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Background: Overexpression of periostin (POSTN) is associated with prostate cancer (PCa) aggressiveness. We investigated the prognostic significance of POSTN expression in tumor biopsy samples of patients with PCa., Methods: We scored POSTN expression by immunohistochemistry analysis on 215 PCa biopsy samples using an anti-POSTN-specific antibody. A total immunoreactive score (T-IRS) was calculated by adding the POSTN staining scores of stromal and epithelial tumor cells. Prostate-specific antigen (PSA) progression/recurrence-free survival (PFS), radiographic progression/recurrence-free survival (rPFS), and overall survival (OS) were the study end points., Results: A total of 143 patients received therapy with radical attempt, whereas 72 had locally advanced or metastatic disease and received hormone therapy alone. Median T-IRS was 9 and 12 (range, 0-20), respectively (P = .001). Overall, we found a weak positive correlation of T-IRS with prebiopsy PSA levels (r = 0.166, P = .016) and Gleason score (r = 0.266, P < .000). T-IRS ≥ 8 independently predicted for shorter PSA-PFS and OS (hazard ratio [HR] [95% confidence interval (CI)] ≥ 8 versus < 8: 1.50 [1.06-2.14], P = .024 and 1.92 [1.20-3.07], P = .007, respectively). In the subgroup analysis, the association between T-IRS and patient outcome was retained in patients who received therapy with radical attempt (HR [95% CI] ≥ 8 vs. < 8: rPFS: 2.06 [1.18-3.58], P = .01; OS: 2.36 [1.24-4.50], P = .009) and in those with low to intermediate Gleason scores (HR [95% CI] ≥ 8 vs. < 8: PSA-PFS: 1.65 [1.06-2.59], P = .028; rPFS: 2.09 [1.14-3.87], P = .018; OS: 2.57 [1.31-5.04], P = .006)., Conclusion: POSTN T-IRS on PCa biopsy samples independently predicted the risk of recurrence, progression, and death in patients with localized disease and in those with low to intermediate Gleason scores., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Gonadotropin releasing hormone (GnRH) antagonists suppress follicle-stimulating hormone (FSH) to lower levels than GnRH agonists. This may partially explain the differences between these agents on prostate cancer outcomes. In this post-hoc analysis, FSH and prostate specific antigen (PSA) responses and the impact of cross-over from leuprolide to degarelix were evaluated from a 1-year comparative study (CS21) and its extension study (CS21A)., Materials and Methods: Overall, 610 patients were enrolled in CS21, wherein PSA and FSH levels were evaluated monthly. CS21A evaluated 386 patients, including those previously treated with degarelix (n = 251) who continued to receive degarelix, and those previously treated with leuprolide (n = 135) who crossed-over to receive degarelix. PSA and FSH levels were evaluated in CS21A for 3 months after cross-over. The associations between measurements were assessed using Spearman's correlation coefficient. The impact of class variables on FSH suppression were evaluated using Analysis of Variance., Results: Rapid PSA and FSH suppression was observed and maintained in the degarelix arm (CS21 and CS21A), while patients on leuprolide experienced rising PSA during CS21. Patients crossed-over from leuprolide to degarelix achieved a suppression of FSH and a significant PSA decrease. PSA and FSH levels were significantly (p < .05) correlated at months 1, 3, 6, 12 and 13 in the degarelix arm., Conclusions: Significant FSH suppression with GnRH antagonists may explain its advantage over GnRH agonists in terms of better prostate cancer control. The effect of profound FSH suppression is analogous to the need for profound testosterone suppression for tumor control.

Different therapeutic options for the management of prostate cancer (PC) have been developed, and some are successful in providing crucial improvement in both survival and quality of life, especially in patients with metastatic castration-resistant PC. In this scenario, diverse combinations of radiopharmaceuticals (for targeting bone, cancer cells and receptors) and nuclear medicine modalities (e.g. bone scan, SPECT, SPECT/CT, PET and PET/CT) are now available for imaging bone metastases. Some radiopharmaceuticals are approved, currently available and used in the routine clinical setting, while others are not registered and are still under evaluation, and should therefore be considered experimental. On the other hand, radiologists have other tools, in addition to CT, that can better visualize bone localization and medullary involvement, such as multimodal MRI. In this review, the authors provide an overview of current management of advanced PC and discuss the choice of diagnostic modality for the detection of metastatic skeletal lesions in different phases of the disease. In addition to detection of bone metastases, the evaluation of response to therapy is another critical issue, since it remains one of the most important open questions that a multidisciplinary team faces when optimizing the management of PC. The authors emphasize the role of nuclear modalities that can presently be used in clinical practice, and also look at future perspectives based on relevant clinical data with novel radiopharmaceuticals.

Background: Collision metastasis is a rare phenomenon in which metastases of carcinoma from 2 separate primary tumors occur in the same lymph node. We summarize here the clinical course and highlight the histological challenges in the diagnosis of this rare phenomenon., Case: A biopsy performed due to gross hematuria by endoscopic resection revealed an infiltrative high-grade urothelial carcinoma in a 75-year-old man receiving androgen deprivation therapy due to biopsy-proven high-grade prostate cancer. A radical cystectomy, with regional lymphadenectomy and prostatectomy, was performed. Three nodes appeared to have metastatic foci from both primary tumors: prostatic and urothelial cancer. The presence of the 2 tumor types colliding in the same lymph nodes was confirmed by immunohistochemical stains., Conclusion: In a patient with simultaneous tumors it is important to remember that a part of lymph node metastases with histological polymorphic appearance may result from a collision metastasis. In light of the important therapeutic consequences, a differential diagnosis is needed, suggesting appropriate immunohistochemical investigations.

Introduction: Antiandrogens are a treatment option in patients with prostate cancer, given either in combination with androgen deprivation or, in selected cases, as monotherapy. New-generation antiandrogens have been recently introduced in clinical practice (enzalutamide) or are under evaluation in clinical trials (ARN-509)., Areas Covered: This review elucidates the safety profile of antiandrogens, in particular focusing on the tolerability profile of each drug either when employed in combination with castration or as monotherapy, in hormone-naive or in castration-resistant patients., Expert Opinion: Non-steroidal antiandrogens are widely used in the management of hormone-sensitive disease in combination with luteinizing hormone-releasing hormone agonists or in patients failing front-line treatment with androgen-deprivative maneuvers. In selected patients, non-steroidal antiandrogen monotherapy appears to yield comparable results as castration. Novel non-steroidal antiandrogens have been investigated with promising results in castration-resistant prostate cancer. Beyond the safety profile specific to any individual compound, increased testosterone and 17β-estradiol levels are commonly observed during antiandrogen monotherapy, leading to gynecomastia and breast pain. The safety profile of old and novel antiandrogens should be taken into account by clinicians in decision making and in selecting the most suitable patients. Beyond patient selection, full clinical evaluation of patient co-morbidities that might affect the drug tolerability and clinical monitoring are anyway required.

Background: Pelvic lymph nodes removed during radical retropubic prostatectomy for prostatic cancer can be found on pathological examination to harbor various unexpected pathologies. Among these, hematologic neoplasms are not infrequent. Given their frequently indolent clinical course, such neoplasms would likely have remained undiagnosed and non-life threatening. Despite this, the case we are reporting describes a rare association between two aggressive neoplasms, and it will be helpful to clinicians who encounter similar combinations of pathologies., Case Presentation: We report the challenging case of a 56-year-old, caucasian man in whom pathological assessment of pelvic lymph nodes removed during radical retropubic prostatectomy for a high-grade prostatic neoplasm revealed Hodgkin lymphoma, which was subsequently classified as stage IV. There are very few published reports of this combination of pathologies. This situation required a cautious and expert approach to delivering the most appropriate treatment with the most appropriate timing for both diseases., Conclusion: This report describes the multidisciplinary clinical approach we followed at our institution. We have also presented a review of published reports concerning the incidence, histologic type, and management of such concurrent malignancies.

The management of prostate cancer (PCa) remains challenging because to date, there has been no way to distinguish between indolent and aggressive tumors. Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is implicated in the network of mechanisms that control androgen receptor (AR) expression. We studied the expression of the two proteins in PCa to evaluate their prognostic potential and elucidate the hnRNP K function in PCa progression. HnRNP K and AR expression were analyzed immunohistochemically in 105 patients who had undergone radical prostatectomy. The association between the expression of hnRNP K and/or AR and PSA progression or death was evaluated by univariate and multivariate analyses. The expression of hnRNP K was also investigated in vitro using the BPH-1 cell line and two different LNCaP populations that recapitulate the progression of PCa towards a more aggressive disease. AR and hnRNP K were differentially expressed between cancer and normal prostate tissues. A strong association with a good prognosis was evident in PCa exhibiting high percentage of AR-positive cells (>75%) (p≤0.005) and more interestingly, the combination of high AR and low cytoplasmic hnRNP K expression emerged as the most significant independent prognostic marker for PSA failure-free survival, in a multivariate analysis (p≤0.001). In vitro, a higher expression of hnRNP K and pERK was associated with higher PSA levels, suggesting a relationship between hnRNP K phosphorylation and AR-regulated genes. These results indicate that the interaction between the AR and hnRNP K has an important role in the progression of PCa. Changes of the expression of the two proteins are strongly associated with the clinical outcome and may be a potential prognostic marker.

Prostate cancer is the first cause of skull metastases in men, accounting for 12-18% of all cases. This condition is generally a late event in the course of the disease, involving patients with disseminated lesions. Quite rarely is skull involvement the first and single site of distant recurrence. We report the case of a patient who developed a single skull lesion 15 years after primary treatment of prostate cancer, in the presence of undetectable PSA levels. Pathological assessment performed after resection of the lesion revealed a metastasis from prostate carcinoma. Basing on this experience the appearance of craniofacial pain or a nerve deficit in patients with a history of prostate cancer should alert the clinician to exclude distant recurrence of disease, even in the presence of undetectable PSA levels and even if many years have elapsed since the treatment of the primary tumor. Knowledge of these manifestations will reduce any diagnostic delay and lead to the effective delivery of appropriate treatment.

Background: Anti-tumor vaccination is a new frontier in cancer treatment applicable to immunogenic neoplasms such as prostate and renal cancers. GX301 is a vaccine constituted by four telomerase peptides and two adjuvants, Montanide ISA-51 and Imiquimod., Objective: The aim of this study was to analyze safety and tolerability of GX301 in an open-label, phase I/II trial. Immunological and clinical responses were also evaluated as secondary endpoints., Experimental Design: GX301 was administered by intradermally injecting 500 μg of each peptide (dissolved in Montanide ISA-51) in the skin of the abdomen. Imiquimod was applied as a cream at the injection sites. The protocol included 8 administrations at days 1, 3, 5, 7, 14, 21, 35, 63. Eligible patients were affected with stage IV prostate or renal cancer resistant to conventional treatments. Patients were clinically and immunologically monitored up to 6 months from the first immunization., Results: No grade 3-4 adverse events were observed. Evidence of vaccine-specific immunological responses was detected in 100 % of patients. Disease stabilization occurred in 4 patients. Prolonged progression-free survival and overall survival were observed in patients showing a full pattern of vaccine-specific immunological responses., Conclusion: GX301 demonstrated to be safe and highly immunogenic. Further studies are needed to determine its clinical efficacy.

Background/aim: To investigate periostin (POSTN) expression in the LNCaP cell line., Materials and Methods: Our LNCaP strain did not constitutively express the POSTN gene. Through cell transfection with a cloning vector, we developed an LNCaP cell line that stably expressed POSTN. LNCaP wild-type and transfected cells were incubated with dihydrotestosterone (DHT) in the presence/or absence of bicalutamide (BIC). POSTN mRNA was detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and growth was measured with the MTT assay., Results: POSTN transfection stimulated LNCaP cell growth. While POSTN transfection did not interfere with the stimulatory effect of DHT, BIC had an inhibitory effect on cell proliferation. However, exposure to either DHT and/or BIC was not able to interfere with POSTN expression per se., Conclusion: We confirmed the role of POSTN in promoting cancer cell growth. Although POSTN transcription is not likely to be androgen-dependent, the fact that increased cell proliferation POSTN-mediated was impaired by BIC suggests an androgen modulation of POSTN interaction proteins.

Background: The purpose of the present study was to evaluate the prognostic value of POSTN expression following prostatectomy., Methods: Periostin (POSTN) expression in prostate cancer (PCa) and in normal specimens was evaluated in 90 patients by an immuno-reactive score(IRS) based on the intensity of immunostaining and on the quantity of stained cells. The t-test was applied to compare IRS values in cancer specimens to values in normal specimens. Pearson's test was used to correlate POSTN expression to clinical pathologic features. PSA progression-free and survival curves were constructed by the Kaplan-Meier method and compared using the log-rank test. Multi-parametric models were constructed according to the Cox technique adding all the covariates predicting for either PSA progression or death into the models after univariate analysis., Results: Both stromal and epithelial POSTN expression were significantly increased in tumor tissues. In particular, we found stromal expression to be significantly higher than epithelial expression as compared to normal tissues (p<0.000 and p=0.001).A significant correlation between POSTN epithelial expression and extra-prostatic extension was found (p=0.03). While high stromal expression was significantly associated with shorter survival (p=0.008), a low epithelial score significantly correlated with shorter PSA-free survival (p=0.04), suggesting that POSTN plays an apparently opposing biological role depending on its compartmentalization.Regardless of the mechanism that is involved, patients showing both high stromal and low epithelial expression made up a subgroup with a very bleak prognosis., Conclusions: Although requiring further validation through larger studies, our findings show that POSTN might represent a novel prognostic marker for PCa.

Background: Bicalutamide (BIC) is an alternative treatment to castration for advanced prostate cancer. Breast events are common adverse effects which can be effectively prevented by the concurrent administration of tamoxifen, a selective estrogen receptor modulator., Materials and Methods: We investigated the effects of BIC, 4-hydroxy Tamoxifen (4OHT), the active metabolite of tamoxifen, and their combination on the expression of a panel of genes implicated in prostate cancer development and progression in LNCaP cells stimulated with dihydrotestosterone., Results: Our findings confirm the anti-proliferative activity of BIC on LNCaP cell growth but also show the down-regulating function of this anti-androgen on the expression of genes involved in tumor proliferation and invasion [cyclins, caspases, epidermal growth factor (EGF)]. The combination with 4OHT exerts a synergistic effect on the downregulation of some genes involved in prostate cancer progression., Conclusion: The observation that the expression of several genes [such as B-cell lymphoma-2 (BCL2), myelocytomatosis oncogene (MYC), caspases] is modulated midly-to-moderately, after 4OHT addition suggests that this combined approach in the clinical setting should be further investigated through appropriate trials.

Purpose: The aim of the study was to correlate nuclear matrix (NM) protein expression profiles with the risk of PSA progression or death in early prostate cancer (PCa)., Methods: High-resolution two-dimensional gel electrophoresis (2D-PAGE) was used to identify tumor-associated NM proteins in the PCa specimens obtained from 94 patients. The association between the expression of each protein and the probability of PSA progression or death was studied through univariate analysis. Unsupervised hierarchical clustering analysis was then used to generate patient clusters showing comparable outcomes by including the proteins that were predictive at univariate analysis. PSA-free and overall survival curves relative to each cluster were constructed by means of the Kaplan-Meier method and curves compared by the log-rank test. Multi-parametric models were constructed according to Cox proportional hazard technique., Results: After a median follow-up of 11.7 years (range, 6.5-16.2), 50 patients progressed and 22 died. Of the eight NM proteins identified through 2D-PAGE, proteins NM-6, NM-7 and NM-8 were confirmed to be individually associated with a higher risk of PSA progression at univariate analysis. Proteins NM-6 and NM-8 were also predictive of survival probability. Hierarchical clustering analysis of these proteins allowed to identify one cluster of tumors co-expressing the three proteins or proteins NM-6 and NM-8, characterized by a very poor outcome, suggesting a specific role for these proteins in PCa progression. The predictive value of this mini-signature in respect to PSA-free survival was confirmed by multivariate analysis., Conclusions: Changes in NM scaffolding are strongly associated with the clinical outcome of patients following radical prostatectomy.

Background: Bicalutamide (BIC) is widely used in prostate cancer therapy. The dose and schedule employed are well tolerated, but about 50% of patients develop gynecomastia. Several studies have shown a significant reduction of the troublesome effects when Tamoxifen is concomitantly administered with BIC. However, the results reported in the literature seem to be preliminary and possible interferences could be present. In order to clarify the molecular mechanisms of the combination of the two drugs, we have investigated whether the expression of the proteins belonging to nuclear matrix (NM), one modulator of hormone action, is altered by BIC and/or 4-hydroxy-tamoxifen (4OHT) in LNCaP cells. We focused above all on heterogeneous nuclear ribonucleoprotein K (hnRNP K) a NM protein with a key role in prostate carcinoma., Methods: NM proteins were analyzed by two-dimensional gel electrophoresis. Modulation and compartmentalization of the androgen receptor and the hnRNP K were studied by Western blotting, confocal microscopy, and immunoprecipitation., Results: Proteomic analysis revealed that there is a similarity in the changes of the NM proteins elicited by drugs alone but that their combination does not result in a simple additive effect. Moreover, we found that in the nucleoplasm the androgen receptor and the hnRNP K colocalize in a complex that is highly proximal to DNA and that both proteins were synchronously modulated by BIC and/or 4OHT treatment., Conclusion: This study confirm the pivotal role of hnRNP K in prostate carcinoma and suggest that this role might be played by the interaction with the androgen receptor., (Copyright © 2011 Wiley-Liss, Inc.)

Using proteomic analysis of the nuclear matrix (NM), we found that heterogeneous nuclear ribonucleoprotein K (hnRNP K), a member of the hnRNP family with pleiotropic functions, was differentially expressed in prostate cancer (PCa) tissues. This study aimed to characterise the expression of hnRNP K and its subcellular localisation in PCa, utilising immunohistochemical and quantitative western blot techniques. Furthermore, the hnRNP K expression was studied in human PCa cell lines in order to determine its modulation by bicalutamide, the anti-androgen widely used in PCa therapy. Immunohistochemical staining of paraffin-embedded tissues showed that hnRNP K was overexpressed in PCa, where it was localised both in the cytoplasm and in the nucleus. Staining of non-tumour tissues showed exclusively nuclear localisation and a less intense or absent signal. Immunoblot analysis demonstrated that the hnRNP K level within the NM was higher in PCa compared with non-tumour tissues and closely correlated with Gleason score (P=0.008). Higher expression within the NM was significantly (P=0.032) associated with poor prognosis. In two-dimensional western blot analysis hnRNP K presented several isoforms; the one with pI 5.1 was the most differently expressed between non-tumour and PCa tissues. Preliminary results indicate that hnRNP K can be modulated in vitro by a non-steroidal anti-androgen. Taken together, our findings suggest that hnRNP K has potential implications at the diagnostic, prognostic and therapeutic levels in PCa.

Background: Abnormal epidermal growth factor receptor expression and pre-clinical data prompted us to investigate the activity of gefitinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, in hormone-refractory prostate cancer., Methods: Eighty-two patients were randomly assigned to receive prednisone plus gefitinib (pG; n = 44) or prednisone plus placebo (ppl; n = 38). On progression, patients initially assigned to placebo were offered the possibility to receive gefitinib. Best prostate-specific antigen response was the primary endpoint., Results: At a median follow-up time of 29.0 months (26.0-32.0), 77 patients progressed and 51 died. Prostate-specific antigen response was recorded in 6/38 (15.8%; 95% CI 4.2-27.4) and in 5/44 (11.4%; 95% CI 2.0-20.8) patients in pG and ppl groups, respectively. There was no difference between groups in time to progression (median pG 4.0 months, range 3.5-4.5; median ppl 4.5 months, range 3.5-5.0) and survival (median pG 26.5 months, range 16.0-37.0; median ppl 20.5 months, range 14.0-27.0). Adverse events occurred in 19 patients in each arm and were generally mild., Conclusions: pG showed a good tolerability profile but only a limited therapeutic activity in hormone-refractory prostate cancer., ((c) 2008 S. Karger AG, Basel.)

Background: There is growing evidence that IGF-1 and binding proteins may be involved in prostate cancer promotion and progression., Patients and Methods: IGF-1 and binding proteins (IGFBP-1 and 3) serum levels were measured at baseline and after 3 and 6 months of treatment in a selected group of patients with prostate cancer who were randomly assigned to treatment with bicalutamide, bicalutamide plus anastrozole or bicalutamide plus tamoxifen in a comparative study investigating the role of pharmacological medication in the development of bicalutamide-induced gynecomastia., Results: Bicalutamide monotherapy does not appear to alter the IGF-1/IGFBP system. In fact, the increase in IGF-1 levels induced by this treatment was paralleled by comparable increases in binding protein (IGFBP-3). No major changes from baseline up to month 6 either in IGF-1 or in IGFBP-1 and 3 were observed in the bicalutamide plus anastrozole arm. The addition of tamoxifen to bicalutamide produced a sharp decrease in IGF-1 levels (p<0.001) coupled with an increase in both IGFBP-1 (p=0.001) and, to a lesser extent, IGFBP-3 (p=0.5)., Conclusions: The concurrent administration of tamoxifen and bicalutamide reduces the synthesis and bioavailability of IGF-1. Moreover, increased binding protein levels might exert antiproliferative and proapoptotic effects on prostate cancer cells, independently of the IGF-1/IGF receptor-mediated survival system. Both effects might have a synergistic inhibitory influence on prostate cancer growth.

The process of carcinogenesis is characterized by definite changes in the protein composition of the nuclear matrix. We have recently found that lamins form, in addition to the nuclear lamina, an intranuclear web of thin fibrils. This finding prompted us to address the question of whether changes in the expression of lamins occur in the course of tumor development. In prostate cancer, lamin B undergoes a significant increase; interestingly, its nuclear content strongly correlates with tumor differentiation. Moreover, all the lamins show reproducible alterations in the distribution of the isoelectric variants, suggesting that dephosphorylation events could trigger changes in the pattern of gene expression by inducing structural rearrangements of the nuclear scaffold.

Background: The present study was aimed at investigating the effects of the co-administration of 4-OH Tamoxifen (4HT) and bicalutamide (BIC) on the human prostate cancer cell line LNCaP in vitro., Materials and Methods: The LNCaP FGC prostate cancer cell line was grown in vitro within a three-dimensional matrix formed by collagen gel under dihydrotestosterone (DHT) (0.1 nM) stimulation. Cells were incubated in the presence either of BIC at escalating concentrations (1 nM; 100 nM; 10 microM) or 4HT Tamoxifen (10 nM; 100 nM) or both compounds at the different concentrations studied. The cells were incubated for 144 hours, and growth was evaluated in non trypsinised cells by crystal violet vital dye staining assay., Results: BIC appeared to exert a dose-dependent inhibitory action, with the maximum inhibitory effect achieved by the 10 microM concentration. A comparable inhibitory effect was also observed after exposure to 4HT at both doses tested. No statistically significant interference was observed when BIC was combined with 4HT., Conclusion: 4HT, even at the higher concentration employed here, showed no major interference with the inhibitory effects of BIC.

Different lines of evidence suggest that the nuclear matrix (NM), the protein scaffold of the nucleus, represents a functional unit playing a pivotal role in the spatial and temporal coordination of the events of gene activation. Any change in the gene expression pattern, which occurs during carcinogenesis, may partially depend on an impairment of the regulatory functions of the NM. Therefore, increasing interest has been addressed to the study of NM modifications associated with malignant transformations and to potential clinical applications. Here, recent results on the NM changes in prostate cancer are discussed. Tumor cells are characterized by a more complex NM protein pattern compared to normal tissue: the development of poorly-differentiated tumors is characterized by the expression of proteins that are not present in hyperplastic tissues or in more differentiated tumors. In addition, a few newly-expressed proteins are significantly correlated with the risk of biochemical progression. The potential application of these proteins at the diagnostic and prognostic levels calls for further studies.

Objective: A randomized multicenter (14 centers) trial was conducted in 114 men with prostate cancer to determine whether the antiestrogen tamoxifen ('Nolvadex') 20 mg or the aromatase inhibitor anastrozole ('Arimidex') 1 mg prevent gynecomastia and breast pain during treatment with the non-steroidal antiandrogen bicalutamide ('Casodex') 150 mg, without compromising efficacy, safety, or quality of life. Plasma samples were collected in a subgroup of these patients to investigate whether trough (pre-dose) concentrations of bicalutamide 150 mg are influenced by concomitant administration of tamoxifen 20 mg or anastrozole 1 mg; the results of this pilot study are reported in this article., Methods: A subpopulation of patients from a randomized placebo-controlled trial evaluating tamoxifen 20 mg and anastrozole 1 mg for the prevention of gynecomastia and breast pain in men receiving bicalutamide 150 mg for early or recurrent prostate cancer were selected on a voluntary basis from three of the trial centers. Plasma samples were collected on days 7, 14, 28, and 84 of therapy and analyzed to determine the plasma concentrations of (R)-bicalutamide and (S)-bicalutamide. In addition, plasma concentrations of tamoxifen, N-desmethyltamoxifen, and anastrozole were determined., Results: A total of 21 patients were selected. There was no significant difference between treatment groups with respect to the trough plasma concentrations of either bicalutamide enantiomer at any point during the study. Plasma concentrations of the enantiomers, and the relative proportion of the (R))- and (S)-enantiomers, were consistent with those reported in previous studies. Plasma concentrations of tamoxifen, N-desmethyltamoxifen, and anastrozole were also similar to those described elsewhere in the literature., Conclusions: The findings of this pilot study suggest that trough plasma concentrations of bicalutamide enantiomers following administration of bicalutamide 150 mg are not markedly influenced by concomitant administration of tamoxifen 20 mg or anastrozole 1 mg. However, an effect of tamoxifen on bicalutamide pharmacokinetics can not be completely excluded due to the size of this study. Further studies are needed to clarify the effect of tamoxifen on bicalutamide pharmacokinetics and prostate cancer control in bicalutamide-treated patients. 'Arimidex', 'Casodex', and 'Nolvadex' are trademarks of the AstraZeneca group of companies.

Purpose: To determine whether tamoxifen or anastrozole prevents gynecomastia and breast pain caused by bicalutamide (150 mg) without compromising efficacy, safety, or sexual functioning., Patients and Methods: A double-blind, placebo-controlled trial was performed in patients with localized, locally advanced, or biochemically recurrent prostate cancer. Patients (N = 114) were randomly assigned to either bicalutamide (150 mg/d) plus placebo or in combination with tamoxifen (20 mg/d) or anastrozole (1 mg/d) for 48 weeks. Gynecomastia, breast pain, prostate-specific antigen (PSA), sexual functioning, and serum levels of hormones were assessed., Results: Gynecomastia developed in 73% of patients in the bicalutamide group, 10% of patients in the bicalutamide-tamoxifen group, and 51% of patients in the bicalutamide-anastrozole group (P < .001); breast pain developed in 39%, 6%, and 27% of patients, respectively (P = .006). Baseline PSA level decreased by > or = 50% in 97%, 97%, and 83% of patients in the bicalutamide, bicalutamide-tamoxifen, and bicalutamide-anastrozole groups, respectively (P = .07); and adverse events were reported in 37%, 35%, and 69% of patients, respectively (P = .004). There were no major differences among treatments in sexual functioning parameters from baseline to month 6. Elevated testosterone levels occurred in each group; however, free testosterone levels remained unchanged in the bicalutamide-tamoxifen group because of increased sex hormone-binding globulin levels., Conclusion: Anastrozole did not significantly reduce the incidence of bicalutamide-induced gynecomastia and breast pain. In contrast, tamoxifen was effective, without increasing adverse events, at least in the short-term follow-up. These data support the need for a larger study to determine any effect on mortality.

Background: After the discovery that nuclear matrix (NM) directs the spatial organization of DNA transcription and replication, there has been an increasing interest in studying NM changes associated with malignant transformation and their potential usefulness in the clinical setting., Methods: High-resolution two-dimensional gel electrophoresis was used to analyze the NM proteins (NMP) of specimens of prostate cancer tissue obtained from the prostates of 75 patients undergoing retropubic prostatectomy., Results: Nine NMP with different molecular weights and isoelectric points have been identified. They were expressed differently by prostate cancer tissues. An increasing trend toward the expression of such proteins like NMP 6-8 was evident with increasing tumor stage and dedifferentiation. NMP 6-8 were also significantly correlated with the risk of biochemical progression. However, Gleason score was the only significant discriminant in this regard in multiparametric models., Conclusions: This study confirms that prostate cancer progression is related to profound changes in NMP expression patterns. However, due to the complexity of the methods required to define these latter, the clinical relevance of NMP appears to be still limited., (Copyright 2003 Wiley-Liss, Inc.)

Objectives: To compare the efficacy of bicalutamide monotherapy to maximal androgen blockade in advanced prostatic cancer., Patients and Methods: Previously untreated patients with histologically proven stage C or D (American Urological Association Staging System) disease were randomly allocated to either bicalutamide (B) or goserelin plus flutamide (G+F). After disease progression, patients treated with B were assigned to castration. The primary endpoint for this trial was overall survival. Prostate cancer-specific survival and progression were included among secondary endpoints., Results: In total 108 patients received B and 112 received G+F. At a median follow-up time of 54 months (range 1-89), 151 patients progressed and 113 died. There was no significant difference in the duration of either progression-free or overall survival. Hazards of progression, death and cancer-specific death, corrected by disease stage, tumor grade and baseline PSA level, showed that patients initially assigned to B had a higher risk of progression but a comparable risk of death and cancer-specific death with the exception of patients with G3 tumors who had an increased risk of death)., Conclusions: In patients with well or moderately well differentiated tumors, B monotherapy followed by castration may offer the same survival chance as maximal androgen deprivation. In those patients it thus represents a reasonable choice that can avoid the side effects of androgen deprivation for considerable periods of time.

The nuclear matrix-intermediate filament complex (NM-IF) is a protein scaffold which spans the whole cell, and several lines of evidence suggest that this structural frame represents also a functional unit, which could be involved in the epigenetic control of cancer development. Here we report the characterization by high resolution two-dimensional gel electrophoresis and Western blot analysis of the NM-IF complex isolated from prostate cancer (PCa); tumor-associated proteins were identified by comparing the electrophoretic patterns with those of normal human prostate (NHP). Extensive changes in the expression of both the NM and IF proteins occur; they are, however, related in a different way to tumor progression. Poorly differentiated PCa (Gleason score 8-9) shows a strong down regulation of several constitutive cytokeratins (CKs 8, 18, and 19); their expression significantly (P < 0.05) decreases with respect to both NHP and benign prostatic hyperplasia (BPH) and, more interestingly, also with respect to moderately (Gleason score 6-7) and well (Gleason score 4-5) differentiated tumors. Moreover, we have identified a tumor-associated species which is present in all of the tumors examined, systematically absent in NHP and occurs only in a few samples of BPH; this polypeptide, of M(r) 48,000 and pI 6.0, represent a proteolytic fragment of CK8. At variance with these continuing alterations in the expression, the NM proteins undergo stepwise changes correlating with the level of differentiation. The development of less differentiated tumors is characterized by the appearance of several new proteins and by the decrease in the expression of others. Six proteins were found to be expressed with a frequency equal to one in poorly differentiated tumor, namely in all the samples of tumor examined, while in moderately and well differentiated tumors the frequency is less than one, and decreases with increasing the level of differentiation. When tumors of increasing Gleason score are compared with NHP a dramatic increase in the complexity of the protein patterns is observed, indicating that tumor dedifferentiation results in a considerable increase in the phenotypic diversity. These results suggest that tumor progression can be characterized using an appropriate subset of tumor-associated NM proteins., (Copyright 2000 Wiley-Liss, Inc.)

Androgen suppressive maneuvers still represent the gold standard for prostate cancer patients. However, they are associated with side effects (fatigue, sexual impotence, hot flushes, anemia, anxiety, depression and osteoporosis) all of which have a negative impact on quality of life. Nonsteroidal antiandrogens compete with dihydrotestosterone for the linkage of its own receptors. These compounds are commonly used in combination with suppressive maneuvers. However, there is a growing experience with them as monotherapy, based on the possibility to spare gonadal function and therefore prevent the effects related to its suppression. Many studies have demonstrated the feasibility and safety of this approach, which can represent a valuable alternative to suppressive maneuvers for patients wishing to retain sexual function, especially for those without distant metastases. Unfortunately, none of the comparative studies performed so far had the power to detect the equivalence between monotherapy and castration.

Objective: The aim of this study was to compare the effects of the nonsteroidal antiandrogen flutamide plus the LH-RH analogue goserelin acetate (combined androgen blockade [CAB]) with goserelin acetate alone in patients with advanced prostate cancer. The original analyses at 25 and 56 months of follow-up have been reported previously, and here we report the final survival analysis after 10 years of follow-up., Methods: 589 patients with advanced prostate cancer (55% with metastatic [M1] and 45% with locally advanced [M0] disease) were randomized to receive goserelin acetate 3.6 mg either alone or in combination with flutamide (250 mg three times daily)., Results: A total of 583 patients were included in the analysis. There was a small, but nonsignificant, benefit for CAB compared with goserelin acetate alone in all patients with respect to survival (hazard ratio 0.88, 95% CI 0.73, 1.06). Subgroup analysis of M0 and M1 patients showed similar results (M0: hazard ratio 0.92, 95% CI 0.68, 1.25; M1: hazard ratio 0.85, 95% CI 0.66, 1. 08). The treatment effect was not significantly different for M0 and M1 patients (p = 0.685)., Conclusions: In this large randomized trial containing significant numbers of M0 patients, after 10 years there was a small but nonsignificant benefit for CAB over castration alone.

Purpose: To compare the efficacy of bicalutamide monotherapy to maximal androgen blockade (MAB) in the treatment of advanced prostatic cancer., Patients and Methods: Previously untreated patients with histologically proven stage C or D disease (American Urological Association Staging System) were randomly allocated to receive either bicalutamide or MAB. After disease progression, patients treated with bicalutamide were assigned to castration. The primary end point for this trial was overall survival. Secondary end points included response to treatment, disease progression, treatment safety, quality-of-life (QOL), and sexual function., Results: A total of 108 patients received bicalutamide and 112 received MAB. There was no difference in the percentage of patients whose prostate-specific antigen returned to normal levels. At the time of the present analysis (median follow-up time, 38 months; range, 1 to 60 months), 129 patients progressed and 89 died. There was no difference in the duration of either progression-free survival or overall survival. However, a survival trend favored bicalutamide in stage C disease but MAB in stage D disease. Overall and subgroup trends were confirmed by multivariate analysis. Serious adverse events and treatment discontinuations were more common in patients receiving MAB (P =.08 and P =.04, respectively). Fewer patients in the bicalutamide group complained of loss of libido (P =. 01) and of erectile dysfunction (P =.002). Significant trends favored bicalutamide-treated patients also with respect to their QOL, namely relative to social functioning, vitality, emotional well-being, and physical capacity., Conclusion: Bicalutamide monotherapy yielded comparable results relative to standard treatment with MAB, induced fewer side effects, and produced a better QOL.

Objectives: To compare the efficacy of oral liarozole, the first retinoic acid metabolism-blocking agent (RAMBA) to be developed as differentiation therapy for human solid tumors, with that of cyproterone acetate (CPA), an antiandrogen for the treatment of metastatic prostate cancer. Liarozole promotes differentiation of cancer cells by increasing the intratumoral levels of retinoic acid., Methods: A total of 321 patients with metastatic prostate cancer in relapse after first-line endocrine therapy entered a Phase III international multicenter study (recruitment from February 1992 to August 1994) comparing liarozole (300 mg two times daily) with CPA (100 mg two times daily)., Results: Accounting for differences in baseline prognostic factors, the adjusted hazard ratio for survival was 0.74 in favor of liarozole (P = 0.039), indicating a 26% lower risk of death than in patients treated with CPA. Median crude (unadjusted) survival time was the same in the liarozole group as in the CPA group (10.3 months). More patients showed a PSA response (at least 50% reduction in PSA from baseline) when treated with liarozole (20%) than with CPA (4%) (P < 0.001). Prostate-specific antigen (PSA) responders had a median survival benefit of 10 months over nonresponders, irrespective of treatment (hazard ratio 0.43; P = 0.0018). PSA response was apparent within 3 months in approximately 90% of patients who responded. Pain improved more in the liarozole group than in the CPA group (P = 0.03). PSA responders had lower median pain scores than nonresponders (1.7 versus 2.5) and better quality of life (median Functional Living Index-Cancer score 108 versus 98) at end point, ie, treatment discontinuation, as well as throughout the treatment period. Among the most frequently occurring adverse events in the liarozole group were dry skin (51% of patients), pruritus (25%), rash (16%), nail disorders (16%), and hair loss (15%). These adverse events were generally mild to moderate in severity and did not affect the overall quality of life score. There were no detectable effects of either treatment on vital signs such as blood pressure, heart rate, electrocardiogram, and body weight., Conclusions: Liarozole is superior to CPA in terms of PSA response, PSA progression, and survival, and is capable of maintaining patients' quality of life. The observed adverse events were mild to moderate in nature. These results show that liarozole is a possible treatment option after first-line endocrine therapy has failed.

Purpose: Previous studies indicate that suramin may be an active agent for treating hormone-refractory prostate cancer. However, antitumour responses were observed in initial experiments only when plasma suramin concentrations were maintained in excess of 250 micrograms/ml. Dose-limiting toxicity, especially neurological toxicity, is directly related to the duration of exposure and sustained plasma drug concentrations of 300 micrograms/ml or more. Combination with other agents such as epidoxorubicin, a drug with demonstrable activity in metastatic prostatic carcinoma, could be more effective and allow reduced suramin doses, while maintaining the suramin antitumor effect; this could make suramin therapy more feasible. On the basis of preclinical synergistic activity for combined suramin/doxorubicin in prostate cancer cell lines, a pilot study in patients with metastatic hormone refractory prostate cancer was performed., Materials and Methods: Ten patients with hormone-refractory prostate cancer received a fixed dosing scheme of suramin infusion in combination with weekly epidoxorubicin at 25 mg/m2. Therapy was discontinued for dose-limiting toxicity or progressive disease., Results: None of the ten patients achieved a prostate-specific antigen reduction of more than 50% and no objective responses were observed in any patient. Dose-limiting toxicity was observed in four patients: grade 3 neurotoxicity was observed in three patients and grade 3 nephrotoxicity in one patient., Conclusions: Suramin/epidoxorubicin association, despite the encouraging preclinical results, was not able to improve the antitumour activity of suramin and showed significant toxicity. The results achieved in our study, although in a small number of patients, seem to suggest that this regimen cannot be recommended for use in the treatment of metastatic hormone-refractory prostate cancer.

The clinical presentation of prostate-hormone refractory tumours in 90% of patients is characterised by sclerotic bone metastasis which is not assessable by classic phase II response criteria. Restriction of investigational study of new agents to the minority of patients, with bidimensionally measurable lesions, assessable by conventional WHO response criteria, has been criticised because such cases may represent a highly selected tumour cell population. To circumvent this problem, a variety of response criteria have been proposed. However, prostate specific antigen (PSA) levels have become an integral component, used singly or in combination with other markers of response evaluation. As a result, different response proportions could also be reported using the same single agent in this category of patients. This study repors a different evaluation of carboplatin activity by using WHO, NPCP modified criteria and PSA post-therapy decline as measures of carboplatin activity. It is suggested that treatment efficacy in this category of patients wold be more correctly measured by the proportion of patients who "fail treatment" after a reasonable number of therapy courses, rather than those achieving a conflicting definition of "objective response". Finally, in hormone refractory prostate cancer PSA post therapy declines may represent a measure of treatment efficacy and can be used as a surrogate end point for clinical phase II trials.

Introduction: The therapeutic potential of R75251, a ketoconazole derivative which has shown marked antitumor activity in animals and in men, was investigated in 16 patients with advanced prostatic cancer progressing after one or more lines of hormone therapy., Patients and Methods: Patients were given the drug at 150 mg/b.i.d. for one month. After the first month of treatment, the dose was increased to 300 mg/b.i.d. In all patients, treatment was continued until disease progression or the development of sever toxicity. Clinical and biochemical assessments were performed on days 0, 14 and 28 and then repeated on a monthly basis., Results: Of the 13 evaluable patients, 12 showed stable disease by strictly employing US-NPCP criteria. However, in 3 patients a clear effect was observed on the volume of their measurable lesions. In addition, 2 of them showed a more than 50% decrease of prostate-specific antigens (PSA). Overall, 50% of patients showed some decrease in PSA baseline levels. Overall tolerance to treatment was good., Conclusions: Our results, although achieved in a small number of patients, suggest that R75251 has a moderate but definite activity in patients with hormone-refractory prostate cancer and that the value of this drug as second-line treatment in these patients should be further investigated.

The nonsteroidal androgen-receptor antagonist nilutamide has previously been shown to inhibit adrenal androgen steroidogenesis in patients with prostatic carcinoma treated in combination with an LHRH agonist. In order to understand better the mechanisms subserving this observation, we have studied the effects of nilutamide alone on the serum concentrations of androstenedione (A), dehydroepiandrosterone (DHEA), and DHEA-sulphate (DHEA-S) in 12 patients with prostatic cancer and compared them with those achieved in 21 patients treated with the agonist D-Trp-6-LHRH. In addition, the adrenocorticotropic hormone (ACTH)-stimulated adrenal response and the thyrotropin releasing hormone (TRH)-stimulated prolactin (PRL) response observed in the patients treated with nilutamide were compared with a control group of healthy age-matched controls. No significant variation in the basal concentrations of adrenal androgens occurred either within or between both treatment groups. In response to ACTH, a decreased 17-alpha hydroxyprogesterone (17-OHP) accumulation and an augmented A/17-OHP ratio were observed in the antiandrogen group (P < 0.05 for both), suggesting the partial removal of the 17,20 lyase block which was distinctive of the untreated controls, while no significant difference was found for other steroids. Basal PRL levels were not affected by the antiandrogen, but the response to TRH was increased. We conclude that no significant inhibition of adrenal androgen secretion occurs after nilutamide or LHRH agonist treatment. Rather, administration of the antiandrogen alone may partially remove the physiological decrease in adrenal androgen secretion observed in the elderly.

Suramin, a polysulphonated naphthylurea, inhibits the activity of several growth factors in in vitro experiments and clinical responses have been reported in human solid tumors. We decided to investigate the relationship between suramin treatment and serum levels of insulin-like growth factor I (IGF-I) and II (IGF-II) in advanced breast, prostate and lung cancer patients. The serum IGF-I, IGF-II levels were determined by radioimmunoassay. A significant decline of IGF-I and IGF-II serum levels was demonstrated in suramin treated patients. Our results suggest that suramin-induced IGF suppression could be one of the possible mechanisms of suramin action.

The claimed ability of non-steroidal antiandrogens to preserve libido and sexual potency is sought as a potential improvement in the palliative management of prostate cancer. A critical issue for the clinical use of these compounds is, however, the reported evidence in the rat of an excessive increase in testosterone concentrations as a consequence of the androgen negative feedback interruption. On the other hand, the recovery of testicular function after long-term inhibition by luteinizing hormone-releasing hormone (LHRH) analogs is also an important concern in view of the proposed use of these compounds for the treatment of several non-malignant conditions. We addressed these issues by studying the long-term endocrine effects induced by the administration of either the non-steroidal antiandrogen nilutamide or the depot preparation of D-Trp6-LHRH in men with prostate cancer. Treatment with the antiandrogen induced a marked increase in gonadotropin levels, LH concentrations rising from a mean (SEM) of 17.5 +/- 1.6 to a maximum of 56.6 +/- 6.9 kU/l (p < 0.001), while mean testosterone and 17 beta estradiol-concentrations rose only by about 50% and 70% over pretreatment values, testosterone levels reaching a plateau after 1 month of treatment. In the subjects treated with the LHRH agonist, 6 months after discontinuation of long-term administration the mean (+/- SEM) LH had risen to 36.9 +/- 6.8 IU/l while mean testosterone levels were still as low as 1.7 +/- 0.7 and rose only to a maximum of 4.2 +/- 1 nmol/l after high-dose human chorionic gonadotropin loadings.(ABSTRACT TRUNCATED AT 250 WORDS)

The hormonal treatment of advanced prostate cancer is still a controversial matter although new drugs are being tested in clinical trials all over the world. The results of these trials are the subject of dispute for reasons related to the natural history and clinical evolution of prostate cancer.

25 patients with measurable or evaluable metastatic prostate cancer, progressive after hormonal treatment, were treated weekly with carboplatin 150 mg/m2 intravenously. The weekly schedule allowed higher dose intensity carboplatin administration with respect to the common monthly cycles. Toxicity was manageable even in elderly patients with extensive bone metastases and consisted primarily of myelosuppression. 4 out of 24 evaluable patients (17%) had a partial response and 12 (50%) had disease stabilisation. The median response duration was 7 months. Prostate-specific antigen and prostatic acid phosphatase serial values showed a correlation with disease response in only 47 and 50% of patients, respectively. These results suggest that carboplatin possesses a moderate but definite activity in prostate cancer patients.

From March 1987 to December 1990, 373 patients with stage C and D prostate cancer were randomized to receive either goserelin acetate alone or goserelin acetate plus flutamide. At a median follow-up time of 24 months, there was no significant difference in the response rate, progression-free and overall survival between the two treatment groups. In particular, median time to progression was 18 months in the goserelin arm and 24 months in the combined treatment arm (P = 0.09). However, median time to progression in stage D patients was 12 months in both treatment groups. Median time to death was 32 and 34 months, respectively. The combination regimen produced a more rapid normalisation of prostatic acid phosphatase levels and a prompt relief of bone pain. However, significantly more patients in the combination arm experienced treatment-related side-effects such as diarrhoea and increases in transaminase levels. The concurrent use of goserelin acetate and flutamide does not seem to significantly improve the results that can be achieved with goserelin acetate alone.

Twenty-one patients with metastatic prostate cancer who had become refractory to hormonal therapies received lonidamine (150 mg tid and 600 mg daily dose in 17 and 4 patients, respectively). In all but 4 patients, treatment was continued until disease progression or the development of severe toxicity. Toxicity was minimal and reversible (score 1 or 2) and included myalgia (8 cases), arthralgia (6 cases), gastrointestinal toxicity (11 cases), fatigue (14 cases) and testicular pain (9 cases). The response was evaluated after at least one month of therapy with lonidamine, according to NPCP-USA recommendations. Of 21 patients who entered the study, only 15 were evaluable for response; 2 died (1 for severe toxicity and 1 for drug-unrelated reasons). No objective response was obtained in the series. In fact, only 6 patients achieved stable disease and 9 progressed. Median survival time from the beginning of treatment was no longer than that of patients in a similar condition who were treated with standard palliative maneuvers. We conclude that this therapeutic approach with lonidamine is not active in hormone-refractory prostatic cancer patients with distant metastasis.

A prospective randomized trial was conducted to compare the effects of the nonsteroidal antiandrogen flutamide (250 mg. 3 times daily) plus the luteinizing hormone-releasing hormone analogue goserelin acetate (Zoladex) (3.6 mg. subcutaneous depot injection every 28 days) with goserelin acetate alone in advanced prostatic carcinoma. A total of 571 eligible patients, of whom 57% had distant metastases, showed no difference in subjective or objective response rates, interval to progression, treatment failure or survival after a median followup of 2 years. In the combination group more patients had an early decrease in elevated levels of tumor markers and the small number of patients with an increase in signs and symptoms within the first 4 weeks showed a significant decrease. However, increased gastrointestinal and hepatic toxicity in the combination group resulted in 44 patients being withdrawn from the trial. These results indicate that the combination of goserelin acetate with flutamide provides no long-term clinical benefit in patients with advanced prostatic carcinoma compared to goserelin acetate alone.

A total of 26 previously untreated patients with metastatic carcinoma of the prostate received the pure nonsteroidal antiandrogen nilutamide as a single agent. Objective response rate was 38.5 +/- 18.7% (95% confidence interval). Median progression-free survival and median survival were 9 and 23 months, respectively. Of 13 patients with progression on antiandrogen 5 showed an additional objective response to a second-line endocrine treatment. The drug was generally well tolerated, except for 2 patients who discontinued treatment because of moderate gastrointestinal symptoms. Approximately a third of the patients complained of decreased adaptation to darkness. An electroretinogram and dark adaptation test revealed the presence of functional damage and visual complaints reversed in all patients on cessation of therapy. The other most frequent side effects were slight nausea (26.9% of the patients) and alcohol intolerance (19.2%). A nonsignificant increase in testosterone levels was shown within 1 month of treatment, after which the levels remained stable. Approximately half of the sexually active men claimed maintenance of libido and sexual potency during treatment. A slightly significant increase in hemoglobin was observed during the long term, suggesting the occurrence of a trophic effect by androgens on erythropoiesis. The results indicate that nilutamide as a single agent has an acceptable toxicity and a moderate activity, and may maintain sexual interest in a discrete number of cases. Whether monotherapy with nonsteroidal antiandrogens offers a valid option in the palliation of advanced disease remains to be seen in comparative prospective trials.

Between March 1986 and March 1987, 48 patients with stage D prostate carcinoma were entered into a multicentric pilot study using the pure nonsteroidal antiandrogen nilutamide (Anandron--RU 23908) at the dose of 100 mg t.i.d. as the only therapy until disease progression or the occurrence of toxicity. Minimum follow-up was 15 months. Median age of patients was 72 (56 to 83) and median initial Performance Status (PS) was 1 (0 to 3). Of the 48 patients, 29 were untreated, while 19 patients were progressing following treatment by orchiectomy, LHRH analogs, or other endocrine therapies. According to the National Prostatic Cancer Project (NPCP) criteria, 43 patients were evaluable for response. Overall best response in untreated patients was partial response (PR), 41.6%; stationary disease (SD), 54.1%; 73.6% of pretreated patients achieved SD. Median progression-free survival and overall survival in untreated patients were 325 and 696 days, respectively, and 174 and 447 days, respectively, in pretreated patients. The more common side effects were G.I. toxicity (65%), hemeralopia (27%), and alcohol intolerance (6.2%). Results of this study suggest that Anandron may be a safe and effective treatment for patients with advanced prostatic cancer.

The activity of the pure non-steroidal antiandrogen nilutamide as a single agent was evaluated in 44 patients with metastatic carcinoma of the prostate. Objective (partial) response rates (95% confidence limits) were 38.5 (18.7)% in 26 previously untreated patients and 5.5 (11%) in 18 patients progressing on primary androgen suppressive procedures. The most frequent side-effects were decreased adaptation to darkness (29.5%), slight nausea (31.8%) and alcohol intolerance (18.2%). In addition, treatment was discontinued in 3 patients because of gastrointestinal symptoms. A non-significant increase in testosterone levels was shown in the untreated group during the first month of treatment, after which the levels remained stable. About half of the sexually active men claimed the maintenance of libido and sexual potency during treatment. Although our study confirms a significant incidence of visual disturbances, the activity data coupled with the ability of maintaining sexual interest suggest that single therapy with non-steroidal antiandrogens may deserve comparison to conventional endocrine treatment in controlled trials.

Since March 1987, 304 evaluable patients with stage C and D prostate cancer have been entered into a prospective trial comparing Zoladex and Zoladex plus flutamide. To date, there has been no significant difference in over-all and progression-free survival between the 2 treatment groups. However, combined treatment produced a higher response rate (particularly in stage D patients) and a more rapid normalization of abnormal prostatic acid phosphatase levels. In addition, more prompt relief of bone pain was evident in the Zoladex plus flutamide group. However, significantly more side-effects were associated with combined treatment. These findings should be considered with caution because they form an interim analysis, and follow-up time is short. The results do suggest, however, that there is no particular advantage in using a combination of Zoladex plus flutamide compared to adding flutamide on failure of treatment with Zoladex alone.