INTRODUCTION:It is believed that men diagnosed with prostate cancer and a low baseline serum testosterone (BST) may have more aggressive disease, and it is frequently recommended they forego testosterone replacement therapy. We used two large Phase III trials involving androgen deprivation therapy and external beam radiation therapy to assess the significance of a BST. METHODS AND MATERIALS:All patients with a BST and complete data (n = 2,478) were included in this analysis and divided into four categories: "Very Low BST" (VLBST) ≤16.5th percentile of BST (≤248 ng/dL; n = 408); "Low BST" (LBST) >16.5th percentile and ≤33rd percentile (>248 ng/dL but ≤314 ng/dL; n = 415); "Average BST" (ABST) >33rd percentile and ≤67th percentile (314-437 ng/dL; n = 845); and "High BST" (HBST) >67th percentile (>437 ng/dL; n = 810). Outcomes included overall survival, distant metastasis, biochemical failure, and cause-specific survival. All outcomes were adjusted for the following covariates: treatment arm, BST, age (<70 vs. ≥70), prostate-specific antigen (PSA; <10 vs. 10 ≤ PSA <20 vs. 20 ≤), Gleason score (2-6 vs. 7 vs. 8-10); T stage (T1-T2 vs. T3-T4), and Karnofsky Performance Status (60-90 vs. 100). RESULTS:On multivariable analysis age, Gleason score, and PSA were independently associated with an increased risk of biochemical failure, distant metastasis and a reduced cause-specific and overall survival (p < 0.05), but BST was not. CONCLUSIONS:BST does not affect outcomes in men treated with external beam radiation therapy and androgen deprivation therapy for prostate cancer.

Results: DNA nondiploidy was not associated with any of the other prognostic factors in univariate analyses. In Kaplan-Meier analyses, 5-year overall survival was 70% for those with diploid tumors and 42% for nondiploid tu- mors. Cox proportional hazards regression revealed that nondiploidy was independently associated with reduced overall survival. No correlation was observed between DNA ploidy and distant metastasis. The diminished survival in the absence of an increase in distant metastasis was related to a reduction in the effect of salvage androgen ablation; patients treated initially with RTTAB and who had nondiploid tumors had reduced survival after salvage androgen ablation. Conclusions: Nondiploidy was associated with shorter survival, which seemed to be related to reduced response to salvage hormone therapy for those previously exposed to short-term TAB. J Clin Oncol 21:1238-1248. © 2003 by American Society of Clinical Oncology.

5123 Background: Controversy exists regarding the outcomes of prostate cancer patients (PCP) presenting with ultra-high (UH; defined as PSA ≥ 50 ng/ml) PSA levels. The objectives of this study were to assess the outcome of this patient population compared to other high-risk patients and to identify predictors associated with biochemical/clinical outcomes. Methods: PCP from two phase III RTOG PC clinical trials (9202 and 9413) were divided into two groups; high-risk patients with and without UH baseline PSA level. Predictive variables included age, Gleason score, T stage, KPS, and treatment arm. Outcomes included overall survival (OS), distant metastasis (DM), and biochemical failure (BF) by Phoenix definition. A Cox proportional hazards regression model was used for OS, and Fine and Gray's regression model was used for DM and BF to test the hypotheses that a difference in each outcome exists between the two groups. Results: There are 401 PCP in the UH PSA and 1792 in the non-UH PSA cohort. Median age was 70 years and PCP were evenly distributed across the Gleason groups (2–6, 7, 8–10) for the non-UH (median PSA 22.4 ng/ml) and the UH PSA (median PSA 72.8ng/ml) cohort. The UH PSA cohort had a larger proportion of T1-T2 disease (p = 0.01) and a smaller proportion of Gleason 8 disease (p = 0.04) than the non-UH group. PCP with UH PSA was found to have inferior OS (HR 1.19, 95% CI 1.02–1.39), DM rate (HR 1.51, 95% CI 1.19–1.92), and BF rate (HR 1.50, 95% CI 1.29–1.73) when compared to other high-risk PCP in multivariable modeling. In the UH cohort, PSA level was found to model risk of DM (HR 1.01, 95% CI 1.001–1.02) but not OS and BF. Gleason grade 8–10 was found to consistently predict for poor OS, DM, and BF outcomes (with HR estimates ranging from 1.41 to 2.36) in both the overall and UH cohort multivariable analyses. Conclusions: UH PSA levels at diagnosis are related with detrimental changes in OS, DM, and BF. All three outcomes assessed in this investigation can be modeled by various combinations all predictive variables tested. Supported by RTOG U10 CA21661, CCOP U10 CA37422, and Stat U10 CA32115 grants from the NCI. This abstract's contents are the sole responsibility of the authors and do not necessarily represent the official views of the NCI. No significant financial relationships to disclose.

PURPOSE:To determine whether adding 2 years of androgen-deprivation therapy (ADT) improved outcome for patients electively treated with ADT before and during radiation therapy (RT). PATIENTS AND METHODS:Prostate cancer patients with T2c-T4 prostate cancer with no extra pelvic lymph node involvement and prostate-specific antigen (PSA) less than 150 ng/mL were included. All patients received 4 months of goserelin and flutamide before and during RT. They were randomized to no further ADT (short-term ADT [STAD] + RT) or 24 months of goserelin (long-term ADT [LTAD] + RT). A total of 1,554 patients were entered. RT was 45 Gy to the pelvic nodes and 65 to 70 Gy to the prostate. Median follow-up of all survival patients is 11.31 and 11.27 years for the two arms. RESULTS:At 10 years, the LTAD + RT group showed significant improvement over the STAD + RT group for all end points except overall survival: disease-free survival (13.2% v 22.5%; P < .0001), disease-specific survival (83.9% v 88.7%; P = .0042), local progression (22.2% v 12.3%; P < .0001), distant metastasis (22.8% v 14.8%; P < .0001), biochemical failure (68.1% v 51.9%; P <or= .0001), and overall survival (51.6% v 53.9%, P = .36). One subgroup analyzed consisted of all cancers with a Gleason score of 8 to 10 cancers. An overall survival difference was observed (31.9% v 45.1%; P = .0061), as well as in all other end points herein. CONCLUSION:LTAD as delivered in this study for the treatment of locally advanced prostate cancer is superior to STAD for all end points except survival. A survival advantage for LTAD + RT in the treatment of locally advanced tumors with a Gleason score of 8 to 10 suggests that this should be the standard of treatment for these high-risk patients.

(Purpose:) under bar We evaluated whether posttreatment prostatic-specific antigen doubling time (PSADT) was predictive of prostate cancer mortality by testing the Prentice requirements for a surrogate endpoint.(Methods and Materials: ) under bar We analyzed posttreatment PSA measurements in a cohort of 1,514 men with localized prostate cancer (T2c-4 and PSA level < 150 ng/mL), treated and monitored prospectively on Radiation Therapy Oncology Group Protocol 92-02. From June 1992 to April 1995, men were randomized to neoadjuvant androgen deprivation and 65-70 Gy of radiation therapy (n = 761), or in combination with 24 months of adjuvant androgen deprivation (n = 753). Using an adjusted Cox proportional hazards model, we tested if PSADT was prognostic and independent of randomized treatment in this cohort. The endpoints were time to PSADT (assuming first-order kinetics for a minimum of 3 rising PSA measurements) and cancer-specific survival (CSS).(Results: ) under bar After a median follow-up time of 5.9 years, randomized treatment was a significant predictor for CSS (p(Cox) = 0.002), PSADT < 6 months (pc. < 0.001), PSADT < 9 months (P-Cox < 0.001), and PSADT < 12 months (P-Cox < 0.001) but not for PSADT < 3 (P-Cox = 0.4). The significant posttreatment PSADTs were also significant predictors of CSS (P-Cox < 0.001). After adjusting for T stage, Gleason score and PSA, all of Prentice's requirements were not met, indicating that the effect of PSADT on CSS was not independent of the randomized treatment.(Conclusions) under bar Prostatic specific antigen doubling time is significantly associated with CSS, but did not meet all of Prentice's requirements for a surrogate endpoint of CSS. Thus, the risk of dying of prostate cancer is not fully explained by PSADT. (c) 2006 Elsevier Inc.

PURPOSE:The purpose of this investigation is to determine the mechanism of seed migration after prostate implant and to develop procedures to minimize the risk of seed migration. METHODS AND MATERIALS:Radioactivity survey of prostate cancer patients after permanent brachytherapy with (125)I to detect pulmonary seed embolization is routinely performed using a seed migration detector. The seed migration detector is made from a low-energy, high-sensitivity scintillation survey meter by adding a single-hole collimation cap to the scintillation probe. If a seed migration is suspected, a pair of chest radiographs is ordered to document the location of the migrated seed. A comprehensive investigation is elicited if there are discrepancies between the seed migration detector survey and the radiographic examination. RESULTS:One hundred five patients have been surveyed, and 20 patients have demonstrated pulmonary seed embolization. In 1 patient, the seed migration detector sensed radioactivity in the thorax, but repeat chest radiographic examinations failed to show a radiopaque foreign body in the chest cavity. Owing to the signal variation mimicking heart rate, an (125)I seed located in the intracardiac region was suspected. This suspicion was confirmed in a high-quality fluoroscopy examination. CONCLUSIONS:Seed embolization to the intracardiac region is rarely reported. The true rate may be higher, but has not been adequately documented owing to the limitation of diagnostic quality of chest radiographs to detect seed migration to the intracardiac region. The seed migration detector, on the other hand, demonstrated its efficacy in the detection of seed migration, particularly in the detection of a seed located in the intracardiac region.

Controversies in the management of prostate cancer make treatment selection one of the most challenging areas in contemporary oncology. External beam radiotherapy (EBRT) is the one treatment modality that has applications at every stage in the natural history of carcinoma of the prostate. In early disease, it is a curative therapy that can eradicate organ-confined tumor with maximal preservation of adjacent normal tissues. Its efficacy is similar to that of surgery and its side effect profile is favorable. In the past few years, we have seen major advances in the technique of dose delivery. Three-dimensional conformal planning has become widespread and has been proven to allow safe escalation of the radiation dose and to increase disease control [1–5]. Intensity modulated radiotherapy, an advanced form of three-dimensional planning currently under study, holds promise to further improve dose distribution. Another area of intense investigation has been the use of interstitial radioactive implants, alone or in combination with EBRT. In locally advanced prostate cancer (tumor with extension beyond the confines of the glandular capsule, into the seminal vesicles, or into regional structures), EBRT combined with androgen deprivation has become the standard of care [6–9]. For those patients who have undergone surgical resection as the primary form of management, retrospective studies have identified a role for adjuvant EBRT; it provides improved local control for tumors with poor pathologic features (eg positive margins, high grade, advanced pathologic tumor stage) [10–17]. Randomized studies looking at the impact of this treatment on overall survival have now been completed; the results are awaited. EBRT also has a role in salvage therapy for patients with late local recurrences following surgery, whether detected on biochemical studies or by physical examination [14,18–21]. Finally, EBRT has a well-established role in the management of symptomatic osseous metastases, and it generally provides quick and effective pain control.KeywordsProstate CancerRadical ProstatectomyGross Tumor VolumeRadiation Therapy Oncology GroupAdvanced Prostate CancerThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Nondiploidy was associated with shorter survival, which seemed to be related to reduced response to salvage hormone therapy for those previously exposed to short-term TAB.

The natural history of prostate cancer has long been related to the male hormone testosterone, and treatment has focused on depletion of this androgen to slow or prevent growth of prostate cancer tissue. It has become clear recently, however, that more than androgens influence the progression of prostate cancer, with recent interest focusing on the gonadotropin, follicle-stimulating hormone (FSH). Research of the last decade has found that FSH is produced in and FSH receptors are expressed in the prostate. Investigators have found as well that production of FSH is altered in prostate cancer: FSH levels are increased and receptor production raised in the cancerous prostate. It also has been shown that there are endogenous compounds such as prostatic inhibin peptin that can modulate FSH levels. All of these findings are outlined in this paper, and suggest that FSH may affect the pathogenesis and progression of prostate cancer and that altering FSH production may prove to be an active therapeutic maneuver.

The natural history of prostate cancer has long been related to the male hormone testosterone, and treatment has focused on depletion of this androgen to slow or prevent growth of prostate cancer tissue. It has become clear recently, however, that more than androgens influence the progression of prostate cancer, with recent interest focusing on the gonadotropin, follicle-stimulating hormone (FSH). Research of the last decade has found that FSH is produced in and FSH receptors are expressed in the prostate. Investigators have found as well that production of FSH is altered in prostate cancer: FSH levels are increased and receptor production raised in the cancerous prostate. It also has been shown that there are endogenous compounds such as prostatic inhibin peptin that can modulate FSH levels. All of these findings are outlined in this paper, and suggest that FSH may affect the pathogenesis and progression of prostate cancer and that altering FSH production may prove to be an active therapeutic maneuver.

Although bone pain from osteoblastic metastases can be ameliorated 50% to 80% of the time by use of intravenously or orally administered radiopharmaceuticals, we cannot accurately predict who will or will not

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 greater than or equal to7 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. (C) 2001 Elsevier Science Inc.

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.

Background. Prostate cancer is the most frequently diagnosed malignancy in the Western countries. Apoptosis targeted drug development could represent a specific and effective weapon against the disease (Tang and Porter 32: 284-293, 1997). We previously demonstrated that the arachidonate 12-lipoxygenase and its metabolic products could function as survival factors for many solid tumors (Tang et al., Proc. Natl. Acad. Sci. USA 93: 5241-5246 1996; Tang and Honn, J. Cell. Physiol. 172: 155-170, 1997). Materials and Methods. In this study, we synthesized a series of novel cyclic hydroxamic acid compounds that demonstrated varying degrees of inhibitory effects on the arachidonate 12-lipoxygenase. Subsequently we studied the effects of these novel compounds on human prostate cancer cells. First, all these compounds were screened on androgen-independent PC3 adenocarcinoma cells. Second, based on the results (i.e., the LD(50) values) of the primary secondary and tertiary screening, lead compounds were determined Third the lead compounds were utilized to study their cytotoxic effects on various prostate cancer cells as well as several types of normal cells. Finally the molecular nature of the cell death was thoroughly characterized and the potential mechanisms of cell death were determined. Results. About 30% of the compounds screened induced a strong apoptotic death of androgen-independent prostate cancer cells, PC3, with an LD(50) mostly at 10 - 20 mu M. A lead compound BMD188 [cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one], was subsequently identified which inhibited the growth of PC3 cells with an LD(50) at similar to 10 mu M. Comparative studies indicated that BMD188 induced a more potent apoptotic response in PC3 cells than several conventional chemotherapeutic drugs. Furthermore, unlike the above drugs, BMD188 could induce 100% apoptosis in tumor cells. BMD188 also caused apoptosis of other types of prostate cancer cells including cells with multidrug resistance phenotype, independent of the androgen-dependence and p53 status. By contrast, BMD188 generally demonstrated 2-5 fold lower cytotoxicity towards sever al normal cell types including normal prostate epithelial cells. The growth inhibition by BMD188 was due to apoptosis induction as evidenced by DNA ladder formation PARP [poly(ADP-ribose) polymerase] cleavage, and typical apoptotic morphology. BMD188-induced apoptosis does not depend on its inhibitory effects on lipoxygenase since target cells (i.e., PC3 and Du145) did not express the lipoxygenase mRNA and protein. In contrast, the apoptosis-inducing effect of BMD188 in PC3 cells could be significantly inhibited by severe protease inhibitors TPCK and TLCK as well as by caspase inhibitors DEVD and zVAD. The involvement of caspases in the apoptotic effects of BMD188 was further confirmed by the activation of caspase-3 (CPP32). In the accompanying paper; we show that BMD188 also inhibits the primary growth and local invasion of Du145 prostate cancer cells orthotopically implanted into the SCID or athymic nude mice. Conclusion. The data presented here suggest that these novel cyclic hydroxamic acid compounds, via induction of apoptotic death, may find potential clinical applications in the treatment of human prostate cancers.

Purpose/Objective:To report the long term results of a randomized, clinical trial comparing neutron radiotherapy vs. photon radiotherapy for primary treatment of locally-advanced prostate cancer.

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.