SECONDARY HORMONAL MANIPULATIONS IN HORMONE REFRACTORY PROSTATE CANCER

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HORMONE REFRACTORY PROSTATE CANCER

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SECONDARY HORMONAL MANIPULATIONS IN HORMONE REFRACTORY PROSTATE CANCER David M. Reese, MD, and Eric J. Small, MD

For more than five decades, the preferred treatment for advanced prostate cancer has been suppression of testicular androgen production by medical or surgical ca~tration.~~, 30 Eventually, resistant disease develops in all patients treated with androgen deprivation as manifested by rising levels of prostate-specific antigen (PSA), progressive disease on imaging studies, and, ultimately, worsening symptoms. The treatment of patients with hormone-refractory prostate cancer, once thought to represent a relatively futile endeavor, has changed significantly in the past several years with the development of new therapeutics. One of the most important new treatment strategies involves secondary hormonal manipulation after the failure of primary androgen deprivation. This approach is predicated on the recognition that hormone refractory prostate cancer is a heterogeneous disease, and some patients may respond to alternative hormonal interventions despite the presence of castrate levels of testosterone. DEFINING HORMONE SENSITIVITY

Prostate cancers in all stages of the disease remain sensitive (to a greater or lesser degree)

to androgens. Accumulating evidence suggests that it is necessary to maintain castrate levels of testosterone in patients who have experienced disease progression after primary androgen deprivation, and that discontinuation of medical castration may have adverse clinical consequences. Silver and cow o r k e r ~noted ~ ~ increases in PSA and serum testosterone in three patients after discontinuation of goserelin acetate. Their observation was expanded in a retrospective analysis of 341 patients treated in four separate Eastern Cooperative Oncology Group clinical trials. In that study, 55 patients (16%)had discontinuation of medical castration, and continued androgen suppression was an independent predictor of survival.68A review of 205 patients studied by the Southwest Oncology Group did not show a survival advantage with continued testicular androgen ablation. In this study, 32 patients (16%)had discontinuation of medical castration, but the median survival of all patients was very short (6 months), suggesting that these were patients with very advanced disease in whom a survival difference would be difficult to detect.31 Evidence suggests that treatment with exogenous androgen may induce disease pro-

From the Urologic Oncology Program (DMR, EJS), Departments of Medicine (DMR, EJS) and Urology (EJS), University of California, San Francisco/Mount Zion Cancer Center, University of California, San Francisco, San Francisco, Cali-

fornia

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gression. Fowler and Whitmore22reported that of 52 men with metastatic prostate cancer who were treated with exogenous testosterone while enrolled in a variety of clinical protocols, progressive disease developed in 87%. A significant number of these patients experienced serious complications such as pain flare, cord compression, or death.23 In another trial, use of testosterone priming prior to 32Por chemotherapy was associated with rapid disease progre~sion.~' Currently, the preponderance of clinical data indicate that most prostate tumors that have developed the ability to proliferate despite castrate levels of testosterone remain sensitive to androgens and can derive a further growth advantage upon exposure to androgen. Therefore, despite the potential financial pressures, continued gonadal androgen suppression should be considered standard care for patients with progressive hormone refractory prostate cancer. The previous observations coupled with the recognition of steroid withdrawal syndromes and the experience using a variety of alternative hormonal therapies have led to the development of new classification schemes for hormone refractory prostate cancer. Scher and colleagues have proposed a model according to which tumors can be categorized as hormone-na'ive (responsive to therapies that decrease testosterone levels or block the cellular action of testosterone), androgen-independent but hormone-sensitive (resistant to castration but sensitive to other hormonal manipulations), and hormone-independent (resistant to all hormonal intervent i o n ~ ) .j",~51~ ,This system has the advantage of explicitly categorizing tumors according to their hormone responsiveness and underscores the clinical heterogeneity of hormone refractory prostate cancer. Acknowledgment of the varying degrees of hormonal sensitivity among patients with hormone refractory prostate cancer will become increasingly important in the design of clinical trials, particularly those involving biologic agents that may have effects on androgen levels, and the stratification of patients according to prior hormonal treatment and hormone sensitivity may be necessary.62

ASSESSING DISEASE RESPONSE TO TREATMENT

One of the barriers in the development of new therapeutics for hormone refractory prostate cancer has been the difficulty in evaluating disease response to treatment. Because more than 70% of patients with metastatic hormone refractory prostate cancer do not have bidimensionally measurable disease, the use of surrogate response markers such as PSA has become routine in most studies. In addition, there now exists a population of patients who have a rising PSA after primary androgen deprivation as the sole manifestation of disease progression. How valid is serial measurement of PSA levels as an indicator of disease response? Evidence suggests that a decline in PSA level of 50% or greater defines a subset of patients with hormone refractory prostate cancer and treated with cytotoxic chemotherapy who have improved survivaP6,63; however, the utility of PSA in evaluating therapies such as suramin or other biologic agents remains contro~ersial.'~ This issue is particularly important when considering secondary hormonal manipulations because in vitro data indicate that a number of these agents may have effects on cellular PSA production that are uncoupled from proliferation. In the LNCaP prostate cancer cell line, which has a mutated androgen receptor but is androgenresponsive, treatment with dihydrotestosterone or estrogen results in cellular proliferation at low concentrations but neutral or growth-inhibitory effects at high hormone concentrations. In contrast, PSA production increases in a dose-dependent fashion with increasing hormonal c~ncentration.~" Likewise, antiandrogens and other steroids have varied and complex effects on tumor growth and PSA secretion in LNCaP cells.19,71 Complicating the interpretation of these studies is the fact that LNCaP cells have been extant for many years, and their behavior may not be representative of the majority of clinical tumors. Despite these experimental data and the corresponding potential clinical limitations, PSA, in general, has proved a useful indicator of response in patients treated with

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Table 1. SELECTED REPORTS OF ANTIANDROGEN WITHDRAWAL ~~

Study

Drug

Scher et ill': Small and Srinivas'" Figg et al"' Herrada et ill?' Schellhammer et a P

Flutamide Flu tamide Flutamide Flutamide Flutamide Bicalu tamide Bicalutamide

Nieh" TOTAI. NR

=

No. of Patients

Patients with 50% PSA Response (%)

Duration of Response (months)

57 82 21 39 8 14 3 224

16 (28) 12 (15) 7 (33) 11 (28) 4 (50) 4 (29) 1 (33) 55 (25)

4.0 3.5 3.7 3.3 NR NR 6.0 -

not reported.

gen either at the time of initial medical or surgical castration or after progression after testicular ablation. This approach is based on the hypothesis that adrenal androgen production may provide additional stimulation to prostate tumor cells after c a ~ t r a t i o nThe .~~ utility of combined androgen blockade remains controversial because large randomized trials have yielded conflicting results, and a meta-analysis of 22 studies demonstrated no clear benefit for this therapy.4,I h , 32, 4h, 72 What is not in doubt is that some patients with disease progression while receiving an antiandrogen will experience subjective and objective improvement upon removal of that agent. The serendipitous observation that four patients with progressive metastatic prostate cancer withdrawn from flutamide experienced symptomatic, objective, and biochemical improvement led to the identification of the antiandrogen withdrawal syndrome in

currently available secondary hormonal agents. Secondary hormonal therapy in hormone refractory prostate cancer can be divided logically into several broad categories: (1)antiandrogen (steroid) withdrawal (Table l), (2) deferred use of an antiandrogen after castration or use of second-line antiandrogen treatment, (3) inhibition of adrenal steroidogenesis, and (4) treatment with alternative steroids such as glucocorticoids or progestins. The remainder of this review focuses on the available clinical data regarding these approaches. A summary of selected contemporary trials of secondary hormonal manipulations is provided in Table 2.

ANTIANDROGEN WITHDRAWAL

Most patients with advanced prostate cancer in the United States receive an antiandro-

Table 2. SELECTED TRIALS OF SECONDARY HORMONAL AGENTS

Study

Kelly et ill" Storlie et alN Tannock et alh' Dawson et al; Sartor et al'; Small et alSx Small et ali7 Dawson et al" Osborn et all' Scher et al'" Joyce et al" AAWD

=

No. of Patients

Treatment

Hydrocortisone Dexamethasone Prednisone Hydrocortisone AAWD Aminoglutethimide + hydrocortisone + AAWD Ketoconazole + hydrocortisone Ketoconazole + hydrocortisone AAWD Megestrol acetate Megestrol acetate High-dose bicalutamide High-dose bicalutamide

+

simultaneous antiandrogen withdrawal; NR

=

+

not reported.

50% PSA Response (.Yo)

Duration of PSA Response (months)

30 38 81 34 29

20 61 22 29 48

4.0 NR 4.0 1.8 4.0

50 20

63 55

3.5 8.5

149 14 51 31

12 14 14 23

NR NR 4.0 NR

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the early 1 9 9 0 ~Although .~~ initially described for flutamide, PSA decline with or without symptomatic or objective benefit has also been observed after discontinuation of two other nonsteroidal antiandrogens, bicalutamidea2,5y and nilutamide.26,28 In addition, withdrawal responses have been documented after removal of the steroidal antiandrogens megestrol acetateXand chlormadinone acetate,' as well as estrogens such as diethylstilbestrol.2 Currently, more than 200 patients have been formally evaluated for the antiandrogen withdrawal syndrome (Table 1). Withdrawal responses occur in 15% to 30% of patients, although the prospective identification of patients most likely to respond has proven difficult. Clinical variables such as the type of castration, the inclusion or exclusion of antiandrogen as part of combined androgen blockade or added after disease progression, age, performance status, and biochemical data (PSA level, hemoglobin, creatinine, alkaline phosphatase) have not been reliable independent predictors of response.52* Duration of exposure to flutamide may be a more useful indicator of response likelihood; the largest series have demonstrated an association between the length of treatment with flutamide and the likelihood of response,52,61 although this finding has not been universal.'l, 27 Patients treated with an antiandrogen for as little as 2 months may experience the withdrawal syndrome.61

Most patients responding to flutamide withdrawal will experience a decrease in PSA within 4 weeks (Fig. l), but responses may occur later with bicalutamide owing to its longer half-life.48Patients who are withdrawn from bicalutamide or nilutamide and who are clinically stable should be observed for 6 to 8 weeks to rule out a withdrawal response. The median duration of response to antiandrogen withdrawal is approximately 4 months (Table l), although some patients may experience prolonged symptomatic and biochemical benefit lasting several years. The mechanism underlying the antiandrogen withdrawal syndrome has not been identified. One possibility is that mutations in the androgen receptor result in an altered response to antiandrogens and steroid hormones. In some patients with hormone refractory prostate cancer, the hormone-binding domain of the androgen receptor is mutated,25,67, 69 and these receptors may be stimulated rather than inhibited by specific antiandrogens. Biochemical studies on the LNCaP prostate cancer cell line, which has a point mutation in the steroid-binding region of the androgen receptor, indicate that flutamide, nilutamide, and cyproterone acetate activate the mutant receptor; bicalutamide, in contrast, inhibits growth in LNCaP cells.1y,71 The interactions of antiandrogens with mutated androgen receptor in vivo are also likely to be complex, dependent on both the precise domain of the receptor altered and differing

Flutamide withdrawal 700 600 500 $ 400 300 4 g 200 100 0

a

-.

-

0

3

6

9

12 13 14 15 16 17 18 19 20 Months

Figure 1. Time course of PSA response after withdrawal of flutamide in a patient with hormone refractory prostate cancer.

SECONDARY HORMONAL MANIPULATIONS IN HORMONE REFRACTORY PROSTATE CANCER

structural interactions of the various antiandrogens with the androgen receptor. Further correlative studies to determine the precise functional relevance of androgen receptor mutations and the response to antiandrogen withdrawal are ongoing. Amplification of the wild-type androgen receptor gene has been suggested as an explanation for the molecular basis of the antiandrogen withdrawal syndrome. Gene amplification has been demonstrated in some tumors obtained from men with hormone refractory prostate cancer and may confer exquisite sensitivity to even low levels of androgen or a n t i a n d r ~ g e n .This ~ ~ hypothesis requires further clarification using additional human tumor samples. Identification of the antiandrogen withdrawal syndrome has expanded treatment options for patients with hormone refractory prostate cancer and provided insights into the development of progressive disease. In addition, recognition of the antiandrogen withdrawal syndrome suggests that some patients with hormon-refractory prostate cancer may not be truly hormone resistant and has led to formal evaluation of other secondary hormonal maneuvers. It is now mandatory for a trial of antiandrogen withdrawal to be performed as a first intervention in patients with progressive disease. This maneuver is nontoxic and can be expected to benefit a significant minority of patients. Adequate antiandrogen withdrawal prior to enrollment in clinical trials is also crucial to avoid confusion when assessing response to new agents.

USE OF DEFERRED OR SECOND ANTIANDROGENS As noted previously, most patients in the United States with advanced prostate cancer receive primary therapy with a combination of castration and the use of an antiandrogen. Evidence suggests that patients treated initially with castration alone may benefit from the later addition of an antiandrogen. Fowler and colleaguesz1used flutamide to treat 90 men with localized ( n = 40) or metastatic ( n = 50) prostate cancer and a rising PSA after castration. They noted an 80% PSA response

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rate in those with localized disease and a 54% response rate in those with metastatic cancer.*I In another trial, the deferred use of high-dose bicalutamide produced PSA responses in 2 of 13 men with progressive disease after medical or surgical ~ a s t r a t i o nThe .~~ addition of an antiandrogen may therefore yield PSA responses in patients with progressive disease who have been treated with castration alone, but the impact of this maneuver on overall survival (if any) remains unknown. Different antiandrogens probably have different functional interactions with the androgen receptor. Bicalutamide has a significantly longer half-life than flutamide (1 week versus 5 to 6 hours) and greater binding affinity for the androgen re~eptor.’~ In addition, flutamide and bicalutamide function as an agonist and antagonist, respectively, in the LNCaP cell line.19,71 Thus, despite their apparent similarities, there is the possibility that cross-resistance to antiandrogens may not be present in all patients with hormone refractory prostate cancer. This hypothesis has been tested directly in at least two clinical trials. Scher and co-worke r treated ~ ~ 51~ patients with progressive metastatic prostate cancer with high-dose bicalutamide (200 mg/day). In this series, 10 of 26 patients (38%) who had prior flutamide therapy had a greater than 50% decline in PSA level. Significantly, responses were seen in patients with (5 of 12) or without (5 of 14) a prior withdrawal response to flutamide. In addition, response to bicalutamide was more likely in patients who had only one prior hormonal therapy when compared with those with two or more previous interventions (31% versus 0%). In a second study, Joyce and colleagues% reported a 22.5% response rate to high-dose bicalutamide (150 mg/ day) among 31 treated patients. The majority of responders (six of seven) had received prior flutamide, and the two most significant clinical responses occurred in patients who had experienced a flutamide withdrawal response. It is therefore clear that bicalutamide may induce responses in a fraction of patients previously treated with flutamide. Recently, a case report of response to nilutamide after flutamide failure has also been p~b1ished.l~ Whether flutamide or nilutamide are effective in patients

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with prior bicalutamide exposure is unknown but may merit investigation.

ADRENAL ANDROGEN INHIBITORS

It has been postulated that in some patients with progressive hormone refractory prostate cancer, adrenal androgen production, the source of 5% to 10% of peripheral testosterone, may provide continued stimulation to tumor cells.39Surgical adrenalectomy was performed in the past to treat patients with progressive disease after medical or surgical castration and produced occasional responses.3 Surgery was largely abandoned with the development of aminoglutethimide, which blocks several steroid hydroxylation steps and induces a functional adrenalectomy.I3 A substantial number of reports indicate that aminoglutethimide when combined with glucorticoid replacement to prevent steroid insufficiency produces responses in approximately 30% of patients with hormone refractory prostate cancer; however, randomized trials have suggested that a proportion of responses in these patients may have resulted from the concomitant use of hydrocortisone.'z,-'5 More recent studies have examined the use of aminoglutethimide with hydrocortisone after antiandrogen withdrawal. Sartor and colleague^^^ noted a 48% PSA response rate when aminoglutethimide and hydrocortisone were combined with flutamide discontinuation, a substantially higher rate than seen with flutamide withdrawal alone. This same group reported a 65% response rate to concomitant aminoglutethimide therapy and flutamide withdrawal in a small cohort of patients with progressive metastatic disease after treatment with luteinizing hormonereleasing hormone analogue, flutamide, hydrocortisone, and suramin.'* Dupont and coworkers'-' found that 80% of patients already receiving aminoglutethimide and hydrocortisone experienced significant PSA declines after flutamide withdrawal. A study of suramin and aminoglutethimide given simultaneous with or after antiandrogen withdrawal found a 14% PSA response rate in subjects treated after withdrawal compared with a

44% response rate with simultaneous therapy.6 There was also a suggestion of a survival benefit for the latter group, although the trial was not randomized. These data suggest that adrenal androgens most likely contribute to disease progression in at least some patients with hormone refractory prostate cancer; however, whether simultaneous aminoglutethimide and antiandrogen withdrawal provides an ultimate clinical advantage over sequential therapy remains unknown, and the relative importance of hydrocortisone in this regimen requires further evaluation. Ketoconazole, a systemic antifungal agent, is another clinically useful antagonist of adrenal steroidogenesis. Ketoconazole inhibits the cytochrome P-450 system and effectively suppresses both testicular and adrenal androgen production. Interestingly, ketoconazole may also have direct cytoxic effects on prostate tumor cells." Originally used as a therapy for advanced prostate cancer before the advent of PSA as a tumor marker, ketoconazole was reported to produce objective clinical responses in approximately 10% of patients and stable disease in another 35Y0.~~ More recent reports have focused on patients with hormone refractory prostate cancer who have undergone antiandrogen withdrawal. In one series of 50 consecutive men treated at the authors' center with high-dose ketoconazole (1200 mg daily) and hydrocortisone, 62.5% of evaluable patients (30 of 48) had a greater than 50% decrease in PSA.58Prior response to flutamide withdrawal did not affect response to ketoconazole. The median duration of response was 3.5 months, although occasional prolonged responses were seen (Fig. 2). A second trial examined simultaneous antiandrogen withdrawal and ketoconazolel hydrocortisone treatment and noted a similar response proportion, although, in this study, the median duration of response was 8.5 months.57An ongoing study is comparing simultaneous with sequential ketoconazole in patients undergoing antiandrogen withdrawal to determine whether the timing of therapy influences response rates or survival. The primary toxicity of ketoconazole is gastrointestinal (nausea, vomiting, or both), which occurs in approximately 15% of treated patients.57The drug requires an acidic pH for

SECONDARY HORMONAL MANIPULATIONS IN HORMONE REFRACTORY PROSTATE CANCER

2 E

-2

$ I

d

317

90 80 70 60 50 40

30 20 10 0

Months Figure 2. PSA response in a patient treated with high-dose ketoconazole and hydrocortisone. The patient developed progressive disease after flutamide withdrawal and then had a prolonged biochemical and symptomatic response to ketoconazole and hydrocortisone.

optimal absorption; therefore, patients should be instructed to take the medication between meals if possible (although, frequently, ketoconazole needs to be taken with meals to avoid gastrointestinal upset) and to avoid antacids, H, blockers, and proton pump inhibitors. Occasional elevations in liver transaminases may be encountered but are rarely clinically significant. Newer-generation adrenal inhibitors are being investigated in advanced prostate cancer. Liarozole is a potent inhibitor of P-450dependent enzymes, blocks the degradation of retinoids, and inhibits aromatase. Preclinical studies suggest that liarozole may have antiproliferative effects on both androgen-dependent and androgen-independent prostate adenocarcinomas.'OLiarozole has also been investigated in early-stage clinical trials. In a phase I / I1 dose-escalation study, 30% of heavily pretreated patients with hormone refractory prostate cancer experienced a PSA res p o n ~ ehowever, ~~; a large randomized phase 111 international trial was recently halted, and it is unclear whether further development of the drug will occur. OTHER HORMONAL MANIPULATIONS

Several other secondary hormonal manipulations may be useful in the treatment of hor-

mone refractory prostate cancer. Glucocorticoids have been used for decades as a palliative measure, and, recently, more formal evaluation of their efficacy using PSA response and quality-of-life endpoints has occurred. In an early study, Tannock and coll e a g u e ~treated ~~ 37 patients with advanced hormone refractory prostate cancer with lowdose prednisone (7.5 to 10 mg, daily). Nearly 40% of patients reported an improved quality of life at 1 month, and 20% maintained this improvement for a median of 4 months. There was little toxicity from the steroid therapy. In a second large randomized study, this group compared low-dose prednisone with mitoxantrone and prednisone in a similar patient population. Overall, 17 of 81 patients (21%) randomized to prednisone alone had improved quality of life as assessed by decrease in pain intensity or reduction in analgesic usage.66 Twenty-two percent of patients treated with steroid alone also had a greater than 50% decline in PSA levels, although there was not a perfect correlation between PSA decrease and improved quality of life. The latter observation underscores the need to combine PSA response data with other objective measures of treatment efficacy whenever possible when evaluating secondary hormonal manipulations in hormone refractory prostate cancer. Other trials conducted in the PSA era have

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examined the effectiveness of glucocorticoids after antiandrogen withdrawal. Kelly and colleague~ treated ~ ~ 30 men with hormone refractory prostate cancer with hydrocortisone (40 mg, daily) and observed a 20% PSA response rate; 22 of these men had undergone prior flutamide withdrawal. Dawson and co-worke r ~ 'undertook concomitant flutamide withdrawal and hydrocortisone treatment (30 mg, daily) in patients with hormone refractory prostate cancer and detected a 29% PSA response rate, although in contrast to the Kelly report, none of 18 patients treated with hydrocortisone after prior flutamide withdrawal experienced a PSA response. In a more recent study, 16% of 230 patients randomized to placebo and hydrocortisone (40 mg, daily) in a trial evaluating the effectiveness of suramin experienced a 50% PSA decline; all treated patients in this trial had progressive disease after antiandrogen withdrawal.h0It is not clear whether the different doses used in these studies had any impact on the results, although it is possible that a dose-response effect exists for glucocorticoid treatment. Corticosteroids other than hydrocortisone and prednisone may provide palliative benefit in patients with hormone refractory prostate cancer. In a recent retrospective study, dexamethasone (0.75 mg, twice daily) was reported to produce symptomatic improvement in 79% of 38 patients.64Twenty-three (61%) of these patients also experienced a PSA decrease. This observation is particularly important because dexamethasone is frequently employed as a premedication in paclitaxel- or docetaxel-based chemotherapy regimens used in the treatment of hormone refractory prostate cancer and could potentially contribute to response; however, at least one study has indicated that the short-term steroid use in these regimens probably does not influence chemotherapy response ratess5 Megestrol acetate has been used for some time as a treatment for hormone refractory prostate cancer. The drug has several effects that may contribute to its effectiveness, including suppressing the release of luteinizing hormone, blocking binding of DHT to the androgen receptor, and inhibiting 5-a-reductase. In studies prior to the routine use of PSA as a tumor marker, megestrol acetate

was found to be modestly effective. Pate1 and c011eagues~~ treated 29 men with hormone refractory prostate cancer with megestrol acetate and noted three objective responses (10%) and 20 patients (68%) with stable disease. Crombie and co-workerss also observed a low (< 10%) objective response rate in men with metastatic prostate cancer progressing after diethylstilbestrol or orchiectomy. More recent studies have substantiated these low response rates. Dawson and c o - w o r k e r ~found ~ an overall 12% PSA response rate in patients with hormone refractory prostate cancer treated with low (160 mg) or high (640 mg) daily doses, and Osborn and c o - ~ o r k e r s ~ ~ confirmed these findings in a small retrospective study. Thus, although megestrol acetate may produce responses in some patients, it is generally less effective than other secondary hormonal manipulations, and its use is best reserved for patients unable to tolerate other therapies or who have side effects such as hot flashes that may be ameliorated by the drug. Withdrawal of megestrol acetate in patients with progressive disease may result in a PSA decline, even in those receiving low-dose (20 to 40 mg, daily) therapy for hot flashes.

FUTURE DIRECTIONS The recognition that hormone refractory prostate cancer is a clinically heterogeneous disease and that many patients retain sensitivity to hormonal manipulations has significantly changed the approach to therapy in the last 5 years. Antiandrogen withdrawal is now essential for all patients with progressive disease who are receiving combined androgen blockade, and further treatment with an alternate antiandrogen, adrenal steroid inhibitor, or glucocorticoid may provide subjective and objective clinical benefit in 20% to 65% of patients. Despite these advances, the duration of response is short for most patients, and no trial has demonstrated a significant survival advantage for patients treated with these agents. To make further progress, clinical and scientific knowledge must be expanded in a number of directions. First, patients most likely to respond to secondary hormonal ma-

SECONDARY HORMONAL MANIPULATIONS IN HORMONE REFRACTORY PROSTATE CANCER

nipulation must be identified prospectively. Currently, no pretreatment clinical variables allow clinicians to select those patients who will benefit from secondary hormonal treatment or to determine which specific intervention is likely to be efficacious in a given patient. The patient with a large tumor burden, a rapid PSA doubling time, and a previous poor response to primary hormonal treatment will probably not be a good candidate for secondary hormonal manipulation; the challenge will be to identify those patients with more indolent disease who will respond to such maneuvers. The availability of markers (such as steroid precursor levels or molecular analysis of the androgen receptor) would facilitate this task. The most effective use of currently available agents must be determined. The usual approach is to employ these drugs sequentially and as single agents, but incorporation of secondary hormonal compounds into combination regimens, such as with cytotoxic chemotherapy or novel biologic agents, may provide enhanced clinical benefit. Ketoconazole has been combined with doxorubicin in one and further investigation of this general approach is warranted. Most importantly, increased understanding must be obtained of the molecular alterations that lead to hormonal resistance in patients with advanced prostate cancer. Androgen receptor function is intricately regulated on the molecular level. Dissecting these processes should allow for the more rational use of existing therapeutics as well as the development of novel targeted therapies.

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5. Crombie C, Raghavan D, Page J, et al: Phase I1 study of megestrol acetate for metastatic carcinoma of the prostate. Br J Urol 59:443-446, 1987 6. Dawson N, Figg WD, Brawley OW, et al: Phase I1 study of suramin plus aminoglutethimide in two cohorts of patients with androgen-independent prostate cancer: Simultaneous antiandrogen withdrawal and prior antiandrogen withdrawal. Clin Cancer Res 4:37-44, 1998 7. Dawson NA, Cooper MR, Figg WD, et al: Antitumor activity of suramin in hormone-refractory prostate cancer when hydrocortisone treatment and flutamide withdrawal are prospectively controlled for as potentially confounding variables. Cancer 76:453-462, 1995 8. Dawson NA, McLeod DG: Dramatic PSA decline in response to discontinuation of megestrol acetate in advanced prostate cancer: Expansion of the antiandrogen withdrawal syndrome. J Urol 153:1946-1947, 1995 9. Dawson NA, Small EJ, Conaway M, et al: Megestrol acetate (MA) in men with hormone-refractory prostate cancer (HRPC): Prostate specific antigen (PSA) response and antiandrogen withdrawal (AAWD). Cancer and Leukemia Group B (CALCB) 9181 [abstract]. Proc Am Soc Clin Oncol 15:241, 1996 10. Dijkman A, Van Moorselaar RJA, Van Ginkel R, et al: Antitumor effects of liarozole in androgen-dependent and independent R3327-Dunning prostate adenocarcinomas. J Urol 151:217-222, 1994 11. Dixon SC, Zalles A, Giordano C, et al: In vitro effect of gallium nitrate when combined with ketoconazole in the prostate cancer cell line PC-3. Cancer Lett 113:111-116, 1997 12. Dowsett M, Shearer RJ, Ponder BAJ, et al: The effects of aminoglutethimide and hydrocortisone, alone and combined, on androgen levels in post-orchiectomy prostatic cancer patients. Br J Cancer 57190-192,1988 13. Drago JR, Santen RJ, Lipton A, et al: Clinical effect of aminoglutethimide, medical adrenalectomy, in treatment of 43 patients with advanced prostatic cancer. Cancer 53:1447-1450, 1984 14. Dupont A, Gomez J, Cusan L, et al: Response to flutamide withdrawal in advanced prostate cancer in progression under combination therapy. J Urol 1501908-913, 1993 15. Eastham JA, Sartor 0 Nilutamide response after flutamide failure in postorchiectomy progressive prostate cancer. J Urol 159:990, 1998 16. Eisenberger M, Crawford E, McLeod D, et al: A comparison of bilateral orchiectomy (orch) with or without flutamide in stage D2 prostate cancer (PC) [abstract]. Proc Am Soc Clin Oncol 16:2a, 1997 17. Eisenberger MA, Nelson WG: How much can we rely on the level of prostate-specific antigen as an end point for evaluation of clinical trials? A word of caution! J Natl Cancer Inst 88:779-781, 1996 18. Figg WD, Dawson N, Middleman MN, el al: Flutamide withdrawal and concomitant initiation of aminoglutethimide in patients with hormone refractory prostate cancer. Acta Oncol 35:76%765, 1996 19. Figg WD, McCall NA, Reed E, et al: The in vitro response of four antisteroid receptor agents on the hormone responsive prostate cancer cell line LNCaP. Oncol Rep 2295-298, 1995 20. Figg WD, Sartor 0, Cooper MR, et al: Prostate specific antigen decline following the discontinuation of flutamide in patients with stage D2 prostate cancer. Am J Med 98:412414, 1995 21. Fowler JE, Pandey P, Seaver LE, et al: Prostate specific

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Address reprint requests to David M. Reese, MD Urologic Oncology Program University of California, San Francisco/ Mount Zion Cancer Center 2356 Sutter Street, 5th Floor San Francisco, CA 94115