[Intermittent androgen deprivation].
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Androgen Antagonists↗
Biomedical subjects
U W Tunn
Publications and source records attributed to U W Tunn.
The significance of serum levels of insulin-like growth factor-1 in patients with prostate cancer.
OBJECTIVES: To compare the serum levels of insulin-like growth factor-1 (IGF-1) in patients with prostate cancer and in control patients with no malignancy, and to evaluate any possible influence of testicular androgen withdrawal on the level of IGF-1 in patients with prostate cancer. PATIENTS AND METHODS: IGF-1 was measured in serum samples from 238 patients using both a chemiluminescence method and a radio-immunoassay. From a subgroup of 19 patients presenting with newly diagnosed carcinoma of the prostate, IGF-1 and testosterone values were measured before and during the course of testicular androgen withdrawal, achieved by the administration of luteinizing hormone-releasing hormone (LHRH) analogues combined with anti-androgens. RESULTS: There were no significant differences in the mean serum levels of IGF-1 patients with and without prostate cancer (158.6 and 159.1 ng/mL, respectively). There were no significant differences in mean IGF-1 levels before and after antiandrogen therapy; the mean (median, SD, range) levels of testosterone (microg/L) and IGF-1 (ng/mL) before androgen withdrawal were 4.81 (4.84, 1.26, 3.11-6.93) and 157.1 (152.5, 26.7, 122.8-195. 1). After androgen withdrawal the corresponding values were 0.303 (0. 218, 0.24, 0.13-0.81) and 169.7 (31.7, 168.6, 124.9-227.6). A linear regression analysis (P = 0.76) and Spearman rank order correlation test (correlation coefficient -0.0613, P = 0.64) showed no association between levels of testosterone and IGF-1. Freeze and thaw cycles applied to the samples had no effect on the IGF-1 values measured. CONCLUSIONS: There was no significant association between IGF-1 serum levels and prostate cancer. Short-term androgen withdrawal using LHRH analogues combined with anti-androgens had no effect on the levels of IGF-1.
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Prostate specific membrane antigen (PSM) is expressed in various human tissues: implication for the use of PSM reverse transcription polymerase chain reaction to detect hematogenous prostate cancer spread.
Detection of prostate-specific membrane antigen (PSM)-mRNA expression in blood samples using reverse transcription polymerase chain reaction (RT-PCR) is discussed as a new diagnostic marker of circulating micrometastases in prostate cancer patients. We applied the RT-PCR technique to different human tissues and obtained positive signals for PSM transcripts in human genital and multiple extra-genital tissue sites. The cDNAs were prepared from different human tissues and prostatic cell lines. RT-PCR and nested RT-PCR for PSM was performed with primers derived from the published PSM cDNA. The RT-PCR fragments obtained were cloned and showed 100% sequence homology to PSM. Southern blot hybridization with labeled probes was used to confirm the specificity of the amplicons. In addition to the known PSM expression in the human brain, PSM-mRNA was detected in cDNA isolated from human testis, epididymis and seminal vesicles and in the PC-3 prostatic cancer cell line. Furthermore, we found PSM-mRNA in heart, liver, lung, kidney, spleen, and thyroid gland. The results indicate that PSM expression is not restricted to the prostate gland, but represents a more general component of genital and extra-genital human tissues. This must be considered when RT-PCR and nested RT-PCR screening for PSM expression is performed as a diagnostic measure in blood from prostate cancer patients.
Antigens, Surface↗
Intermittent complete androgen blockade in PSA relapse after radical prostatectomy and incidental prostate cancer.
OBJECTIVES: To determine the efficacy, safety and feasibility of intermittent androgen deprivation (IAD) in patients with prostate-specific antigen (PSA) relapse after radical prostatectomy or with an incidental prostate cancer (pT1B) after transurethral resection of the prostate (TURP). METHODS: Open, nonrandomized, prospective pilot study using the luteinizing hormone-releasing hormone analogue (LH-RHa), leuprorelin acetate (1-month depot) and cyproterone acetate. RESULTS: Forty-four patients have been enrolled. After a 30-64 months' follow-up no progression to androgen-independent status has been observed. Of the entire observation period, 26.6 months (44-58%) remained treatment-free. During the treatment-free periods, normal testosterone levels were obtained, resulting in a cessation of the symptoms of androgen suppression and an improvement in quality of life. CONCLUSIONS: These results indicate that IAD is an effective and feasible therapy in patients with early stages of prostate cancer. Larger trials are necessary to confirm these encouraging results. Therefore, a European prospective, randomized, multicenter study (RELAPSE study) has been started to compare IAD with continuous androgen blockade in terms of time to tumor progression, safety and quality of life in patients with PSA relapse after radical prostatectomy.
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Comparison of LH-RH analogue 1-month depot and 3-month depot by their hormone levels and pharmacokinetic profile in patients with advanced prostate cancer.
In an open, randomized phase II pharmacokinetic study conducted in Germany and Italy, a total of 42 patients with advanced or metastatic prostate cancer (PCa) were treated for 9 months with the luteinizing hormone-releasing hormone analogue (LH-RH-a) leuprorelin acetate depot in two different formulations. Fifteen patients received the 1-month depot and 27 patients received the newly developed 3-month depot, containing 3.75 mg and 11.25 mg, respectively. In both groups, subcutaneous injections of leuprorelin acetate injected monthly or at 3-month intervals produced a complete down-regulation of the pituitary and led to persistent suppression of testosterone and dihydrotestosterone to the castrate range (< or = 50 ng/dl for testosterone) within the first month of treatment, which thereafter could be maintained over the entire observation period of 9 months. In 10 patients, pretreatment with an antiandrogen for the prevention of clinical flare-up resulted in a slightly more profound and earlier drop in serum testosterone. The 3-month depot showed a higher median peak serum concentration (Cmax) of leuprorelin at 20.8 ng/ml than the 1-month depot at 10.7 ng/ml but, conversely, this did not influence the rise in serum testosterone levels. Cmax occurred at 3 h for the 3-month and at 1 h for the 1-month depot formulation. During the steady state, constant release could be detected, starting on day 3 and day 7 for the 1-month and 3-month depot, respectively. A marked decrease in median prostate-specific antigen levels of 97.8% (1-month depot) and 96.6% (3-month depot) compared with baseline was observed, indicating an objective clinical response for more than 80% of all patients in both arms. Based on European Organization for Research and Treatment of Cancer criteria, the best response in terms of complete/partial remissions and stabilization was comparable in the two arms at 86.7% (1-month depot) and 85.2% (3-month depot). 6.7% in the 1-month group and 3% in the 3-month depot group showed progression of the disease. The most common side effects in both treatment groups were related to hormone deprivation. Both formulations of the potent LH-RH-a leuprorelin acetate were highly effective in the treatment of advanced PCa and led to comparable endocrine and clinical effects.
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Neo-adjuvant hormonal therapy of prostate cancer.
At present, only locally confined carcinoma of the prostate can be cured if all of the tumor tissue can be removed by surgery [36]. Early detection strategies using serum prostate-specific antigen (PSA), digital rectal examination (DRE) and transrectal ultrasound (TRUS) have been increasingly used. However, exact clinical determination of the local tumor extension is only possible to a limited extent [4, 13, 28, 34]. Up to 60% of clinical locally confined tumors are understaged after histopathological examination of the radical prostatectomy specimen. Furthermore a high incidence of positive margins of up to 60% has been reported [7, 21]. Although a clear surgical margin does not exclude local or distant disease recurrence, it is regarded as a good prognostic factor [3, 25]. Androgen withdrawal prior to radical prostatectomy is an attractive theoretical option to decrease the risk of disease recurrence, since tumor regression can be induced by any procedure that reduces the intracellular concentration of dihydrotesterone by more than 80%. The benefit of preoperative medical androgen deprivation is controversial [6-8, 13, 15-17, 20, 23, 35, 37]. A priori a benefit would not be expected in any case if androgen withdrawal had no effect on the tumor. We therefore investigated the effects of a neo-adjuvant androgen-ablative therapy (NAT) in a large population of 375 patients who underwent radical retropubic prostatectomy (RRP) after NAT. We report in particular the effects of NAT on prostate volume measured by TRUS, PSA, clinical stage and tumor morphology including positive surgical margins. Furthermore the recently reported first results of prospective randomized trials comparing RRP alone versus NAT plus RRP are discussed to analyze the possible impact of NAT.
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Effects of androgen deprivation prior to radical prostatectomy in 375 patients.
The effects of pharmacotherapeutic complete androgen deprivation treatment for 2 months before radical retropubic prostatectomy (RRP) were investigated in an open study in 375 patients. Prostate volume, tumor staging and prostatespecific antigen (PSA) were investigated as clinical parameters. The RRP specimens were analyzed particularly in terms of tumor cell regressions, pathological tumor staging and grading. Before neoadjuvant therapy (NAT) the 375 patients were classified according to stage: 36 (9.6%) were T1B; 137 (46.1%) were T2, and 166 (44.3%) were T3 stage. After NAT, the clinical investigation (digital rectal examination + transrectal ultrasonography) gave an impression of a T0 stage in 11% of the T2 patients, and a T2 tumor stage in 39% of the T3 patients. The histopathological analysis of the initial T1B and T2 cases did not reveal any tumor in the RRP specimen in 11 (3.8%) cases, a pT2 tumor in 153 (73%) cases, and a pT3 tumor in 48 (23.5%) cases. In the patients initially classified as T3, a tumor was no longer found in 1 (0.6%) case, and a pT2 tumor was found in 48 (29.3%) cases and a pT3 tumor in 113 (67.7%) cases. Under NAT, the prostate volume fell by 34% in T3 tumors and by 24% in T2 tumors. The fall in PSA averaged 85% without significant differences in the individual tumor stages. A statistically significant correlation could not be demonstrated between the fall of PSA and the definitive pathological tumor stage. Tumor cell regressions were found in all preparations. The degree of regression was predominantly RII. These results document the direct effect on tumor cells of an inductive androgen-ablative pharmacotherapy. Regression and volume reduction of the tumor might lead to an improvement of the local surgical control. A final clinical evaluation of NAT will only be possible after long-term analysis of ongoing prospective, randomized studies.
Androgen Antagonists↗
Intermittent endocrine therapy of prostate cancer.
INTRODUCTION: Permanent androgen suppression is the therapy of choice in the treatment of advanced prostate cancer. Intermittent androgen deprivation (IAD) through reversible medical castration results, hypothetically, in androgen-induced differentiation of tumor stem cells with recovery of the apoptotic potential. The cycle of periods with and without androgen withdrawal should delay androgen-independent tumor progression. RESULTS: In initial pilot studies, the IAD concept proved less successful in patients with a high tumor burden than in those with locally advanced prostatic cancer. In our own pilot study, patients with a low tumor burden could be successfully treated with IAD. CONCLUSION: Until further studies have been completed, the therapeutic concept with IAD should be regarded as experimental. Only further prospective randomized phase III studies will be able to establish whether survival and quality of life of patients with prostatic cancer can be considerably improved by IAD.
Androgen Antagonists↗
Placebo controlled double-blind study to test the efficacy of the aromatase inhibitor atamestane in patients with benign prostatic hyperplasia not requiring operation. The Schering 90.062 Study Group.
PURPOSE: We tested the theoretical concept that a selective decrease in estrogens has a beneficial therapeutic effect on established benign prostatic hyperplasia. MATERIALS AND METHODS: In a double-blind study 160 patients from 14 centers were randomized between 2 groups to receive either placebo or the aromatase inhibitor atamestane (1-methyl-androsin-1,4 diene-3 17-dione, 400 mg. daily for 48 weeks). RESULTS: The aromatase inhibitor decreased the mean estradiol level by approximately 40% and estrone by 60%. The testosterone concentration increased by more than 40% and dihydrotestosterone increased to 30%. Analysis of clinical parameters showed no difference between placebo and atamestane. CONCLUSIONS: The counter regulatory increase in androgens may counterbalance any positive effect of the decrease in estrogens to preserve intraprostatic homeostasis.
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Endocrine therapies for BPH: scientific rationale, clinical results, and patient selection.
In 1993, medical therapy for BPH is a reality. Androgen deprivation therapy (LHRH agonists, antiandrogens, and 5 alpha-reductase inhibitors) has been shown to be effective by reducing the static component of BPH. Of these agents, the 5 alpha-reductase inhibitors have the greatest promise because of their low toxicity profile. Aromatase inhibitors, which function via a different mechanism, however, have not been demonstrated, as monotherapy, to be effective in the treatment of symptomatic BPH. It is still theoretically possible that aromatase inhibitors could have a role in the management of prostatism if they are utilized in conjunction with an antiandrogen or 5 alpha-reductase inhibitor. Although the early results for this endocrine therapies are encouraging, several issues relating to medical treatment remain unanswered. Not everyone with significant prostatism will respond to androgen deprivation therapy. How does the physician identify pre-treatment the patient most likely to achieve a significant improvement in voiding function with 5 alpha-reductase inhibitor therapy? At the present time, there is no method--based on symptoms, DRE findings, serum hormone and PSA levels, or histopathologic criteria--for recognizing the ideal patient for androgen deprivation therapy. Without question, it is a subjective decision. As a result, the benefits and risks of these medical approaches as well as those of the minimally invasive and surgical therapies must be discussed with the patient so that he can participate in the management decision. In this manner, the expectations and needs of the patient will be best served.
5-alpha Reductase Inhibitors↗
Management of benign prostatic hyperplasia with particular emphasis on aromatase inhibitors.
The pathogenesis of human benign prostatic hyperplasia (BPH) has not been fully elucidated. There is, however, evidence that estrogens--besides other factors--might play an important role for the growth of the prostate. Consequently, estrogen deprivation might be a new, useful principle for a conservative treatment of BPH. Atamestane, a new, highly selective steroidal aromatase inhibitor has been proven to be successful in antagonizing experimentally-induced estrogen-related stromal overgrowth of the prostate in dogs and monkeys. Double-blind placebo controlled studies are now underway in Europe and the U.S.A. It is anticipated that these studies will give us a definite answer of the clinical validity of this concept in BPH patients in the near future. However, it is very important to take into consideration that for an effective treatment of BPH, a reduction of both the glandular and stromal elements has to be achieved. In other words, both androgens and estrogens seem to be involved in the regulation of (over)growth of the prostate. Therefore, a combination of an androgen and estrogen deprivation might be a more promising approach than any single treatment.
Androstenedione↗
Effects of estrogen deprivation on human benign prostatic hyperplasia.
Sex steroids are thought to play an essential role in the pathogenesis of human benign prostatic hyperplasia (BPH). Since recent studies in animal models and in men have shown that estrogens might be causally linked to the onset and maintenance of BPH, we examined the effect of 1-methyl-androsta-1,4-diene-3,17-dione (Atamestane), a newly developed aromatase inhibitor, in men with BPH. In an open multicenter study 49 men (mean age 70.1 years, range 55 to 84) with obstructive BPH were treated with atamestane (3 x 200 mg/day) for 3 months. Of the 49 patients 44 completed the treatment period; the other patients discontinued the study for reasons unrelated to treatment. With treatment BPH-related symptoms such as daytime voiding frequency, nycturia, peak flow and residual urine improved considerably; however, these parameters did not reach statistical significance. The mean prostatic volume decreased significantly from 74.2 +/- 31.7 to 64.0 +/- 31 ml (mean +/- SD). Serum estrogen levels decreased markedly during treatment. In addition intraprostatic estrogen concentration decreased with treatment as compared to estrogen levels in hyperplastic prostates from untreated patients. The following conclusions can be drawn from this study: first, estrogens appear to have an important supportive role in established BPH, and second, estrogen deprivation improved BPH-related symptoms and reduced significantly prostatic volume.
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Mitomycin C versus estramustine in the treatment of hormone resistant metastatic prostate cancer: the final analysis of the European Organization for Research and Treatment of Cancer, genitourinary group prospective randomized phase III study (30865).
A total of 171 patients with progressive metastatic prostate cancer following hormonal therapy was randomized to receive either 560 to 700 mg. estramustine orally per day or 15 mg./m.2 mitomycin C by intravenous infusion every 6 weeks. The patients were recruited during a 2.5-year period, and 70% had undergone more than 1 previous therapy for prostate cancer, with some having received as many as 5 different previous treatments. The overall results were disappointing. The median time to progression was 5 months and 50% of the patients died within 10 months. There was no difference in efficacy between the 2 treatment arms. Toxicity was severe in both arms but appeared earlier in those patients receiving estramustine, leading to a tendency for earlier deterioration in performance status. In this group of heavily pretreated patients there appears to be no justification for the use of either of these agents at the present time.
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[Aromatase inhibitors in the medical treatment of benign prostatic hypertrophy].
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Androstenedione↗
Initial treatment of prostatic cancer by endocrine measures and cytotoxic drugs.
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Antineoplastic Agents↗
[Endocrinologic factors in the development of benign prostatic hyperplasia].
The development of benign prostatic hyperplasia is determined by aging and a functioning testis. This concept of the pathogenesis is supported by studies showing that regression of the enlarged prostate can be achieved by means of drugs that interfere with either the synthesis or the action of testosterone. Since both these therapeutic principles lead to symptoms of hypogonadism their therapeutic value is limited. Recent observations, however, indicate the feasibility of developing agents that will relieve the obstruction of urinary outflow and cause shrinkage of the enlarged prostate without impairing the action of androgen in other tissues.
Androgens↗
Cyproterone acetate in the management of prostatic cancer.
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Androgen Antagonists↗
[Prostatic cancer. Staging via transrectal prostatic sonography and computed tomography with histopathological correlation].
Pre-operative staging, using transrectal prostatic sonography and CT, was carried out in 30 patients with cytologically confirmed carcinomas of the prostate and the results compared with the clinical findings. All patients underwent radical prostatectomy and the pre-operative findings could be verified histologically. Transrectal prostatic sonography is better than CT or clinical examination for determining local tumour spread or penetration of the capsule. A high proportion of enlarged pelvic lymph-nodes shown by CT had non-specific changes; failure to demonstrate enlarged nodes excludes lymph node metastases with considerable certainty. Transrectal prostatic sonography provides a higher degree of information regarding local tumour spread, whereas CT indicates the presence or absence of lymph node metastases.
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