntarily recalled. As of June 2002 BotanicLab ceased pro-
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`
`UROLOGY 60 (Supplement 3A), September 2002
`
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`

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