Testosterone recovery in the off-treatment time in prostate cancer patients undergoing intermittent androgen deprivation therapy.

BACKGROUND: Intermittent androgen deprivation (IAD) for prostate cancer was studied with the objective of reducing the side effects of treatment and potentially delaying the development of hormone resistance. There also appears to be a quality of life benefit during off-treatment intervals owing to the recovery of serum testosterone levels. METHODS: In this multicentre European prospective randomised phase III trial EC507, testosterone serum concentrations were analysed in prostate cancer patients with PSA progression after radical prostatectomy. Patients were randomised to a continuous androgen deprivation (CAD) and IAD therapy using a 3-month depot with 11.25 mg leuprorelin acetate as microcapsule formulation. A complete IAD cycle comprises both a 6-month androgen deprivation therapy plus the off-treatment time (OTT). RESULTS: Serum testosterone recovery was recorded in 109 patients during OTT in the IAD group. Testosterone recovery to baseline values was achieved in 79.3% during the first and in 64.9% during the second IAD cycle, respectively. Median time to testosterone normalisation was 100 days in the first and 115 days in the second cycle, respectively. No significant difference was observed up to 1000 days between IAD and CAD with regard to time to androgen-independent progression. This is the first prospective study of leuprorelin acetate 11.25mg demonstrating normalisation of testosterone levels in the off-treatment period in patients undergoing IAD. CONCLUSIONS: The prerequisite of an IAD treatment is the testosterone recovery during off-treatment periods. In this study, in patients with PSA relapse after radical prostatectomy, a real achievement of intermittent castration with normalisation of testosterone levels during off-treatment periods could be confirmed.

Safety and clinical efficacy of a new 6-month depot formulation of leuprorelin acetate in patients with prostate cancer in Europe.

This multicentre European study compared the safety and tolerability of the existing 11.25 mg 3-month depot of leuprorelin acetate with a new 30 mg 6-month depot in men with newly diagnosed prostate cancer or prostate-specific antigen relapse after radiotherapy or prostatectomy. The primary end points were safety and tolerability and secondary end points were clinical response based on European Organization for Research and Treatment of Cancer (EORTC) criteria and response rate by time point for testosterone suppression (castrate level

Management of prostate-specific antigen relapse in prostate cancer: a European Consensus.

A European Consensus on the management of prostate-specific antigen (PSA) relapse in patients with prostate cancer has been formulated. The key recommendations proposed are that total PSA is the best detection tool for prostate cancer, with free and complexed PSA having a role in the PSA range 1-4 ng/ml. PSA relapse after radical prostatectomy (RP) has been defined as a value of 0.2 ng/ml with one subsequent rise, while the ASTRO definition should be used after radiotherapy. A PSA level of less than 0.4 ng/ml after hormonal therapy can be considered an indicator of a positive response. Continuous assessment using nomograms or artificial neural networks will help to determine whether progression after local therapy is distant or local, which is the basis for treatment decisions. Secondary treatment after local failure of RP should be initiated when PSA levels reach 1.0-1.5 ng/ml and salvage radiotherapy can be considered with or without hormonal therapy. Local failure after radiotherapy can be treated with a choice of high-intensity-focused ultrasound, salvage RP (only in highly selected patients), cryotherapy or external beam radiation. Treatment of distant failure involves hormonal manipulation, the type and the timing of which is based on both physician and patient preferences.

[Gemcitabine/cisplatin vs. MVAC. 5 year survival outcome of the phase III study of chemotherapy of advanced urothelial carcinoma in Germany]. / Gemcitabin/Cisplatin vs. MVAC. 5-Jahres-Ergebnisse der Phase-III-Studie zur Chemotherapie des fortgeschrittenen Urothelkarzinoms in Deutschland.

Of 405 patients with stage IV transitional cell carcinoma from an international multicenter phase III trial, 70 were randomized in Germany to receive either gemcitabine/cisplatin or standard MVAC systemic chemotherapy for locally advanced or metastatic urothelial cancer. Overall survival as the primary endpoint of the study was similar in both arms (median survival GC 15.4 months vs MVAC 16.1 months), as were tumor-specific survival and time to progressive disease. In the intent-to-treat analysis, the 5-year overall survival rate was 10% for patients randomized to GC and 18% randomized to MVAC. Tumor overall response rates (GC 54%, MVAC 53%) were similar. The toxic death rate was 0% in the GC arm and 3% (one patient) in the MVAC arm. Significantly more GC than MVAC patients experienced grade 3/4 anemia (GC 52%, MVAC 20%) with significantly more red blood cell transfusions in the GC arm.Significantly more GC than MVAC patients had grade 3/4 thrombocytopenia (GC 54%, MVAC 17%) without grade 3/4 hemorrhage or hematuria in either arm. More MVAC patients experienced grade 3/4 neutropenia (GC 56%, MVAC 61%, p=1.000), neutropenic or leukopenic fever (GC 0%, MVAC 10%, p=0.237), mucositis (GC 0%, MVAC 7%, p=0.495), and alopecia (GC 6%, MVAC 36%, p=0.004). GC represents a reasonable alternative for the palliative treatment of patients with locally advanced and metastatic transitional cell carcinoma. Sustained long-term survival was only found for patients with locally advanced cancer, lymphatic metastases, or solitary distant metastasis but not for visceral metastatic disease.

Management of locally advanced prostate cancer: a European consensus.

This report summarises the findings of a European Consensus Group review of current standards of care in locally advanced prostate cancer defined as (a) untreated cancer extending clinically beyond the prostatic capsule in patients with no evidence of lymph node invasion or distant metastases, and (b) residual disease remaining after local treatment with positive surgical margins, seminal vesicle invasion, persistent prostate-specific antigen (PSA) and/or secondary PSA relapse. There was no overall consensus as to the standard of care in clinically apparent locally advanced prostate cancer. It was agreed, however, that hormonal therapy (e.g. with a gonadotrophin releasing hormone analogue [GnRHa]) represents a valid treatment in these patients. Treatment practices and regimens vary considerably between European countries, but GnRHa is widely used, either alone or in combination with antiandrogens. Hormonal therapy alone is a valid option, though the optimal modality, timing and duration of treatment remain to be defined. Adjuvant therapy with a GnRHa has been shown to improve survival in patients undergoing external beam radiotherapy. It is a viable option after prostatectomy in patients with persistent or secondary relapsing PSA. It was determined that optimal treatment will be different according to PSA, clinical staging and Gleason score, and the treatment of locally advanced disease should be individually tailored after discussion between physician and patient. In many instances, patients prefer and expect some form of treatment in preference to watchful waiting. Treatment nomograms such as the Kattan nomograms provide precise, comprehensive and invaluable tools for everyday use and may be used to predict outcomes and guide treatment decisions.

Endogenous pro-inflammatory cytokines in children and adolescents during chemotherapy-induced neutropenia.

Monocyte-derived pro-inflammatory cytokines such as GM-CSF, IL-12, and IP-10 might protect patients with chemotherapy-induced neutropenia against infections. In settings with abundant neutrophils, G-CSF has been described as a suppressor of IL-12, but also as an inducer of GM-CSF. In 25 pediatric patients with chemotherapy-induced neutropenia the authors measured plasma levels of these four cytokines. GM-CSF was detectable in only a minority of patients (6/25). It was, however, positively correlated with high plasma levels of IL-12 and IP-10. G-CSF levels, however, were in no way correlated with the levels of any of these three cytokines.

Intermittent androgen blockade in prostate cancer: rationale and clinical experience.

Cancer of the prostate continues to be one of the most common malignancies in men in Europe, with a large number of patients presenting with advanced disease. The current standard treatment for metastatic cancer of the prostate, permanent androgen withdrawal, is palliative. Patients treated with permanent androgen blockade usually relapse and die secondary to prostate cancer's ability to progress to an androgen-independent state of growth. Based on experimental and preclinical studies, intermittent androgen blockade appears to be a potential alternative to permanent androgen blockade. Through the cycling of reversible androgen suppression, there appears to be recovery of apoptosis and subsequent slower progression to an androgen-independent state. In this paper experimental and preclinical studies concerning intermittent androgen blockade are reviewed. At present several prospective randomized trials are under way to test intermittent androgen blockade as an alternative treatment in various stages of cancer of the prostate. However, until the results of these trials are available, this approach remains experimental.

3D interstitial HDR brachytherapy combined with 3D external beam radiotherapy and androgen deprivation for prostate cancer. Preliminary results.

BACKGROUND: Evaluation of feasibility, tolerance and efficiency for a new 3D interstitial HDR brachytherapy technique combined with 3D external beam radiotherapy and androgen deprivation for prostate cancer. PATIENTS AND METHODS: Between January 1997 and August 1998 we treated 35 patients with stage cT1-3 N0 M0 prostate cancer. Thirty-two patients with a follow-up of 12 to 28 months (median: 18 months) were evaluated. After ultrasound-guided transrectal implantation of 4 non-parallel needles, CT based 3D brachytherapy treatment planning ("Offenbach system") was performed. All patients received 4 fractions brachytherapy using a fractional dose of 5 or 7 Gy. Time between each fraction was 14 days. After brachytherapy 3D external irradiation followed up to 39.6 or 45.0 Gy. All patients received androgen deprivation, starting 2 to 19 months before brachytherapy, ending 3 months after 3D external radiotherapy. RESULTS: Posttreatment PSA levels dropped to < 1.5 ng/ml in 29/32 patients (91%). In 25 patients PSA levels were < 0.5 ng/ml, in 4 patients 0.5 to 1.5 ng/ml. In 2 patients we noted biochemical relapse. Transrectal implantation was very well tolerated. Grade 3 acute urinary toxicity occurred in 1 patient. We noted no Grade 2 or higher acute gastrointestinal toxicity. One patient developed a Grade 3 late urinary toxicity. No patient showed late gastrointestinal side effects. All 140 dose-volume histograms for 3D HDR brachytherapy were analyzed. CONCLUSIONS: The new 3D HDR brachytherapy technique, combined with 3D external irradiation and androgen deprivation, is a feasible, so far well-tolerated and effective treatment in the short-time follow-up of median 18 months.

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.

New interstitial HDR brachytherapy technique for prostate cancer: CT based 3D planning after transrectal implantation.

We have developed a new interstitial HDR brachytherapy technique for the treatment of prostate cancer using CT based 3D planning after transrectal implantation of four non-parallel needles. CT based needle reconstruction, target definition, evaluation and documentation, including DVHs and 3D imaging, is a feasible, safe and well tolerated treatment concept.

Transdifferentiation of distal but not proximal tubular epithelial cells from human kidney in culture.

Human renal proximal and distal (thick ascending limb and early distal convoluted tubule) epithelial cells have been isolated according to their specific antigen expression. The cells were well characterized by flow cytometry, enzyme cytochemistry and electron microscopy and cultured for up to 3 months. Cultured tubular cells coexpressed cytokeratin and vimentin as intermediate filament proteins. While primary isolated cells, proximal as well as distal, revealed the phenotypic characteristics of their nephron origin, cultured distal cells showed the tendency to dedifferentiate/transdifferentiate. Distal cells lost their characteristic expression of Tamm-Horsfall glycoprotein and started de novo expression of the proximal marker proteins aminopeptidase M, gamma-glutamyl transferase and dipeptidyl peptidase IV. The expression of these antigens by distal cells could be shown by flow-cytometric analysis and fluorescence microscopy. Enzyme activity assays revealed the activity of aminopeptidase M, gamma-glutamyl transferase and dipeptidyl peptidase IV, but not of the proximal marker enzyme alkaline phosphatase. This antigenic shift could not be prevented in different culture media, and the original phenotype could not be restored. Cultured cells displayed characteristic hormonal stimulation patterns indicative of their proximal and distal origins, as shown by activation of adenylate cyclase by different peptide hormones. These results indicate that distal tubular cells possibly transdifferentiate to a more proximal phenotype in view of loss of the distal marker enzyme Tamm-Horsfall protein and de novo expression of proximal marker enzymes like dipeptidyl peptidase IV and aminopeptidase M.

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.