Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate

OBJECTIVES: Androgen ablation with luteinizing hormone-releasing hormone (LHRH) agonists, orchiectomy, or oral estrogens has significant untoward sexual side effects. We evaluated a combination of finasteride and flutamide as potency-sparing androgen ablative therapy (AAT) for advanced adenocarcinoma of the prostate. In addition, we evaluated whether finasteride provided additional intraprostatic androgen blockade to flutamide. METHODS: Twenty men with advanced prostate cancer were given flutamide, 250 mg orally three times daily. Serum prostate-specific antigen (PSA) values were measured weekly. At a nadir PSA value, finasteride, 5 mg orally every day, was added. PSA values were then measured weekly until a second nadir PSA value was achieved. Sexual function was evaluated at baseline, at the second nadir PSA value, and every 3 months thereafter. Testosterone, dihydrotestosterone (DHT), and dehydroepiandrostenedione (DHEA) levels were measured at baseline and at the first and second nadir PSA values. RESULTS: The median follow-up period was 16.9 months. Therapy failed in 1 patient with Stage D2 disease at 12 months, but an additional response to subsequent LHRH agonist therapy was observed. One patient developed National Cancer Institute grade 3 diarrhea and was withdrawn from the study. Seven of 20 men developed mild gynecomastia, and 3 of 20 developed mild transient liver function test elevations. Mean PSA levels were 94.6 +/- 38.2 ng/mL at baseline and 7.8 +/- 2.7 and 4.7 +/- 2.2 ng/mL at the first and second PSA nadir values, respectively (P = 0.034). Mean percent decline in PSA value from baseline was 87.0 +/- 3.1% with flutamide alone and 94.0 +/- 1.9% with both flutamide and finasteride (P = 0.001). Eleven of 20 men were potent at baseline. At the second nadir PSA value, 9 (82%) of 11 were potent, whereas 2 (18%) of 11 were impotent. With longer follow-up (median 16.4 months), 6 (55%) of 11 men were potent, 2 (18%) of 11 were partially potent, and 3 (27%) of 11 were impotent. With flutamide alone, testosterone rose a mean of 77 +/- 14.7% of baseline (P = 0.0001), DHEA fell a mean of 32.4 +/- 4.6% (P = 0.0001), and DHT was unchanged. With the addition of finasteride, testosterone rose another 14 +/- 6% (P = 0.06, not significant), DHEA was unchanged, and DHT fell a mean of 34.8 +/- 4.7% (P = 0.0009). CONCLUSIONS: Finasteride and flutamide were safe and well tolerated as AAT for advanced prostate cancer. Finasteride provided additional intraprostatic androgen blockade to flutamide, as measured by additional PSA suppression. Sexual potency was preserved initially in most patients, although there was a reduction in potency and libido in some patients on longer follow-up. Further evaluation of this therapy is needed.     

Genetic alterations in the development of mammary and prostate cancer in the C3(1)/Tag transgenic mouse model

PURPOSE: Finasteride therapy for benign prostatic hyperplasia (BPH) results in a marked lowering of serum prostate specific antigen (PSA) levels. However, little is known about the effect of finasteride on unbound or free serum levels of PSA. Such information would be important since percent free PSA may substantially improve the cancer specificity of PSA testing. Thus, we prospectively studied the effect of finasteride therapy on total and free serum PSA levels. MATERIALS AND METHODS: In a randomized, placebo controlled, double-blind trial 40 men with histologically confirmed BPH (age range 52 to 78 years) were treated with either 5 mg. finasteride daily (26 patients) for 9 months or placebo (14) for 6 months. Prostate volume was assessed by transrectal ultrasound. Serum levels of free and total PSA were measured from archived serum samples stored at -70C at baseline and for as long as 9 months of treatment. RESULTS: In the finasteride group mean total PSA levels declined from 3.0 ng./ml. at baseline to 1.5 ng./ml. after 6 months of treatment (50% decrease, p <0.01). In the placebo group, with similar baseline levels, no significant change was observed. PSA density declined significantly in finasteride treated men (p <0.01) but not in men receiving placebo. The mean percent free PSA (13 to 17% at baseline) was not altered significantly by finasteride or placebo. CONCLUSIONS: Total PSA serum levels decreased by an average of 50% during finasteride therapy but percent free PSA did not change significantly. This information is potentially useful in the interpretation of PSA data used for early detection of prostate cancer in men receiving finasteride. However, further studies are required to demonstrate the use of percent free PSA to detect the development of cancer.     

Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin

OBJECTIVES: Prostate cancer recurrence, evidenced by rising prostate-specific antigen (PSA) levels after radical prostatectomy, is an increasingly prevalent clinical problem in need of new treatment options. Preclinical studies have suggested that for tumors in general, settings of minimal cancer volume may be uniquely suitable for recombinant vaccine therapy targeting tumor-associated antigens. A clinical study was undertaken to evaluate the safety and biologic effects of vaccinia-PSA (PROSTVAC) administered to subjects with postprostatectomy recurrence of prostate cancer and to assess the feasibility of interrupted androgen deprivation as a tool for modulating expression of the vaccine target antigen, as well as detecting vaccine bioactivity in vivo. METHODS: A limited Phase I clinical trial was conducted to evaluate the safety and biologic effects of vaccinia-PSA administered in 6 patients with androgen-modulated recurrence of prostate cancer after radical prostatectomy. End points included toxicity, serum PSA rise related to serum testosterone restoration, and immunologic effects measured by Western blot analysis for anti-PSA antibody induction. RESULTS: Toxicity was minimal, and dose-limiting toxicity was not observed. Noteworthy variability in time required for testosterone restoration (after interruption of androgen deprivation therapy) was observed. One subject showed continued undetectable serum PSA (less than 0.2 ng/mL) for over 8 months after testosterone restoration, an interval longer than those reported in previous androgen deprivation interruption studies. Primary anti-PSA IgG antibody activity was induced after vaccinia-PSA immunization in 1 subject, although such antibodies were detectable in several subjects at baseline. CONCLUSIONS: Interrupted androgen deprivation may be a useful tool for modulating prostate cancer bioactivity in clinical trials developing novel biologic therapies. Immune responses against PSA may be present among some patients with prostate cancer at baseline and may be induced in others through vaccinia-PSA immunization.     

Early detection of recurrent prostate cancer with an ultrasensitive chemiluminescent prostate-specific antigen assay

OBJECTIVES: Treatment failure after radical prostatectomy is most commonly heralded by an increase in serum prostate-specific antigen (PSA) to detectable levels. We evaluated the clinical utility of an ultrasensitive chemiluminescent PSA assay. METHODS: We evaluated the assay in banked sera obtained from 170 men after radical prostatectomy. Controls consisted of 142 females, 29 men who had undergone cystoprostatectomy without evidence of prostate cancer, and 25 men without evidence of recurrent disease at least 5 years after prostatectomy for organ-confined disease. Lead time to diagnosis of recurrence was based on comparisons with the IMx or Tandem E assays using a cutoff of 0.1 ng/mL (100 pg/mL). RESULTS: The biologic level of detection of this assay is 8 pg/mL. Serum PSA levels were undetectable in 82.4% of females, 86.2% of the cystoprostatectomy patients, and 96% of the radical prostatectomy controls. After radical prostatectomy, PSA levels were undetectable at last check in 104 of 168 (61.9%) men. In the 24 men with prostate cancer recurrence, the enhanced sensitivity of 8 pg/mL provided a mean lead time based on conservative calculations of 12.7 to 22.5 months over conventional assays. Thirty-four of the 41 men with detectable PSA levels and no evidence of disease recurrence had PSA levels of 30 pg/mL or less. CONCLUSIONS: PSA levels are undetectable in most men who do not have recurrence of disease after radical prostatectomy. Low but detectable serum PSA levels less than or equal to 30 pg/mL can be produced by nonmalignant sources of PSA. PSA assays with enhanced sensitivity can detect recurrent prostate cancer with significant lead time over conventional assays.     

Early results of a prospective study of hormone therapy for patients with locally advanced prostate carcinoma

BACKGROUND: Locally advanced prostate carcinoma is usually not curable with surgery or radiation therapy. Primary hormone therapy is an alternative therapeutic option, but contemporary prospective studies of the outcomes of such therapy are not available. METHODS: The authors conducted a prospective, hospital-based study of gonadal androgen ablation with deferred antiandrogen therapy in 103 men with prostate carcinoma clinically classified as T3-4NXM0. The median potential follow-up was 51 months (range, 36-74 months), and the median period of observation was 43 months (range, 6-74 months). RESULTS: Each patient experienced regression of the primary tumor, and none experienced significant morbidity from the primary tumor during the study period. The projected 5-year cause specific, metastasis free, PSA disease free (no PSA elevation > 1.0 ng/mL after the beginning of antiandrogen therapy), and all-cause survival rates were 84%, 84%, 68%, and 58%, respectively. CONCLUSIONS: Primary hormone therapy is a reasonable treatment option for locally advanced prostate carcinoma in elderly men or in men with significant comorbid disease who request therapeutic intervention.     

Antiandrogen suppression syndrome in patients with hormone-resistant cancer of the prostate

OBJECTIVE: To analyze the evolution of serum prostate specific antigen (PSA) levels and the clinical response following the suppression of the antiandrogen in patients with metastatic prostate cancer who undergo complete androgen blockade in a hormone refractory status. MATERIAL AND METHODS: 19 patients were evaluated. Following flutamide suppression, their PSA serum levels were measured monthly and the subjective clinical response assessed. Additionally, the objective clinical response was also assessed at three months. RESULTS: In 11 patients (57.9%), PSA serum concentration continued to increase and no clinical response was seen in any of them. In the 8 remaining cases (42.1%) there was a decrease in PSA serum levels ranging between 2.1 and 84.5%; this decrease was greater than 50% in 5 patients (26.3%). Mean duration of the biochemical response was 4.5 months (2-11). Subjective clinical responses were reported in 5 patients (26.2%), while an objective clinical response was seen in 2 (10.5%) cases who had PSA reductions greater than 50% and were maintained for periods of over 6 months. CONCLUSIONS: Antiandrogen suppression in patients with hormone refractory prostate cancer with complete hormone blockade, can result in considerable albeit short biochemical and clinical responses. For this reason, this should be considered as the first therapeutical approach, whereas in responder patients any other second line treatment could be delayed until a new PSA increase or symptomatic worsening is detected.     

Contemporary hormonal management of advanced prostate cancer

The traditional definition of "advanced" prostate cancer includes only patients with widespread osteoblastic or soft-tissue metastases (clinical or pathologic stage T any N any M1; or stage D2). Current evidence indicates that this definition should be broadened. Because many patients with T3 disease or local lymph node metastases progress to distant metastases, the concept of advanced prostate cancer should also include stages C and D1 (T3, T4, and any T N1). Furthermore, based on pretreatment prostate-specific antigen (PSA) levels, many men treated for clinically localized disease will progress rapidly and, depending on their age and general health, should be included in the advanced-disease category. Also, using prognostic marker modeling with PSA, tumor grade, and other factors, recurrences can be predicted even earlier in many cases. This may be particularly significant in light of recent clinical data indicating that early androgen ablation therapy delays disease progression and improves survival in patients with advanced (M0 or M1) disease. The luteinizing hormone-releasing hormone (LHRH) agonists have become the preferred method of androgen ablation in patients with advanced prostate cancer. Use of an LHRH agonist, alone or combined with an antiandrogen, is more acceptable to many patients than orchiectomy and lacks the potential cardiotoxicity associated with estrogens. Combined hormonal therapy remains controversial but may provide a modest survival benefit, especially in men with minimal metastatic disease. Intermittent hormonal therapy has great appeal, particularly because of the potentially deleterious effects of long-term hormonal therapy; however, its efficacy has yet to be proven.     

A worse prognosis for men with testicular atrophy at therapeutic orchiectomy for prostate carcinoma

BACKGROUND: The significance of testicular atrophy at the time of therapeutic orchiectomy for prostate carcinoma has not been examined even though pretreatment hypogonadism has been associated with poor prognosis during chemical androgen ablation for these tumors. METHODS: Survival after therapeutic orchiectomy was determined for 78 men with prostate carcinoma and related to the histologic severity of testicular atrophy. Included in analysis were the presence or absence of prior radiation therapy, tumor grade and stage at diagnosis, host age, obesity, and smoking habits. RESULTS: Among 35 men who underwent therapeutic orchiectomy for progressive disease after primary radiation therapy to the prostate bed, the 25 men with testicular atrophy had worse 5-year, tumor specific, postorchiectomy survival than the 10 men without testicular atrophy (30% vs. 89%) (P=0.02). These 25 men had tumors of more advanced stage and greater undifferentiation at the time of diagnosis an average of 45 months before orchiectomy, but neither characteristic was related to postorchiectomy survival. Among 25 men with Stage D2 disease (American Urologic Association staging system) with orchiectomy as the primary treatment, the 7 men with testicular atrophy more often had undifferentiated tumors and had lower 2-year tumor specific survival than the 18 men without atrophy (43% vs. 72% ) (P > 0.10). CONCLUSIONS: Testicular atrophy at the time of therapeutic orchiectomy for prostate carcinoma is associated with poor postorchiectomy prognosis in men with prior prostate bed radiation therapy and perhaps in men without prior radiation. The association may reflect a high frequency of inherently more aggressive tumors (often relatively nonandrogen-dependent) among those tumors that are progressing in hypogonadal men.     

Bicalutamide for advanced prostate cancer: the natural versus treated history of disease

PURPOSE: To determine the therapeutic effects of bicalutamide 200 mg in patients with prostate cancers of different hormone sensitivities. METHODS: Patients with progressive prostate cancer were treated with bicalutamide 200 mg daily. Before treatment, patients' tumors were classified on the basis of prior hormone exposure and by serum testosterone levels into androgen-dependent and androgen-independent groups. Prior exposure to flutamide and response to flutamide withdrawal was also considered. Outcomes were reported independently on the basis of posttherapy changes in prostate-specific antigen (PSA), measurable disease, and radionuclide bone scans. RESULTS: Outcomes varied by prior hormone exposure as a higher proportion of patients with progression of androgen-dependent tumors showed posttherapy PSA decreases of more than 50% or more than 80%, measurable disease regression, and improvement on radionuclide bone scans than did patients with androgen-independent progression. Within the category of androgen-independent progression, clinical benefit was observed in patients who had previously progressed on flutamide, independent of the response to flutamide withdrawal. Patients who had progressed on a gonadotropin-releasing hormone (GnRH) analog alone had a low response proportion, whereas those who progressed after two or more hormone therapies did not respond. Overall, the drug was well tolerated. After progression on bicalutamide monotherapy, one third of patients with androgen-dependent progression responded to medical castration with a GnRH analog. CONCLUSION: Classifying patient tumors on the basis of prior hormone exposure permits a more precise estimate of the potential benefit of a specific hormone therapy for the individual patient. The precision is further increased by reporting the effects of a drug on each parameter of disease independently. The difference in outcomes for patients with androgen-independent progression suggests that the specific hormone therapy administered and the response to that therapy can influence the biology of the relapsing tumor and the sensitivity to subsequent therapies. The sensitivity to bicalutamide after progression on flutamide deserves further study.     

Radiotherapy for regionally localized hormone refractory prostate cancer

PURPOSE: Patients with regionally localized hormone refractory adenocarcinoma of the prostate are often referred for radiotherapy to relieve local symptoms, prevent further local progression, or prevent impending urinary tract obstruction. However, the merits of radiotherapy for this patient population have not been documented. In this retrospective series, the results of 29 such patients treated at our institution between 1987-1992 are reviewed. METHODS AND MATERIALS: Prior to androgen ablation, the majority of these patients (79%) had Stage D0 or D1 disease. After androgen ablation, radiotherapy was given to 16 (55%) for progressive symptoms (mostly urinary obstructive), 11 (38%) for palpable local progression in the absence of symptoms, and 2 for a rising prostate specific antigen (PSA) profile without palpable disease. None of the patients had distant metastasis at the time of radiotherapy. The median dose to the prostate was 66 Gy and the median follow-up after radiotherapy was 43 months. RESULTS: Following local-regional radiotherapy, the actuarial rate of local failure at 4 years was only 39%. However, 80% had disease progression or a rising PSA in this time period. The actuarial survival at 4 years following radiotherapy was 39%. Univariate analyses of potential prognostic factors revealed that preandrogen ablation Gleason score, preradiotherapy PSA, and preradiotherapy prostatic acid phosphatase (PAP) were predictive of patient outcome. Most importantly, doses above 60 Gy to the prostate at standard fractionation were associated with symptom-free local control in 90% of patients at 3 years. The majority of the patients were treated using limited fields (n = 20). CONCLUSIONS: The regionally localized hormone refractory prostate cancer patients described benefited from high dose, continuous course, local radiotherapy in that excellent local control rates were obtained for an extended period. Because the majority of these patients fail with distant metastasis within 4 years, this treatment represents an aggressive approach to palliation that is justified by the maintenance of freedom from local symptoms.     

Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study

OBJECTIVES: To affirm the feasibility of using intermittent androgen suppression in patients with hormone-naive prostate cancer. METHODS: Leuprolide and flutamide were administered for 9 to 12 months and then discontinued until prostate-specific antigen (PSA) levels reached a threshold value determined by the baseline PSA value. This constituted one cycle of treatment. Androgen suppression was then administered intermittently as described until there was evidence of androgen independence. RESULTS: Twenty-two patients with PSA failure after primary therapy with surgery and/or radiation and untreated early or Stage D2 disease were treated. Twenty-one patients completed androgen suppression during cycle 1, with a median time to PSA nadir of 3.5 months (range, 2 to 12). Fifteen patients completed cycle 1 with a median time off treatment of 6 months (range, 2 to 19) or 38% (range, 17% to 64%) of a treatment cycle. Six patients continued off treatment during cycle 1 for 1+ to 31+ months. During cycle 2, 12 patients achieved a PSA nadir in a median time of 3.5 months. Two patients completed cycle 2 with a median time off treatment of 10 months (51%). Median follow-up for all patients is 26 months (range, 10 to 51). While off treatment, all patients reported a reduction of symptoms associated with androgen suppression. CONCLUSIONS: Intermittent androgen suppression is a feasible alternative to continuous androgen suppression for treatment of prostate cancer, and quality of life is improved while off treatment.     

Evaluation of 6 weeks treatment of terbinafine in tinea unguium in a double-blind trial comparing 6 and 12 weeks therapy. The Lagos V Study Group

OBJECTIVES: This study sought to characterize the postoperative prostate-specific antigen (PSA) doubling time and time to biochemical recurrence in patients who have failed radical prostatectomy. METHODS: Of 539 consecutive patients who underwent radical prostatectomy between 1984 and 1992, postoperative PSA levels in 80 initially became undetectable (less than 0.07 ng/mL) before eventually increasing, as evidenced by rising PSA levels above the residual cancer detection limit of the Tosoh AIA-600 immunoassay run in the ultrasensitive mode (i.e., 0.07 ng/mL or higher). The PSA doubling time and time to biochemical recurrence were calculated for each of the 80 patients and were correlated with the histopathologic variables from the operative specimen. RESULTS: Postoperative PSA doubling times were predicted by the extent of capsular penetration, percent Gleason grade 4 or 5, lymph node involvement, and tumor volume on univariate analysis and by capsular penetration, percent Gleason grade 4 or 5, lymph node involvement, and patient age on multivariate analysis. Times to recurrence were predicted by the presence of positive margins and percent Gleason grade 4 or 5 in both univariate and multivariate regression models. The PSA doubling time did not correlate with recurrence time. The median PSA doubling time for all patients was 284 days, and the median time to recurrence was 648 days. CONCLUSIONS: These results demonstrate that PSA doubling time and recurrence time are indicative of different biologic characteristics of recurrent prostate cancer: Doubling time appears to represent the aggressiveness of the original prostate cancer, whereas time to recurrence reflects the extent of residual postoperative disease. This information should aid in the selection of men who need greater vigilance during postoperative surveillance.     

Epidemiology and clinical features of prostate cancer in Japan

The incidence rate of clinically manifest prostate cancer in 1992 was estimated 15.7 per 100,000 men, although it is increasing exponentially. Accordingly, 5399 deaths from prostate cancer in 1995 will be increased to 13,494 deaths in 2015. Change in dietary habit (more Western-style diet) is considered to be a major cause of the increase. Escalating number of elderly people in the Japanese population is another major reason of elevated incidence. On the other, public awareness of prostate cancer and introduction of serum PSA measurement to health check-up undoubtedly have raised the detection rate of early stage disease. The way of androgen ablation do not seem to have influenced on survival of the advanced disease so far. It remains to be clarified whether the combined androgen blockade using pure anti-androgens with castration provide better patients' survival than castration alone.     

Effect of finasteride on the percentage of free PSA: implications in the early diagnosis of prostatic cancer

OBJECTIVE: To analyze the behaviour of free PSA percentage in finasteride-treated patients and to evaluate whether this ratio allows an increased PSA specificity in the early diagnosis of prostate cancer. MATERIAL AND METHODS: Evaluation of PSA serum levels and free PSA ratio in 336 patients initially diagnosed with prostate benign hyperplasia (PBH). A group of 82 patients were treated with finasteride for 14 to 58 months. A second group of 254 patients received no treatment. All patients were within the same age range and had similar PSA serum levels. In total, 141 prostate biopsies were performed: 19.5 (16/82) and 49.1 (125/254) respectively. RESULTS: Median PSA level in PBH patients was 1.6 ng/mL for the finasteride-treated group and 3.5 for the untreated group, p < 0.0001. Free PSA ratio was 18.6 and 18.8%, respectively, p > 0.05. Carcinoma detection rate was 25% (4/16) for the finasteride group and 27.2% (34/125) for the untreated group. If biopsy had been requested when PSA percentage was below 25%, 17.7 and 19.8% respectively would have been prevented and all carcinoma detected. CONCLUSION: Long-term treatment with finasteride reduces PSA serum concentration about 50% without changing the free PSA ratio. Carcinoma detection rate was similar in finasteride-treated and untreated patients. Free PSA ratio allows to increase PSA specificity and avoid unnecessary biopsied also in finasteride-treated patients.     

Prognostic implications of prostate-specific antigen in patients with locally advanced prostate cancer treated with high energy neutron beam therapy: preliminary results

Serial serum prostate-specific antigen (PSA) levels were analyzed retrospectively for prognostic implications in 70 patients with locoregional (Stages B2, C, and D1) prostate cancer who were managed with high energy neutron beam therapy. Three groups of patients were identified. Group I included 30 patients whose serum PSA level decreased to the reference range (0-4 ng/mL) following neutron therapy and remained so subsequently: 28 (93%) remained disease-free and 2 (7%) have failed distantly. All 30 patients (100%) had no evidence of locally progressive disease. This group was categorized as having a good prognosis. The mean time for serum PSA value to decline to reference range was six months; calculated mean time to achieve a stable base-line PSA was 53 +/- 37 days. Follow-up period ranged from twelve to fifty-six months (median: 21 months). Group II consisted of 13 patients in whom there was an initial decrease in serum PSA to reference range followed by a subsequent increase: 6 of 13 (46%) have no overt clinical progression of disease; 7 (54%) have either persistent locoregional or distant metastatic disease. Follow-up period was from twelve to seventy-two months (median: 39 months). Calculated mean time to achieve stable baseline PSA for serum PSA in this group was 61 +/- 21 days. Group III patients had a persistently elevated or rising serum PSA concentration. Of 27 patients in this group, only 9 (33%) have no evidence of disease progression, while 18 patients (67%) have failed already, either locoregionally or distantly. Follow-up period ranged from twelve to sixty-nine months (median: 21 months). Mean time to achieve stable baseline of serum PSA in this cohort of patients with a poor prognosis was 108 +/- 76 days. We conclude that PSA has a predictable prognostic value in patients with locally advanced prostate cancer managed with high energy neutron beam therapy. Rapid normalization of PSA after therapy indicates a good prognosis. Persistent elevation signifies either presence of persistent locoregional disease or development of distant metastases. Subsequent elevation of the serum PSA concentration after definitive therapy signals progression of prostate cancer.     

Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol)

PURPOSE: Substantial experimental and epidemiological data indicate that 1,25-dihydroxyvitamin D3 (calcitriol) has potent antiproliferative effects on human prostate cancer cells. We performed an open label, nonrandomized pilot trial to determine whether calcitriol therapy is safe and efficacious for early recurrent prostate cancer. Our hypothesis was that calcitriol therapy slows the rate of rise of prostate specific antigen (PSA) compared with the pretreatment rate. MATERIALS AND METHODS: After primary treatment with radiation or surgery recurrence was indicated by rising serum PSA levels documented on at least 3 occasions. Seven subjects completed 6 to 15 months of calcitriol therapy, starting with 0.5 microg. calcitriol daily and slowly increasing to a maximum dose of 2.5 microg. daily depending on individual calciuric and calcemic responses. Each subject served as his own control, comparing the rate of PSA rise before and after calcitriol treatment. RESULTS: As determined by multiple regression analysis, the rate of PSA rise during versus before calcitriol therapy significantly decreased in 6 of 7 patients, while in the remaining man a deceleration in the rate of PSA rise did not reach statistical significance. Overall the decreased rate of PSA rise was statistically significant (p = 0.02 Wilcoxon signed rank test). Dose dependent hypercalciuria limited the maximal calcitriol therapy given (range 1.5 to 2.5 microg. daily). CONCLUSIONS: This pilot study provides preliminary evidence that calcitriol effectively slows the rate of PSA rise in select cases, although dose dependent calciuric side effects limit its clinical usefulness. The development of calcitriol analogues with decreased calcemic side effects is promising, since such analogues may be even more effective for treating prostate cancer.     

Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4

Mutations in the androgen receptor (AR), that alter steroid hormone specificity have been identified in a series of androgen-independent prostate cancers. To address the functional properties of these mutant ARs that may have contributed to their selection in vivo, responses to a series of steroid hormones and antiandrogens were assessed. CV-1 cells were cotransfected with wild-type or mutant ARs and a luciferase reporter plasmid regulated by an androgen-responsive element. Dose-response curves were analyzed for 5alpha-dihydrotestosterone, the most active androgen in normal prostate, and androstenedione, a major androgen derived from the adrenals. Although the mutant ARs responded to both of these steroids, the responses were equivalent to or less than the wild-type AR. In contrast, responses to flutamide, a competitive antagonist of the wild-type AR, were markedly increased by three of the mutations. Similar responses were observed with a second antiandrogen, nilutamide. Bicalutamide, another antiandrogen related to flutamide, remained an antagonist for these mutant ARs. Finally, flutamide was observed to be a weak partial agonist of the wild-type AR in this system. These results indicate that flutamide used in conjunction with androgen ablation therapy for prostate cancer may select for tumor cells with flutamide-inducible ARs.     

Antitumor activity of suramin in hormone-refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables

BACKGROUND: A prospective Phase II clinical trial was conducted to assess the clinical activity of a pharmacokinetically guided suramin regimen in patients who had documented progression of metastatic prostate cancer after hydrocortisone plus antecedent or simultaneous withdrawal of flutamide. METHODS: Fifty-four patients whose disease had progressed after castration and flutamide administration were enrolled on this trial. The study was divided into two parts. Initially, 52 patients received hydrocortisone (30 mg/day) and for those patients receiving flutamide, at study entry (34 patients) flutamide was simultaneously discontinued. Forty-three patients whose disease progressed on hydrocortisone received suramin for 6-8 weeks. Six patients who progressed on hydrocortisone became ineligible for suramin due to clinical deterioration, four patients are still responding to hydrocortisone at more than 1 year, and one patient elected to postpone initiation of suramin. Suramin was given as intermittent infusions at fixed doses on days 1-5 and thereafter dosing was guided by adaptive control with feedback to maintain plasma suramin concentrations between 300-175 micrograms/ml. Antitumor activity was assessed by prostate specific antigen (PSA) decline and soft-tissue disease response. RESULTS: Ten patients (19%; 95% CI, 9.6%-32.5%) responded to hydrocortisone therapy with either a 50% or greater PSA decline for at least 4 weeks (9 patients) and/or a partial response of measurable soft-tissue disease (2 patients). Five of these patients (10%) demonstrated a 80% or greater PSA decline. All responders to hydrocortisone had simultaneous flutamide withdrawal, and had been receiving flutamide as part of initial combined androgen blockade. Seven of 37 evaluable patients (19%; 95% CI, 8.0%-35.2%) responded to suramin with a 50% or greater decline in PSA for 4 weeks or longer. One patient (3%) had a 80% or greater decline in PSA. There were no soft-tissue disease responses to suramin. The median time to progression was 1.9 months for hydrocortisone therapy and 2.6 months for suramin therapy. The median survival for all patients was 14.6 months. CONCLUSION: Suramin has antitumor activity in metastatic prostate carcinoma independent of the therapeutic effect of hydrocortisone administration or flutamide withdrawal. The role of prior flutamide withdrawal and hydrocortisone replacement should be taken into account in future studies of suramin.     

Antiandrogen withdrawal syndrome with cyproterone acetate

OBJECTIVES: To determine whether the antiandrogen withdrawal syndrome occurs with the steroidal antiandrogen cyproterone acetate. METHODS: Cyproterone acetate was withheld in 12 patients with progressing androgen-independent metastatic prostate cancer. Eight patients had been receiving cyproterone acetate concomitant with androgen ablation, and in 4 patients it was prescribed after failure of androgen suppression. Time to response and to disease progression were defined by serum prostate-specific antigen (PSA) levels and imaging studies. RESULTS: PSA levels decreased in 5 of the 1 2 patients; in 4 of them (33%), the decrease exceeded 50%. The decline lasted a median of 24 weeks (range 9 to 37.8). All 5 patients had received initial concomitant exposure to androgen ablation and cyproterone acetate. CONCLUSIONS: We recommend that the steroidal antiandrogen cyproterone acetate be added to the list of agents capable of inducing antiandrogen withdrawal syndrome.