Journal Article•
Studies on Prostatic Cancer. I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate
TL;DR: It is demonstrated that a marked rise in acid phosphatase in serum is associated with the appearance or spread of roentgenologically demonstrable skeletal metastases and implies dissemination of the primary tumor and thus is of unfavorable prognostic significance.
Abstract: Carcinoma of the prostate gland is peculiarly favorable for endocrine investigation since frequent serial observations of the activity of phosphatases in serum were found to provide objective indices of activity of the neo/~i~m when the enzymes were increased in amount above normal. In the present paper data are given for the values of serum phosphatases in carcinoma of the prostate and in normal men. We shall demonstrate that the acid phosphatase of serum is reduced in metastatic carcinoma of the prostate by decreasing the activity of androgens through castration or estrogenic injections and that this enzyme is increased by injecting androgens. We have been unable to find previous observations indicating any relationship of hormones to carcinoma of the prostate gland. An enzyme capable of hydrolyzing phosphoric esters was discovered by Grosser and Husler (4) in intestinal mucosa and kidney. Robison (16) found that this enzyme was particularly high in activity in growing bone and cartilage and that its activity was greatest at pH 9 to 9.5. This ~alkaline phosphatase," was found by Kay (9) to be increased in the serum in certain bone diseases including metastasis of neoplasms to bone and later work has shown that among these conditions is carcinoma of the prostate. Davies (3) and Bamann and Riedel (1) discovered that there occurs in the spleen and kidney of swine and cattle, in addition to the alkaline phosphatase, a phosphatase with an activity maximum at pH 4.8. An enzyme believed to be identical with this "acid phosphatase" was found by Kutscher and Wolbergs (11) to be present in very large amount in the human prostate gland. This finding of great activity of acid phosphatase in the prostate gland was confirmed and extended to include prostatic cancer by Gutman, Sproul, and Gutman (7). The serum of certain patients with disseminated prostatic carcinoma was found by Gutman and Gutman (6) and Barringer and Woodard (2) to exhibit increased acid phosphatase activity. Robinson, Gutman, and Gutman'~I5) summarized the acid phosphatase activity levels of 44 patients with carcinoma of the prostate. They concluded that a marked rise in acid phosphatase in serum is associated with the appearance or spread of roentgenologically demonstrable skeletal metastases and implies dissemination of the primary tumor and thus is of unfavorable prognostic significance. METttODS AND MATERIALS
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TL;DR: The evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology is presented.
Abstract: Thereisgrowinginterestinthepossiblehealththreatposedbyendocrine-disruptingchemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor , retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use. We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness. (Endocrine Reviews 30: 293–342, 2009)
3,576 citations
Oregon Health & Science University1, Duke University2, Memorial Sloan Kettering Cancer Center3, University of Paris-Sud4, University of Washington5, Guy's and St Thomas' NHS Foundation Trust6, Institute of Cancer Research7, University of California, Berkeley8, University Health Network9, Nippon Medical School10, Charité11, Astellas Pharma12, Université de Montréal13, Harvard University14, University of Alberta15, Cliniques Universitaires Saint-Luc16
TL;DR: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer.
Abstract: BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
2,426 citations
Harvard University1, Boston University2, Johns Hopkins University3, University of Wisconsin-Madison4, Temple University5, Cleveland Clinic6, Mayo Clinic7, Case Western Reserve University8, University of Virginia9, Washington University in St. Louis10, University of Chicago11, University of Michigan12, Rutgers University13
TL;DR: Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone.
Abstract: BACKGROUND Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone. METHODS We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. RESULTS A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%. CONCLUSIONS Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.)
2,009 citations
TL;DR: Treatment with le uprolide and flutamide is superior to treatment with leuprolide alone in patients with advanced prostate cancer, and Symptomatic improvement was greatest during the first 12 weeks of the combined androgen blockade.
Abstract: To test the hypothesis that maximal androgen blockade improves the effectiveness of the treatment of prostatic cancer, we conducted a randomized, double-blind trial in patients with disseminated, previously untreated prostate cancer (stage D2). All 603 men received leuprolide, an analogue of gonadotropin-releasing hormone that inhibits the release of gonadotropins, in combination with either placebo or flutamide, a nonsteroidal antiandrogen that inhibits the binding of androgens to the cell nucleus. As compared with the 300 patients receiving leuprolide and placebo, the 303 patients randomly assigned to receive leuprolide and flutamide had a longer progression-free survival (16.5 vs. 13.9 months; P = 0.039) and an increase in the median length of survival (35.6 vs. 28.3 months; P = 0.035). The differences between the treatments were particularly evident for men with minimal disease and good performance status; however, further studies should be conducted in this subgroup. Symptomatic improvement was greatest during the first 12 weeks of the combined androgen blockade, when leuprolide alone often produces a painful flare in the disease. We conclude that in patients with advanced prostate cancer, treatment with leuprolide and flutamide is superior to treatment with leuprolide alone.
1,433 citations
TL;DR: Evidence is presented that significant improvement often occurs in the clinical condition of patients with far advanced cancer of the prostate after they have been subjected to castration and this work provides a new concept of prostatic carcinoma.
Abstract: The thesis of this work may be briefly summarized In many instances a malignant prostatic tumor is an overgrowth of adult epithelial cells All known types of adult prostatic epithelium undergo atrophy when androgenic hormones are greatly reduced in amount or inactivated In this paper evidence is presented that significant improvement often occurs in the clinical condition of patients with far advanced cancer of the prostate after they have been subjected to castration Conversely, the symptoms are aggravated when androgens are injected We believe that this work provides a new concept of prostatic carcinoma The evidence that prostatic carcinoma is often composed of an adult type of epithelium derives from a study of such tissue with respect to the phosphatase which manifests optimum activity atpH5 An important advance in the technic of investigation of the prostate gland was made by Kutscher and Wolbergs,1who found that
1,413 citations