Prostatic Neoplasms: Ben-Josef E

Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, Middleton R, Sharp SA, Smith TJ, Talcott J, Taplin M, Vogelzang NJ, Wade JL, Bennett CL, Scher HI, Anonymous00323. · American Society of Clinical Oncology, Alexandria, VA 22314, USA. · J Clin Oncol. · Pubmed #17404365 No free full text.

Abstract: PURPOSE: To update the 2004 American Society of Clinical Oncology (ASCO) guideline on initial hormonal management of androgen-sensitive, metastatic, recurrent, or progressive prostate cancer (PCa). METHODS: The writing committee based its recommendations on an updated systematic literature review. Recommendations were approved by the Expert Panel, the ASCO Health Services Committee, and the ASCO Board of Directors. RESULTS: Seven randomized controlled trials (four new), one systematic review, one meta-analysis (new), one Markov model, and one delta-method 95% CI procedure for active controlled trials (new) informed the guideline update. RECOMMENDATIONS: Bilateral orchiectomy or luteinizing hormone-releasing hormone agonists are recommended initial androgen-deprivation treatments (ADTs). Nonsteroidal antiandrogen monotherapy merits discussion as an alternative; steroidal antiandrogen monotherapy should not be offered. Combined androgen blockade should be considered. In metastatic or progressive PCa, immediate versus symptom-onset institution of ADT results in a moderate decrease (17%) in relative risk (RR) for PCa-specific mortality, a moderate increase (15%) in RR for non-PCa-specific mortality, and no overall survival advantage. Therefore, the Panel cannot make a strong recommendation for early ADT initiation. Prostate-specific antigen (PSA) kinetics and other metrics allow identification of populations at high risk for PCa-specific and overall mortality. Further studies must be completed to assess whether patients with adverse prognostic factors gain a survival advantage from immediate ADT. For patients electing to wait until symptoms for ADT, regular monitoring visits are indicated. For patients with recurrence, clinical trials should be considered if available. Currently, data are insufficient to support use of intermittent androgen blockade outside clinical trials

Loblaw DA, Mendelson DS, Talcott JA, Virgo KS, Somerfield MR, Ben-Josef E, Middleton R, Porterfield H, Sharp SA, Smith TJ, Taplin ME, Vogelzang NJ, Wade JL, Bennett CL, Scher HI, Anonymous00081. · Cancer Policy and Clinical Affairs, 1900 Duke St, Suite 200, Alexandria, VA 22314, USA. · J Clin Oncol. · Pubmed #15184404 No free full text.

Abstract: PURPOSE: To develop a clinical practice guideline for the management of men with metastatic, recurrent, or progressive carcinoma of the prostate. The focus of this document is on the use, combinations, and timing of various forms of androgen deprivation therapy (ADT) for the palliation of men with androgen-sensitive disease. METHODS: An expert panel and writing committee were formed. The questions to be addressed by the guideline were determined, and a systematic review of the literature was performed, which included a search of online databases, bibliographic review, and consultation with content experts. A priori criteria were used to select studies for analysis and study authors were contacted when necessary. RESULTS: There were 10 randomized controlled trials, six systematic reviews, and one Markov model available to inform the guidelines. CONCLUSION: A full discussion between practitioner and patient should occur to determine which therapy is best for the patient. Bilateral orchiectomy or luteinizing hormone releasing hormone agonists are the recommended initial treatments. Nonsteroidal antiandrogen therapy may be discussed as an alternative, but steroidal antiandrogens should not be offered as monotherapy. Patients willing to accept the increased toxicity of combined androgen blockage for a small benefit in survival should be offered nonsteroidal antiandrogen in addition to castrate therapy. Until data from studies using modern medical diagnostic/biochemical tests and standardized follow-up schedules become available, no specific recommendations can be issued regarding the question of early versus deferred ADT. A discussion about the pros and cons of early versus deferred ADT should occur.

Porter A, Ben-Josef E, Crawford ED, Garde S, Huhtaniemi I, Pontes JE. · Department of Radiation Oncology, Wayne State University, Detroit, Michigan, USA. · Mol Urol. · Pubmed #11790281 No free full text.

Abstract: Nonandrogenic hormones are implicated in the growth and function of the prostate, which is itself an endocrine gland that synthesizes and secretes hormones and growth factors, including follicle-stimulating hormone (FSH) and prostatic inhibin peptide (PIP). Findings of increased FSH concentrations and receptor expression in diseased prostate tissue suggest a role for FSH in prostate cancer growth. Not only does PIP suppress circulating levels of FSH, but it responds to and modulates prostatic FSH, suggesting a close interlinkage of these compounds in controlling both healthy and diseased prostate cells. Other focuses of endocrinologic research include androgen receptors, vitamin D, growth factors (including insulin-like growth factors I and II), and retinoids. Issues such as optimal therapy timing, intermittent administration, and the adoption of a multihormonal approach to the management of prostate cancer remain to be resolved.

Ménard C, Camphausen K, Muanza T, Sears-Crouse N, Smith S, Ben-Josef E, Coleman CN. · Radiation Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institute of Health, Department of Health and Human Services, Bethesda, MD 20892, USA. · Semin Oncol. · Pubmed #14727242 No free full text.

Abstract: Tolerance of the normal rectal mucosa to radiation injury limits the dose that can be safely delivered to the prostate gland with definitive external beam radiation therapy. The radioprotective agent amifostine (Ethyol; MedImmune, Inc, Gaithersburg, MD) is approved for intravenous use. Laboratory studies indicate that rectal administration results in preferential accumulation of amifostine in the rectal mucosa, and in clinical studies, neither free parent compound nor free active metabolite has been detected in the systemic circulation. This trial evaluates the rates of early and late rectal toxicities in patients with prostate cancer receiving definitive or adjuvant three-dimensional conformal external beam radiation therapy and concurrent daily endorectal applications of amifostine. Endpoints include Radiation Therapy Oncology Group acute and late toxicity gradings, Expanded Prostate Cancer Index Composite self-assessment questionnaires, and proctoscopic examinations with scoring of mucosal damage measured before, during, and after treatment. Eleven patients have been enrolled to date; 10 have completed radiotherapy and three have been followed-up to 6 months. Two patients received 66 Gy to the prostatic bed post-prostatectomy; five patients received 74 Gy and three received 76 Gy to the prostate gland. In all patients, daily fractionation was 2 Gy, and 1 g of amifostine (50 mg/mL in 20 mL reconstituted saline) was administered endorectally 40 minutes before radiation delivery. Daily endorectal administration was well tolerated. To date, six patients have experienced grade 2 (Radiation Therapy Oncology Group) acute toxicities, all but one because of frequent bowel movements relieved by loperamide. The initial trial will proceed until 18 patients are accrued, at which time an interval evaluation of both early and late toxicity endpoints will be conducted.

Ben-Josef E, Han S, Tobi M, Vargas BJ, Stamos B, Kelly L, Biggar S, Kaplan I. · Department of Radiation Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA. · Semin Radiat Oncol. · Pubmed #11917290 No free full text.

Abstract: Clinically symptomatic late injury to the rectal wall occurs in about one third of patients with prostate cancer treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of these structures. Based on our previous observations that intrarectal application of amifostine resulted in very high concentrations of amifostine and its active metabolite WR-1065 in the rectal wall of Copenhagen rats, the authors initiated a phase I clinical trial in 1998. Twenty-nine patients with localized prostate cancer were accrued. Eligibility criteria included histologically confirmed adenocarcinoma, a Karnofsky performance status of > or =70, and no pelvic lymphadenopathy or distant metastases. The total dose to the prostate was 70.2 Gy (20 patients) and 73.8 Gy (9 patients). Therapy was delivered using a 4-field axial technique and 3-dimensional conformal planning. Amifostine was administered intrarectally as an aqueous solution 30 minutes before irradiation on the first 15 days of therapy. Amifostine dose was escalated, in cohorts, from 500 mg to 2,500 mg. Toxicity was evaluated using the Radiation Therapy Oncology Group late morbidity scale. All patients completed therapy with no amifostine-related toxicity at any dose level. The application was feasible and well tolerated. With a median follow-up time of 21 months, 9 patients (33%) had rectal bleeding (8 grade 1, 1 grade 2). Four patients (14%) had symptoms suggestive of radiation injury, which proved to be secondary to nonrelated processes. These included preexisting nonspecific proctitis (1 patient), diverticular disease of the sigmoid colon, rectal polyp (1 patient), and ulcerative colitis (1 patient). Symptoms developed significantly more often in patients receiving 500 to 1,000 mg than in patients receiving 1,500 to 2,500 mg amifostine (7 of 14 [50%] versus 2 of 13 [15%]; P =.0325, 1-sided chi(2) test). Intrarectal application of amifostine is feasible and well tolerated. A complete lack of systemic toxicity obviates the need for close monitoring of patients during and after administration. Rectal symptomatology after external beam radiotherapy to the pelvis cannot be assumed to reflect late radiation damage, because it often is a manifestation of an unrelated pathologic process. The preliminary efficacy data are encouraging and suggest that intrarectal administration of amifostine may reduce radiation damage. Further clinical studies are warranted.

Ben-Josef E, Han S, Tobi M, Shaw LM, Bonner HS, Vargas BJ, Prokop S, Stamos B, Kelly L, Biggar S, Kaplan I. · Department of Radiation Oncology, Wayne State University School of Medicine, Detroit, MI, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #12128116 No free full text.

Abstract: PURPOSE: Clinical symptomatic late injury to the rectal wall occurs in about one-third of patients with prostate cancer treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of the prostate to the anterior rectal wall. On the basis of our previous observations in an animal model that intrarectal application of amifostine resulted in very high concentrations of amifostine and its active metabolite WR-1065 in the rectal wall, a Phase I dose-escalation clinical trial was undertaken. METHODS AND MATERIALS: Twenty-nine patients with localized prostate cancer were accrued. Eligibility criteria included histologically confirmed adenocarcinoma, Karnofsky performance status >or=70, and no pelvic lymphadenopathy or distant metastases. The total dose to the prostate was 70.2 Gy in 20 patients and 73.8 Gy in 9 patients. Therapy was delivered using a 4-field technique with three-dimensional conformal planning. Amifostine was administered intrarectally as an aqueous solution 30 min before irradiation on the first 15 days of therapy. Amifostine was escalated in cohorts from 500 to 2500 mg. Proctoscopy was performed before therapy and at 9 months after completion. Most patients underwent repeat proctoscopy at 18 months. On Days 1 and 10 of radiotherapy, serum samples were collected for pharmacokinetic studies. The clinical symptoms (Radiation Therapy Oncology Group scale) and a proctoscopy score were assessed during follow-up. RESULTS: All patients completed therapy with no amifostine-related toxicity at any dose level. The application was feasible and well tolerated. No substantial systemic absorption occurred. With a median follow-up of 26 months, 9 patients (33%) developed rectal bleeding (8 Grade 1, 1 Grade 2). At 9 months, 16 and 3 patients developed Grade 1 and Grade 2 telangiectasia, respectively. This was mostly confined to the anterior rectal wall. No visible mucosal edema, ulcerations, or strictures were noted. No significant differences were found between the proctoscopy findings at 9 and 18 months. Four patients (14%) developed symptoms suggestive of radiation damage that, on sigmoidoscopy, proved to be secondary to unrelated processes. These included preexisting nonspecific proctitis (n = 1), diverticular disease of the sigmoid colon (n = 1), rectal polyp (n = 1), and ulcerative colitis (n = 1). Symptoms developed significantly more often in patients receiving 500-1000 mg than in patients receiving 1500-2500 mg amifostine (7 [50%] of 14 vs. 2 [15%] of 13, p = 0.0325, one-sided chi-square test). CONCLUSION: Intrarectal application of amifostine is feasible and well tolerated. Systemic absorption of amifostine and its metabolites is negligible, and close monitoring of patients is not required with rectal administration. Proctoscopy is superior to symptom score as a method of assessing radiation damage of the rectal wall. The preliminary efficacy data are encouraging, and further clinical studies are warranted.

Ben-Josef E, Porter AT, Han S, Mertens W, Chuba P, Fontana J, Hussain M. · Department of Radiation Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI 48201, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #11172951 No free full text.

Abstract: PURPOSE: Current therapy for locally advanced prostate cancer is suboptimal. A treatment regimen was designed to improve systemic control by neoadjuvant targeting of hormone-sensitive and -insensitive micrometastatic disease and to improve local control by escalating the biologic effective dose to the prostate using estramustine (EMP) concurrently with radiotherapy. PATIENTS AND METHODS: Eighteen patients with locally advanced prostate cancer (Stages T3/T4 or T1c/T2b/T2c with a Gleason score of > or =7 and a serum PSA >15 ng/ml) were entered onto this trial. Therapy consisted of two 21-day cycles of oral estramustine (10 mg/kg/day) in three divided doses and oral etoposide (50 mg/m(2)/day, in two divided doses), followed by concurrent estramustine (10 mg/kg/day, PO) and three-dimensional conformal radiotherapy. RESULTS: Two patients required discontinuation of chemotherapy due to development of Grade 3 and 4 toxicity. All others completed both components of therapy per protocol guidelines. Minor toxicities included alopecia (100% of patients), anemia (69%), leukopenia (37%), thrombocytopenia (19%), and nausea (6%) but did not require dose modifications. There were no fatalities. Actuarial 3-year overall survival and disease-free survival (DFS) were 88% and 73%, respectively. Local control rate, assessed by repeated prostate biopsies at 18 months post completion of therapy, was 71%. CONCLUSION: The described regimen is well tolerated, and preliminary efficacy data are encouraging. The underlying concepts of early targeting of both hormone-sensitive and -insensitive micrometastatic clones, in combination with aggressive local therapy, warrant further investigation.

Joshi B, Li L, Taffe BG, Zhu Z, Wahl S, Tian H, Ben-Josef E, Taylor JD, Porter AT, Tang DG. · Biomide Laboratories, Detroit, Michigan 48202, USA. · Cancer Res. · Pubmed #10485482 links to  free full text

Abstract: We recently developed a class of novel anti-prostate cancer compounds, cyclic hydroxamates that elicit a potent apoptotic response in many tumor cells cultured in vitro (D.G. Tang et al., Biochem. Biophys. Res. Commun., 242: 380-384, 1998). The lead compound, termed BMD188, induces programmed cell death in a variety of prostate cancer cells in vitro as well as in vivo (L. Li et al., Anticancer Res., 19: 51-70, 1999). BMD188 kills androgen-independent prostate cancer cells as well as prostate cancer cells with a multidrug-resistance phenotype. The apoptotic effect of BMD188 in prostate cancer cells does not depend on cell cycle, p53 status, or its purported target, arachidonate 12-lipoxygenase, but does require caspase activation and seems to involve mitochondria. To synthesize more specific and effective anti-prostate cancer hydroxamic acid compounds, it is important to understand their mechanism(s) of action. In the present study, we studied the role of mitochondrial respiratory chain (MRC) in BMD188-induced apoptosis in androgen-independent prostate cancer PC3 cells and compared its effect with that of staurosporine (STS), a widely used apoptosis inducer. Several lines of evidence indicate that BMD188-induced cell death depends on MRC: (a) the death could be significantly inhibited by several complex-specific respiration inhibitors; (b) respiration-deficient rho0 cells were more resistant than wild-type parent cells to apoptosis induction by BMD188; and (c) BMD188 induced a rapid increase in reactive oxygen species in mitochondria, an up-regulation of cytochrome c oxidase subunits, a biphasic alteration (i.e., an early hyperpolarization, followed by later hypopolarization) in the mitochondrial membrane potential (delta psi(m)), dramatic changes in mitochondrial morphology and distribution prior to caspase activation, and an abnormal proliferation of mitochondria at the ultrastructural level. By contrast, STS-induced PC3 apoptosis seemed not to depend on MRC. Taken together, the data suggest that the MRC represents a functional target for anti-prostate cancer hydroxamates.

Ben-Josef E, Yang SY, Ji TH, Bidart JM, Garde SV, Chopra DP, Porter AT, Tang DG. · Department of Radiation Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA. · J Urol. · Pubmed #10022736 No free full text.

Abstract: PURPOSE: Understanding growth regulation in hormone-refractory prostate cancer may provide avenues for novel treatment interventions. This study was conducted to characterize the expression of the receptor (FSHR) for follicle-stimulating hormone (FSH) in androgen-independent prostate cancer cell lines and in human malignant prostate tissues. MATERIALS AND METHODS: Western blotting, immunohistochemistry (IHC), and flow cytometric analysis were used to study the expression of FSHR. The effect of FSH on cell growth and clonogenicity was studied using proliferation and clonogenic assays. RESULTS: Immunohistochemistry revealed expression of FSH in PC3 and Du145 cells. FSHR was identified in PC3 and Du145 cells, as well as in human adenocarcinoma of the prostate. The specificity of the FSHR detected on prostate cancer tissues or cells by IHC and Western blotting was confirmed by preabsorbing the antibodies with the immunizing antigens. Stimulation of these hormone-refractory cells with FSH triggered a proliferative response in vitro, suggesting that the receptor is biologically active. CONCLUSION: Hormone-refractory prostate cancer cells express FSH and biologically active FSHR. Our results suggest that FSHR and its ligand may play a role in the regulation of the growth of hormone-refractory prostate cancers.

Garde SV, Basrur VS, Li L, Finkelman MA, Krishan A, Wellham L, Ben-Josef E, Haddad M, Taylor JD, Porter AT, Tang DG. · Procyon Biopharma, Inc., London, Ontario, Canada. · Prostate. · Pubmed #9973097 No free full text.

Abstract: BACKGROUND: PSP94 (prostate secretory protein of 94 aa; also called PIP), one of the predominant proteins secreted into the seminal fluid, was proposed as an independent diagnostic/prognostic marker for prostate cancers. It was also shown to inhibit rat prostate cancer growth. In this study, we investigated the effect of purified PSP94 on the growth of androgen-independent human prostate cancer cells (PC3) and its potential mechanism of action. METHODS AND RESULTS: PSP94, in a dose- and time-dependent manner, inhibited the growth of PC3 cells. The protein demonstrated a stronger inhibitory effect on the colony-forming ability of PC3 cells in soft agar. A daily injection of PSP94 at 5 microg/kg/body weight resulted in a 50-60% inhibition in the growth of PC3 xenografts in athymic mice. PC3 cell growth inhibition by PSP94 resulted from cell death characteristic of morphological apoptosis, which was confirmed by dual fluorescence microscopy, electron microscopy, and DNA fragmentation assays. Mechanistic studies indicated that PSP94 enhanced the expression of proapoptotic protein Bax without affecting Bcl-2 levels. CONCLUSIONS: This study suggests that PSP94 may represent a novel, apoptosis-based, antitumor agent applicable to the treatment of hormone-refractory human prostate cancers.