Androgen deprivation therapy for patients with clinically localized (stages T1 to T3) prostate cancer and for patients with biochemical recurrence after radical prostatectomy

ANDROGEN DEPRIVATION THERAPY FOR PATIENTS WITH CLINICALLY LOCALIZED (STAGES T1 TO T3) PROSTATE CANCER AND FOR PATIENTS WITH BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY GARY D. GROSSFELD, ERIC J. SMALL, DEBORAH P. LUBECK, DAVID LATINI, JEANETTE M. BROERING, AND PETER R. CARROLL

ABSTRACT Recently published studies suggest a benefit for androgen deprivation therapy (ADT) delivered early in the course of prostate cancer. However, the use of ADT specifically in patients with clinically localized disease or biochemical-disease recurrence after local therapy is not well defined. Potential candidates for primary ADT include patients who are poor candidates for definitive local therapy because of advanced age or comorbid conditions, as well as patients with significant local disease who refuse standard therapy. Treatment strategies designed to minimize the side effects of prolonged therapy, such as intermittent ADT or antiandrogen monotherapy, show promise as alternatives to continuous ADT in some patients. The role of ADT in patients with clinically localized and recurrent prostate cancer, whether it is delivered in a continuous or intermittent fashion, must be determined in randomized, prospective trials. UROLOGY 58 (Suppl 2A): 56–64, 2001. © 2001, Elsevier Science Inc.

T

he purpose of this article is to review the use of androgen deprivation therapy (ADT) as a primary treatment modality in patients with clinically localized (stages T1 to T3) prostate cancer, and to review the use of ADT in patients with biochemical-disease recurrence after radical prostatectomy. The benefit of early ADT will be discussed, as well as a variety of novel therapeutic strategies designed to preserve health-related quality of life (HRQOL), while maintaining treatment efficacy. ANDROGEN DEPRIVATION THERAPY: THE BENEFITS OF EARLY TREATMENT Although some have advocated delaying ADT until there is symptomatic disease progression, several lines of evidence suggest that use of this treatment should be considered in select patients

From the Department of Urology (GDG, EJS, DPL, PRC), the Department of Medicine (EJS), the Urology Outcomes Research Group (DPL, DL, JMB), and the Program in Urologic Oncology (GDG, EJS, DPL, PRC), University of California, San Francisco/ Mount Zion Cancer Center, University of California, San Francisco, San Francisco, California, USA. Reprint requests: Gary D. Grossfeld, MD, Department of Urology, U-575, University of California, San Francisco, San Francisco, California 94143-0738.

56

© 2001, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED

with earlier-stage disease. The Veterans Administration Cooperative Research Group (VACURG) studies, first organized in 1959, investigated the treatment of prostate and bladder cancer in randomized clinical trials.1 Among the conclusions of these studies was that medical or surgical castration, with 5 mg diethylstilbestrol (DES) or orchiectomy, delayed distant progression of locally advanced, nonmetastatic prostate cancer when compared with placebo.1 In addition, early medical castration with DES was found to improve actuarial survival rates for patients with locally advanced and metastatic disease when compared with placebo, and that it delayed treatment at the time of symptomatic disease progression.1 Such early treatment appeared to be most beneficial for younger patients with highgrade tumors. More recent studies have suggested a benefit of immediate ADT in patients with locally advanced prostate cancer. In 1997, the Medical Research Council published results of a randomized trial comparing early versus delayed ADT in patients with locally advanced and metastatic prostate cancer.2 Altogether, 938 patients were entered into this trial, with ⬎50% (500 patients) having no ev0090-4295/01/$20.00 PII S0090-4295(01)01243-2

idence of metastatic disease at the time of study entry. This study demonstrated that immediate ADT was associated with significant benefits with respect to local and metastatic disease progression, disease-associated complications (such as spinal cord compression, pathologic fracture, and urinary tract obstruction), and a significant improvement in overall and disease-specific survival when compared with delayed treatment.2 These benefits were most evident in patients with locally advanced, nonmetastatic disease. Although this study has been criticized for methodologic flaws, it supports early ADT in selected patients with clinically localized prostate cancer. Messing et al.3 recently reported results of a prospective, randomized trial of early ADT in men with microscopic lymph-node metastases at the time of radical prostatectomy. In this study, 98 men with microscopic lymph-node metastases at radical prostatectomy were randomized to immediate ADT after prostatectomy or delayed treatment at the time of disease progression. After 10 years, the actuarial survival of patients treated with immediate therapy was approximately 80%, compared with only 55% in patients treated with deferred ADT (P ⫽ 0.02). Although such data cannot be extrapolated to patients with clinically localized prostate cancer who do not receive local therapy, the conclusions of this study provide additional evidence in support of early ADT for patients with high-risk prostate cancer. CONTINUOUS ANDROGEN DEPRIVATION THERAPY FOR CLINICALLY LOCALIZED PROSTATE CANCER Although ADT is effective in inducing local tumor regression in most, if not all, patients with prostate cancer, the use of such treatment in clinically localized disease has been limited for 2 important reasons: (1) ADT may not be curative for patients with prostate cancer, because most patients develop progressive disease while receiving prolonged treatment; and (2) ADT may be associated with a variety of acute side effects, including hot flashes, fatigue, impotence, loss of libido, and cognitive changes or depression. Moreover, patients who receive long-term ADT may also experience anemia, loss of lean-muscle mass, weight gain, and possibly osteoporosis with the attendant risk of bone fracture. Because of these limitations, few studies have examined the use of prolonged ADT in patients with clinically localized, nonmetastatic prostate cancer. Labrie et al.4 reported on 26 patients with clinical stage T2 disease and 115 patients with clinical stage T3 disease who were treated with long-term combined androgen blockade using a luteinizing UROLOGY 58 (Supplement 2A), August 2001

hormone–releasing hormone (LHRH) agonist and flutamide. Median duration of treatment was 7.1 years for clinical stage T2 patients and 5.1 years for clinical stage T3 patients, respectively. During this time, only 1 stage-T2 patient developed disease progression as evidenced by increasing levels of serum prostate-specific antigen (PSA) on treatment. For stage-T3 patients, 5- and 10-year disease-free survival rates were estimated at 74.6% and 53.8%, respectively.4 Interestingly, these investigators stopped ADT in a subgroup of patients from 1 to 10 years after the initiation of therapy. Nearly all stage T2 patients, in whom therapy was stopped after only 1 year of treatment, developed disease progression. In contrast, 18 of 20 (90%) stage-T2 patients who were treated for a median duration of 7.2 years and 21 of 26 (81%) stage-T3 patients who were treated for a median duration of 9.9 years remained disease free with prolonged follow-up after treatment was stopped. These findings suggest either that (1) patients treated with prolonged ADT do not experience a testosterone rebound after cessation of treatment; or (2) prolonged ADT may potentially eliminate all malignant cells in some patients with clinically localized prostate cancer. Akaza et al.5 reported on 151 patients with clinical stages T1 to T3a prostate cancer treated either with an LHRH agonist alone or an LHRH agonist plus the steroidal antiandrogen, chlormadinone acetate. Patients in this study were not considered appropriate candidates for local therapy, either because they were a poor risk for such treatment or because of patient refusal or physician recommendation against local therapy. Disease progression in this study was defined either by an increasing serum PSA level on treatment or by an increase in the size of the primary prostatic lesion on imaging. The 2-year progression-free survival rates for patients receiving the LHRH agonist alone versus patients receiving combination therapy, according to disease stage at presentation, were as follows: (1) 87% versus 87% for stage T1b; (2) 66% versus 57% for stage T2a; (3) 62% versus 91% for stage T2b; and (4) 43% versus 70% for stage T3.6 CONTINUOUS ANDROGEN DEPRIVATION THERAPY FOR PATIENTS WITH PROSTATESPECIFIC ANTIGEN RECURRENCE AFTER RADICAL PROSTATECTOMY Timing and type of treatment for patients with biochemical recurrence after radical prostatectomy remains controversial because of (1) many unresolved issues surrounding the natural history of disease progression in such patients; (2) the limited ability of clinical measures to accurately define local versus distant disease recurrence; and (3) the 57

uncertainty on the appropriate trigger point for initiating therapy. Nevertheless, the use of secondary cancer treatment in this setting is common, occurring in as many as 22% of patients within 3 years of the primary local treatment episode.6 For patients initially treated with radical prostatectomy, secondary treatment appears to be nearly equally divided between postoperative radiation and ADT, whereas approximately 90% of such patients receive ADT after radiation therapy.6 Such differences are clinically significant given the potential of postoperative radiation to eradicate local disease, whereas ADT is generally considered to be palliative. The only “absolute” indication for treatment of patients with PSA recurrence after radical prostatectomy is symptomatic disease progression. However, this is rarely encountered, and patients often seek treatment much earlier in the course of the disease. Relative indications for treatment include (1) clinical evidence of disease on bone scan or other imaging studies; (2) rapid PSA doubling time after prostatectomy; and (3) patient desire for treatment. It is important to distinguish local from distant disease recurrence in these patients, as treatment options may vary significantly. Indeed, local recurrence may be more common than previously thought, occurring in as many as 50% of patients with biochemical recurrence after radical prostatectomy.7 Physical examination and imaging have limited ability to distinguish local versus distant disease recurrence after radical prostatectomy. Thus, clinicians must rely on clinical tumor characteristics, such as pathologic stage, tumor grade, and PSA velocity after surgery to distinguish local versus distant recurrence.8 In patients with a high likelihood of persistent or recurrent local disease after radical prostatectomy, radiation to the prostatic fossa remains a treatment option. Multiple series attest to the effectiveness of this treatment, with disease-free survival rates of approximately 46%, 3 years after postoperative radiation.9 Important predictors of disease-free survival in this setting include (1) low preoperative PSA; and (2) early use of radiation (before the serum PSA level reaches 1.0 ng/mL).10 Other unresolved issues surrounding treatment of patients with biochemical recurrence after radical prostatectomy include the appropriate trigger point for the initiation of therapy as well as the natural history of disease progression in these patients. Pound et al.11 reported on the natural history of disease progression in 304 patients who experienced biochemical disease progression after radical prostatectomy. The median time to distant metastasis was 8 years from the time of PSA elevation. Once metastatic disease developed, the median time to death was reported to be 5 years. A shorter interval to the development of metastatic 58

disease was associated with PSA recurrence ⬍2 years after surgery, a Gleason score ⬎7 of the primary tumor, and PSA doubling time ⬍10 months. Such data suggest that disease progression may take many years in some of these patients, which brings into question the ultimate value of additional therapy on overall survival. However, these data also suggest that PSA kinetics may be important in distinguishing those who are destined to fail early from those in whom a prolonged time to progression can be expected. These issues on biochemical recurrence after radical prostatectomy are important, because any type of treatment in this setting is associated with potential morbidity. For patients with a high risk of systemic disease progression, ADT is generally considered the most appropriate treatment option. Similar to patients with clinically localized disease and no prior local therapy, those with biochemical recurrence who receive ADT will be treated early in the course of disease. Many of these patients will be asymptomatic and can expect a relatively long life expectancy. Therefore, if ADT is considered, patients may be exposed to the potential short- and long-term side effects of such treatment for a prolonged period. Effects on energy/vitality and sexual function may be significant, and the potential for decreased muscle mass, osteoporosis, and anemia would be high. These issues of continuous ADT have led to the search for alternative treatment strategies that optimize the effectiveness of hormonal therapy, while minimizing the adverse effects on patient quality of life. In summary, no consensus yet exists on the appropriate treatment of patients with biochemical recurrence after radical prostatectomy. In general, older patients with a slow increase in PSA after surgery are appropriate candidates for surveillance. In younger patients, in whom disease characteristics and PSA kinetics favor local disease recurrence, radiation appears indicated. ADT may be considered in those with disease characteristics and PSA kinetics suggestive of distant recurrence. Alternatively, these patients may be excellent candidates for clinical trials exploring novel treatment options, such as intermittent ADT or antiandrogen monotherapy. ALTERNATIVE TREATMENT STRATEGIES USING ANDROGEN DEPRIVATION THERAPY FOR PATIENTS WITH CLINICALLY LOCALIZED OR RECURRENT PROSTATE CANCER INTERMITTENT ANDROGEN DEPRIVATION THERAPY It has been hypothesized that prolonged ADT may provide the stimulus for activating cellular and molecular signaling pathways that mediate UROLOGY 58 (Supplement 2A), August 2001

TABLE I. Selected reports of intermittent androgen deprivation Initial Median PSA (ng/mL)

Stage of Disease: Localized/PSA Relapse/Metastatic

Author

Year

N

Klotz25 Goldenberg20 Higano24 Oliver27

1986 1995 1996 1997

20 47 22 20

Grossfeld21

1998

47

8.4

27/20/0

Theyer28 Gleave19 Horwich22 Crook18 Kurek26 Hruby23

1998 1998 1998 1999 1999 1999

52 70 16 54 44 16

31 110 164 37 6.3 33.4

15/0/37 41/0/29 0/0/16 11/4/39 15/29/0 2/6/8

Tunn29

1996

20

NR

NR 158 20 NR

12/0/8 23/0/24 2/10/10 13/0/7

5/15/0

Treatment DES LHRH ⫹ AA LHRH ⫹ AA LHRH ⫹ AA (12) LHRH (6) DES (2) LHRH ⫹ AA (33) LHRH (14) LHRH ⫹ AA LHRH ⫹ AA LHRH LHRH ⫹ AA LHRH ⫹ AA LHRH ⫹ AA (14) LHRH (2) LHRH ⫹ AA

Median Off Cycle Duration (mo) 7.8 7.6 6.0 24.0

7.5 16.0 9.0 8.0 8.0 11.6 8.6 8.3

AA ⫽ antiandrogen; LHRH ⫽ luteinizing hormone–releasing hormone agonist; NR ⫽ not reported; PSA ⫽ prostate-specific antigen.

progression of prostate tumor cells from the androgen-dependent to the androgen-independent state.12–14 Preclinical data suggest that intermittent replacement of androgen may inhibit the biochemical switch leading to the activation of such pathways, thereby delaying the time to androgen independence.12,15–17 Such experimental data, coupled with a desire to minimize the side effects and cost of ADT, has provided the impetus for a number of reports exploring the utility of intermittent ADT in men with prostate cancer (Table I).18 –29 Given the potential for long-term ADT in patients with clinically localized or recurrent prostate cancer after radical prostatectomy, intermittent therapy seems especially well suited for these particular patient populations. We recently updated our experience with intermittent ADT in selected patients with clinically localized and recurrent prostate cancer treated at the University of California, San Francisco. A total of 61 patients have been treated in this manner, including 34 patients with clinically localized prostate cancer who received no prior treatment and 27 patients who developed recurrent disease after local therapy: 10 after radiotherapy, 3 after cryosurgery, 8 after radical prostatectomy, and 6 after radical prostatectomy and adjuvant radiotherapy. No patient had evidence of systemic disease before the initiation of therapy. Mean and median serum PSA levels before the start of treatment were 25.3 ng/mL and 16.0 ng/mL, respectively (range: 0.6 to 190 ng/mL). ADT was achieved either using combined androgen blockade (leuprolide depot 7.5 mg intramuscularly monthly plus antiandrogen; 47 patients) or leuprolide alone (14 patients). It was our policy to UROLOGY 58 (Supplement 2A), August 2001

treat patients with at least 6 to 9 months of ADT during the initial “on” treatment phase of cycle 1. This initial treatment phase continued for 1 to 2 months after serum PSA became undetectable or a nadir PSA level was reached. For patients to be eligible for withdrawal of treatment, the PSA must have reached a nadir as a consequence of ADT, ⬍0.1 ng/mL for patients with prior definitive local therapy or ⬍4.0 ng/mL for patients with no prior local therapy. ADT was then reinstituted (1) when serum PSA reached a predetermined level either ⱖ50% of the pretreatment level or ⬎10 ng/mL; or (2) by patient request. The length of 1 treatment cycle was defined as the number of months on ADT (on-treatment phase) followed by the number of months that treatment was withdrawn (off-treatment phase). The subsequent cycle commenced with reinstitution of ADT. Androgen independence was defined as either the failure of serum PSA to decrease (or an increase in PSA) on 2 separate occasions while receiving treatment, or any objective evidence of disease progression on imaging studies, regardless of serum PSA level. Follow-up time for these patients ranged from 7 to 60 months after the initiation of ADT (mean: 30 months). Patients have received from 1 to 5 treatment cycles. A total of 61 patients started cycle 1; cycle 2 had 52 patients; cycle 3 had 27 patients; cycle 4 had 14 patients; and cycle 5 had 4 patients. All patients responded to their first cycle of ADT, as evidenced by a decrease in serum PSA to an appropriate nadir level. Considering all treatment cycles in which a nadir serum PSA has been reached, the mean and median nadir serum PSA values on ADT have been 0.25 ng/mL and 0.01 ng/mL, respectively. This nadir was reached within 59

TABLE II. Clinical characteristics of patients treated with IAD for clinically localized adenocarcinoma of the prostate: comparison between those patients receiving no prior local treatment (N ⴝ 34) and those patients failing prior definitive local therapy (N ⴝ 27) No Prior Treatment Age (yr) Mean Range Stage at diagnosis T1 T2 T3 Gleason grade at diagnosis 2–4 5–6 7 8–10 PSA at study entry (ng/mL) Mean Median Range Percent time “on” treatment Percent time “off” treatment

68.0 50–92

Prior Local Treatment 68.8 50–80

3 15 16

1 13 13

2 17 11 4

0 11 10 5

25.0 12.0 3.2–190 57% 43%

18.0 14.0 0.6–36.5 51% 49%

PSA ⫽ prostate-specific antigen.

an average of 6 months (range: 4 to 9 months) from the start of a treatment cycle. Patient characteristics based on the indication for starting intermittent ADT are summarized in Table II. The mean and median cycle lengths have been 13 months and 14 months, respectively. During this time, patients have spent an average of 55% of the time on treatment and 45% of the time off treatment. However, as patients have continued to cycle on and off ADT, the time spent off treatment has decreased. The percentage of time spent off treatment was 53% for cycle 1, 48% for cycle 2, 47% for cycle 3, 39% for cycle 4, and 37% for cycle 5. Androgen-independent disease has developed in 5 patients (8.1%). Median time to disease progression was 48 months (range: 24 to 58 months). Overall, 2 of 34 (6%) previously untreated patients experienced disease progression during cycles 4 and 5, which occurred 57 and 58 months after starting intermittent ADT. A total of 3 of 27 (11%) patients with recurrent prostate cancer after local therapy developed androgen-independent disease 24, 33, and 48 months after starting intermittent ADT. Altogether, 2 of these patients were previously treated by radical prostatectomy, and the other patient received cryosurgery. Androgen independence occurred during cycle 2 in 2 of these patients and cycle 4 in the other patient. We evaluated self-reported HRQOL in 10 of the patients undergoing intermittent ADT. HRQOL was measured using the SF-3630 and the University of California Los Angeles (UCLA) Prostate Cancer 60

Index.31 These 10 patients underwent 14 treatment cycles in which HRQOL data were available both on and off ADT. HRQOL scores range from 0 to 100 with higher scores representing better outcomes.32 A change of ⱖ5 points is considered to be clinically significant. Changes in HRQOL were calculated for the entire study population and separately for patients above and below the median age of 71. Average time from the last LHRH-agonist injection to HRQOL measured off therapy was 7.6 months. Overall, 5 of these patients received no previous treatment (intermittent ADT only), and the other 5 patients were treated with intermittent ADT for biochemical recurrence after radical prostatectomy (3 patients) or radiation (2 patients). When analyzing all patients, clinically significant improvements in HRQOL were seen during the off-treatment episodes for vitality/fatigue, sexual function, and sexual bother (Table III). Smaller improvements were seen in physical function, role physical, and urinary bother. We then calculated changes in HRQOL for patients below and above the median age of 71 years. It is possible that older patients may experience less of a testosterone rebound when ADT is withdrawn, thereby abrogating benefits from the off-treatment phase of a cycle in terms of HRQOL. For patients ⬍71 years of age, clinically significant improvements in HRQOL were seen during the off-treatment episodes for (1) role physical; (2) health compared with 1 year before; (3) urinary bother; and (4) sexual bother. UROLOGY 58 (Supplement 2A), August 2001

TABLE III. Changes in health-related quality of life (HRQOL)* for patients on intermittent androgen deprivation Domain Physical function Role physical Bodily pain General health Vitality/fatigue Social function Role emotional Mental health Health compared with 1 year ago Urinary function Urinary bother Bowel function Bowel bother Sexual function Sexual bother

All Patients

Patients <71 Years

Patients >71 Years

⫹2.9 ⫹3.6 ⫺0.4 ⫺0.9 ⫹5.7 0 0 ⫹0.4 ⫹1.8

0.0 ⫹7.1 ⫺0.8 ⫺7.9 ⫹2.8 ⫺3.5 0 ⫹0.8 ⫹7.1

⫹5.7 0 ⫺2.8 ⫹6.1 ⫹8.6 ⫹3.5 0 0 ⫺3.5

⫹0.8 ⫹3.6 ⫹0.9 ⫺3.5 ⫹7.6 ⫹9.2

⫺4.1 ⫹7.1 ⫹1.1 ⫺3.6 ⫹2.8 ⫹16.7

⫹5.7 0 ⫹0.7 ⫺5.6 ⫹12.5 0

* Calculated by subtracting HRQOL score “on” treatment from HRQOL score “off” treatment. Scores ⬎0 represent improvements in HRQOL while off treatment. Scores ⬍0 represent deterioration in HRQOL while off treatment. A change ⱖ5 points is considered clinically significant.

Smaller improvements were seen in vitality/fatigue and sexual function. Interestingly, similar benefits were seen in patients ⬎71 years of age; clinically significant improvements were seen during the offtreatment episodes for (1) physical function; (2) general health; (3) vitality/fatigue; (4) urinary function; and (5) sexual function. Smaller improvements were seen in social function (Table III). ANTIANDROGEN MONOTHERAPY AND FINASTERIDE Nonsteroidal antiandrogens, such as flutamide, nilutamide, and bicalutamide, inhibit the binding of testosterone and dihydrotestosterone (DHT) to the androgen receptor both peripherally and centrally.33,34 The side-effect profile of these agents appears favorable when compared with castration, especially when considering preservation of sexual function. In theory, these agents should be as effective as castration in the treatment of prostate cancer, although there is a risk that substantial elevations in serum testosterone may overcome their inhibitory effect. Several reports have examined the use of antiandrogen monotherapy, either with flutamide or bicalutamide, in patients with advanced prostate cancer. These data indicate that such treatment can produce PSA responses and objective clinical improvement (decreased pain, improvement on imaging studies). Studies in patients with metastatic UROLOGY 58 (Supplement 2A), August 2001

disease, which compare bicalutamide (either 50 mg per day or 150 mg per day) with medical or surgical castration, suggest that castration is superior, regardless of bicalutamide dose (Table IV).35–38 However, in a recent study of 480 patients with locally advanced, nonmetastatic prostate cancer and a median follow-up time of 6.3 years, highdose bicalutamide was reported to be equivalent to castration in time to disease progression and overall survival.39 Moreover, patients receiving bicalutamide monotherapy demonstrated significant benefits with respect to sexual interest and physical capacity. The most common adverse side effects were hot flashes in the castration group, and breast pain and gynecomastia in the bicalutamide group. Therefore, bicalutamide monotherapy may be a potential alternative to castration in patients with locally advanced, nonmetastatic prostate cancer. Finasteride is a competitive inhibitor of the 5␣reductase enzyme that effectively blocks the conversion of testosterone to the physiologically more potent androgen DHT.40 Because finasteride decreases the intraprostatic concentration of DHT, it has been hypothesized that this agent may have efficacy in patients with localized prostate cancer. Finasteride has demonstrated a favorable side-effect profile, especially with respect to sexual function, because potency is maintained in most men using this medication. Presti et al.41 compared finasteride with placebo in the treatment of 28 men with asymptomatic metastatic prostate cancer (Table V). Whereas finasteride produced minor decreases in serum PSA levels (15% decrease after 6 weeks of therapy), this treatment had no effect on levels of prostatic acid phosphatase or on the appearance of metastatic disease on bone scan. Such effects did not approach those expected with castration. Andriole et al.42 treated 120 men with biochemical disease recurrence after radical prostatectomy with finasteride or placebo (Table V). None of these patients had evidence of metastatic disease. Whereas finasteride delayed PSA progression by approximately 14 months in patients receiving 2 years of treatment, there was no significant benefit in the rate of objective tumor recurrence for patients receiving finasteride. Given the limited benefit observed with finasteride alone, finasteride has been tested in combination with flutamide.43– 46 Such treatments may be synergistic in that finasteride can lower DHT levels and flutamide may block the effects of circulating testosterone and DHT. Studies using this combination therapy demonstrate acceptable PSA responses in most patients (Table V). In addition, most patients who are potent before treatment remain so while receiving treatment. Follow-up time 61

TABLE IV. Trials comparing bicalutamide monotherapy with castration Author

N

Dose

Chodak

486

50 mg

Stage D2

Castration

Bales35

1037

50 mg

Stage D2

Castration

Tyrrell37

1453

150 mg

Castration

Boccardo38

229

150 mg

Iversen39

480

150 mg

Metastatic and locally advanced Metastatic and locally advanced Locally advanced

36

Stage of Disease

Comparison

Result

Combined androgen blockade Castration

Longer progression-free with castration Longer median survival with castration Longer survival in M1 patients with castration No difference in progression-free or overall survival No difference in survival

TABLE V. Trials of finasteride with and without flutamide for advanced and recurrent prostate cancer Author

N

Treatment

Patients

Comparison

Result

Finasteride Finasteride

Metastatic PSA recurrence after RRP

Placebo Placebo

Minimal PSA decrease Delays, does not prevent PSA rise 95% with PSA decrease 86% potent 85% PSA ⬍ 4.0 ng/mL 66% potent 72% PSA ⬍ 1.0 ng/mL 82% potent 62% with PSA nadir ⬍ 0.2 ng/mL

Presti Andriole42

28 120

Fleshner44

22

Finasteride ⫹ flutamide

Stage T3/Metastatic

None

Ornstein46

13

Finasteride ⫹ flutamide

Metastatic/PSA relapse

None

Brufsky43

20

Finasteride ⫹ flutamide

Metastatic/PSA relapse

None

Lisle45

73

Finasteride ⫹ flutamide

PSA relapse

None

41

PSA ⫽ prostate-specific antigen.

is too short and patient numbers are too small to draw meaningful conclusions on treatment efficacy. Therefore, although the combination of flutamide and finasteride may be active against hormone-dependent prostate cancer, this treatment regimen remains investigational at the current time. CONCLUSIONS Whereas ADT was previously reserved for patients with symptomatic disease progression, treatment is now given earlier in the course of the disease process. As a result, decisions on the use of such treatment must include careful consideration, not only of disease-specific endpoints, but also of HRQOL. ADT may be considered an option for select patients with clinically localized stages T1 to T3NxM0 prostate cancer. Potential candidates for this treatment include (1) those with significant local disease, who refuse local therapy or (2) those who are poor candidates secondary to advanced age or comorbid conditions. In this setting, ADT may provide long-term control of disease. ADT may also be considered for patients with biochemical recurrence after radical prostatectomy who are 62

at risk for systemic disease based on (1) pretreatment tumor characteristics; (2) pathologic results from the radical prostatectomy specimen; and (3) PSA kinetics after local treatment. Again, ADT may potentially provide long-term control of disease in such patients. Because these patients are treated early in the disease process, novel treatment strategies aimed at minimizing the side effects and cost of treatment while maintaining treatment efficacy should be considered. Although continuous treatment with medical or surgical castration remains the “gold standard” of delivering ADT, other treatment strategies, such as intermittent ADT and antiandrogen monotherapy, have recently been described. Many unanswered questions remain on the appropriate type and timing of ADT for patients with all stages of prostate cancer. These questions are especially important for patients with nonmetastatic disease. These individuals are young and asymptomatic and, therefore may have a long life expectancy, despite their disease. REFERENCES 1. Byar DP, and Corle DK: Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative UROLOGY 58 (Supplement 2A), August 2001

Urological Research Group studies. NCI Monogr 7: 165–170, 1988. 2. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial: the Medical Research Council Prostate Cancer Working Party Investigators Group. Br J Urol 79: 235–246, 1997. 3. Messing EM, Manola J, Sarosdy M, et al: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341: 1781–1788, 1999. 4. Labrie F, Cusan L, Gomez JL, et al: Long-term combined androgen blockade alone for localized prostate cancer. Mol Urol 3: 217–226, 1999. 5. Akaza H, Homma Y, Okada K, et al: Early results of LH-RH agonist treatment with or without chlormadinone acetate for hormone therapy of naive localized or locally advanced prostate cancer: a prospective and randomized study: the Prostate Cancer Study Group. Jpn J Clin Oncol 30: 131– 136, 2000. 6. Grossfeld GD, Stier DM, Flanders SC, et al: Use of second treatment following definitive local therapy for prostate cancer: data from the CaPSURE database. J Urol 160: 1398 – 1404, 1998. 7. Connolly JA, Shinohara K, Presti JC Jr, et al: Local recurrence after radical prostatectomy: characteristics in size, location, and relationship to prostate-specific antigen and surgical margins. Urology 47: 225–231, 1996. 8. Partin AW, Pearson JD, Landis PK, et al: Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 43: 649 – 659, 1994. 9. Grossfeld GD, Tigrani VS, Nudell D, et al: Management of a positive surgical margin after radical prostatectomy: decision analysis. J Urol 164: 93–99, 2000. 10. Nudell DM, Grossfeld GD, Weinberg VK, et al: Radiotherapy after radical prostatectomy: treatment outcomes and failure patterns. Urology 54: 1049 –1057, 1999. 11. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281: 1591–1597, 1999. 12. Bruchovsky N, Rennie PS, Coldman AJ, et al: Effects of androgen withdrawal on the stem cell composition of the Shionogi carcinoma. Cancer Res 50: 2275–2282, 1990. 13. Furuya Y, Sato N, Akakura K, et al: Paracrine growth stimulation of androgen-responsive Shionogi carcinoma 115 by its autonomous subline (Chiba subline 2). Cancer Res 50: 4979 – 4983, 1990. 14. Rennie PS, Bruchovsky N, and Coldman AJ: Loss of androgen dependence is associated with an increase in tumorigenic stem cells and resistance to cell-death genes. J Steroid Biochem Mol Biol 37: 843– 847, 1990. 15. Akakura K, Bruchovsky N, Goldenberg SL, et al: Effects of intermittent androgen suppression on androgen-dependent tumors: apoptosis and serum prostate-specific antigen. Cancer 71: 2782–2790, 1993. 16. Noble RL: Hormonal control of growth and progression in tumors of Nb rats and a theory of action. Cancer Res 37: 82–94, 1977. 17. Sato N, Gleave ME, Bruchovsky N, et al: Intermittent androgen suppression delays progression to androgen-independent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model. J Steroid Biochem Mol Biol 58: 139 –146, 1996. 18. Crook JM, Szumacher E, Malone S, et al: Intermittent androgen suppression in the management of prostate cancer. Urology 53: 530 –534, 1999. 19. Gleave M, Bruchovsky N, Goldenberg SL, et al: InterUROLOGY 58 (Supplement 2A), August 2001

mittent androgen suppression for prostate cancer: rationale and clinical experience. Eur Urol 34: 37– 41, 1998. 20. Goldenberg SL, Bruchovsky N, Gleave ME, et al: Intermittent androgen suppression in the treatment of prostate cancer: a preliminary report. Urology 45: 839 – 844, 1995. 21. Grossfeld GD, Small EJ, and Carroll PR: Intermittent androgen deprivation for clinically localized prostate cancer: initial experience. Urology 51: 137–144, 1998. 22. Horwich A, Huddart RA, Gadd J, et al: A pilot study of intermittent androgen deprivation in advanced prostate cancer. Br J Urol 81: 96 –99, 1998. 23. Hruby G, Gurnry H, Turner S, et al: Long-term follow-up of patients treated with intermittent hormone therapy for advanced prostate cancer. Prostate J 1: 138 –143, 1999. 24. Higano CS, Ellis W, Russell K, et al: Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study. Urology 48: 800 – 804, 1996. 25. Klotz LH, Herr HW, Morse MJ, et al: Intermittent endocrine therapy for advanced prostate cancer. Cancer 58: 2546 –2550, 1986. 26. Kurek R, Renneberg H, Lubben G, et al: Intermittent complete androgen blockade in PSA relapse after radical prostatectomy and incidental prostate cancer. Eur Urol 35: 27–31, 1999. 27. Oliver RT, Williams G, Paris AM, et al: Intermittent androgen deprivation after PSA-complete response as a strategy to reduce induction of hormone-resistant prostate cancer. Urology 49: 79 – 82, 1997. 28. Theyer G, and Hamilton G: Current status of intermittent androgen suppression in the treatment of prostate cancer. Urology 52: 353–359, 1998. 29. Tunn UW: Intermittent endocrine therapy of prostate cancer. Eur Urol 30: 22–25, 1996. 30. Hays RD, Sherbourne CD, and Mazel RM: The RAND 36-Item Health Survey 1.0. Health Econ 2: 217–227, 1993. 31. Litwin MS, Hays RD, Fink A, et al: Quality-of-life outcomes in men treated for localized prostate cancer. JAMA 273: 129 –135, 1995. 32. Ware JE: SF-36 Health Survey: Manual and Interpretation Guide. 2nd ed. Boston, The Health Institute, 1997. 33. Simard J, Luthy I, Guay J, et al: Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues. Mol Cell Endocrinol 44: 261–270, 1986. 34. Mahler C, and Denis L: Clinical profile of a new nonsteroidal antiandrogen. J Steroid Biochem Mol Biol 37: 921– 924, 1990. 35. Bales GT, and Chodak GW: A controlled trial of bicalutamide versus castration in patients with advanced prostate cancer. Urology 47: 38 – 43, 1996. 36. Chodak G, Sharifi R, Kasimis B, et al: Single-agent therapy with bicalutamide: a comparison with medical or surgical castration in the treatment of advanced prostate carcinoma. Urology 46: 849 – 855, 1995. 37. Tyrrell CJ, Kaisary AV, Iversen P, et al: A randomised comparison of ’Casodex’ (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 33: 447– 456, 1998. 38. Boccardo F, Rubagotti A, Barichello M, et al: Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients: results of an Italian Prostate Cancer Project study. J Clin Oncol 17: 2027–2038, 1999. 39. Iversen P, Tyrrell CJ, Kaisary AV, et al: Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol 164: 1579 –1582, 2000. 40. Rittmaster RS: Finasteride. N Engl J Med 330: 120 – 125, 1994. 41. Presti JC Jr, Fair WR, Andriole G, et al: Multicenter, 63

randomized, double-blind, placebo controlled study to investigate the effect of finasteride (MK-906) on stage D prostate cancer. J Urol 148: 1201–1204, 1992. 42. Andriole G, Lieber M, Smith J, et al: Treatment with finasteride following radical prostatectomy for prostate cancer. Urology 45: 491– 497, 1995. 43. Brufsky A, Fontaine-Rothe P, Berlane K, et al: Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate. Urology 49: 913–920, 1997. 44. Fleshner NE, and Trachtenberg J: Combination finas-

teride and flutamide in advanced carcinoma of the prostate: effective therapy with minimal side effects. J Urol 154: 1642– 1645, 1995. 45. Lisle T, Mackenzie S, Ziada A, et al: Androgen deprivation therapy using finasteride and low dose flutamide to treat PSA failure following therapy for clinically localized adenocarcinoma of the prostate (CaP) [abstract]. J Urol 161(suppl): 299, 1999. 46. Ornstein DK, Rao GS, Johnson B, et al: Combined finasteride and flutamide therapy in men with advanced prostate cancer. Urology 48: 901–905, 1996.

DISCUSSION FOLLOWING DR. GARY D. GROSSFELD’S PRESENTATION John Trachtenberg, MD (Toronto, Ontario, Canada): When are you measuring quality of life in the off-cycle? Are you optimizing your results by measuring it when they have the highest androgen levels? Also, those bars in the quality-of-life graph look remarkably close to me. Gary D. Grossfeld, MD (San Francisco, California): Let me address the second point first. In the quality-of-life literature, a change of ⱖ5 points is a validated clinically significant change. Deborah P. Lubeck, PhD (San Francisco, California): With these 0 to 100 scales, even men with prostate cancer tend to rank fairly high, except for sexual functioning. So you are really not looking from 0 to 100. You are looking at something from 50 to 100. Dr. Grossfeld: But to go back to part 1 of the question: The average time from off-treatment to a questionnaire was about 7.5 or 8 months. We felt that gave enough time, at least in the early cycles, for the testosterone to rebound. These people get questionnaires every 6 months now. We need to see if that benefit in health-related quality of life continues as we continue to cycle people on and off. Glenn J. Bubley, MD (Boston, Massachusetts): After 3 years of hormonal ablation, you lose a lot of Leydig cells. How much rebound can you get after 3 years? Dr. Trachtenberg: We once looked at the cell population counts with a view to using luteinizing hormone–releasing hormone (LHRH) agonist as a birth control method. The concept was dropped because a significant proportion of people never recover. Peter R. Carroll, MD (San Francisco, California): It may prove to be an effective treatment for prostate cancer to just put men on LHRH agonists or antagonists for 2 years, period. Then only treat those whose prostate-specific antigen (PSA) levels go up later. Dr. Grossfeld: If you look at the series from Quebec [Mol Urol 3:217–226, 1999], the T2 patients stopped treatment after an average of 7 years, and 90% of those people kept their PSA down, likely because their testosterone levels never recovered. The T3 patients stopped after almost 10 years, and 81% of those patients had no rise in PSA with prolonged follow-up. Dr. William R. Fair, MD (New York, New York): If hormonal therapy fails and the patient goes on chemotherapy, is it mandatory to continue the hormonal therapy? Many medical

64

oncologists feel absolutely that you have to do that. There is not a lot of literature on this subject. If the patient is continuing to have a deterioration in function, and has already had a process that has failed hormonal therapy, is it logical to continue? Dr. Bubley: The issue of continuing LHRH analogs after progression has not been completely resolved. A study by Hussain et al. [J Clin Oncol 12:1868 –1875, 1994] seemed to indicate that contiued androgen suppression for these patients did not improve survival. However, even the authors believed that a prospective randomized trial was needed. Most physicians prefer to maintain LHRH analog therapy even in progressing patients. What also needs to be factored into this is how long the patient has been on hormonal therapy, because many of those men may be castrated for life in any case. If we are now treating D0 patients with hormonal therapy for 4 or 5 years, then we are going to get a different answer than you would when you are treating just D2 patients, as was the case when these studies were done. However, for hormone-refractory trials, it is mandated that the men be androgen ablated, because, obviously, if you are starting to have testosterone recovery in the fifth month of your study, you have a confounding factor that you cannot handle. Dr. Fair: I know the data vary, but if a man has been on hormonal therapy for 1 or 2 years, the likelihood of his testosterone coming back is almost zero. Intuitively, one would think, if this therapy has failed, why keep it up, given the price the patient is paying in terms of anemia, bone density, and other adverse effects. I think it is an important point, and it is a quality-of-life issue. Don W. W. Newling, MBB, Chir (Amsterdam, the Netherlands): For those patients who have suspicion of distant metastases, you go immediately to complete androgen blockade. In the light of this morning’s discussion, would you still do that? Dr. Carroll: Only in high-risk patients who have clinical evidence of disease, an unfavorable disease profile, and adverse PSA kinetics. Those are the patients who are not likely to respond well to novel therapy, and I would probably still give them combined androgen blockade. Now, that actually constitutes a small number of the patients we are seeing, so for the intermediate- or low-risk PSA kinetic profile, I think those are the patients that we would like to get in clinical trials.

UROLOGY 58 (Supplement 2A), August 2001