Effects of Study Area Size on Geographic Characterizations of Health Events: Prostate Cancer Incidence in Southern New England, USA, 1994-1998.

ABSTRACT : BACKGROUND : We consider how representations of geographic variation in prostate cancer incidence across Southern New England, USA may be affected by selection of study area and/or properties of the statistical analysis. METHOD : A spatial scan statistic was used to monitor geographic variation among 35,167 incident prostate cancer cases diagnosed in Massachusetts, Connecticut and Rhode Island from 1994 to 1998, in relation to the 1990 populations of men 20+ years of age living in that region. Results from the combined-states analysis were compared to those from single-states. Impact of scanning procedures set to examine up to 50% or no more than10% of at-risk populations also was evaluated. RESULTS : With scanning set to 50%, 5 locations in the combined-states analysis were identified with markedly distinct incidence rates. Fewer than expected cases were estimated for nearly all Connecticut, Rhode Island and West Central Massachusetts, whereas census tracts on and around Cape Cod, and areas of Southwestern Connecticut and adjacent to greater Boston were estimated to have yielded more than expected incidence. Results of single-state analyses exhibited several discrepancies from the combined-states analysis. More conservative scanning found many more locations with varying incidence, but discrepancies between the combined- and single-state analysis were fewer. CONCLUSION : It is important to acknowledge the conditional nature of spatial analyses and carefully consider whether a true cluster of events is identified or artifact stemming from selection of study area size and/or scanning properties.

Calcium mobilization from the endoplasmic reticulum to the mitochondria during apoptosis in prostate cancer

Previous studies have implicated Ca2+ fluxes in the control of apoptosis but their exact roles in regulating the process remain obscure. Because Ca2+ can serve as a signal for cytochrome c release from isolated mitochondria, we hypothesized that alterations in intracellular Ca2+ compartmentalization might serve as a release signal in whole cells undergoing apoptosis. Exposure of human PC-3 prostate adenocarcinoma cells to staurosporine or DNA damaging agent (doxorubicin) but not to anti-Fas antibody led to early release of Ca2+ from the endoplasmic reticulum and subsequent accumulation of Ca2+ within mitochondria. Both events were blocked in cells stably transfected with Bcl-2 but were not affected by treatment with the pancaspase inhibitor, zVADfmk. The effects of staurosporine were associated with re-localization of Bax from the cytosol to both endoplasmic reticular and mitochondrial membranes. Neither ER Ca 2+ pool depletion nor mitochondrial Ca2+ uptake were observed in DU-145 cells that possess a frameshift mutation in the Bax gene unless wild-type Bax was restored via adenoviral gene transfer. Cytochrome c release and downstream features of apoptosis were attenuated by treatment with an inhibitor of mitochondria) Ca2+ uptake (RU-360). Although, direct pharmacological ER Ca2+ pool emptying in cells treated with thapsigargin did not lead to early cytochrome c release, pretreatment of cells with staurosporine dramatically sensitized mitochondria to thapsigargin-induced cytochrome c release. Together, our data demonstrate that ER-to-mitochondrial Ca2+ fluxes promote cytochrome c release and apoptosis in cells exposed to some (but not all) pro-apoptosic stimuli. ^

Bortezomib modulates TRAIL sensitivity in human bladder and prostate cancer

Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a member of the TNF superfamily of cytokines that can induce cell death through engagement of cognate death receptors. Unlike other death receptor ligands, it selectively kills tumor cells while sparing normal cells. Preclinical studies in non-human primates have generated much enthusiasm regarding its therapeutic potential. However, many human cancer cell lines exhibit significant resistance to TRAIL-induced apoptosis, and the molecular mechanisms underling this are controversial. Possible explanations are typically cell-type dependent, but include alterations of receptor expression, enhancement of pro-apoptotic intracellular signaling molecules, and reductions in anti-apoptotic proteins. We show here that the proteasome inhibitor bortezomib (Velcade, PS-341) produces synergistic apoptosis in both bladder and prostate cancer cell lines within 4-6 hours when co-treated with recombinant human TRAIL which is associated with accumulation of p21 and cdk1/2 inhibition. Our data suggest that bortezomib's mechanism of action involves a p21-dependent enhancement of caspase maturation. Furthermore, we found enhanced tumor cell death in in vivo models using athymic nude mice. This is associated with increases in caspase-8 and caspase-3 cleavage as well as significant reductions in microvessel density (MVD) and proliferation. Although TRAIL alone had less of an effect, its biological significance as a single agent requires further investigations. Toxicity studies reveal that the combination of bortezomib and rhTRAIL has fatal consequences that can be circumvented by altering treatment schedules. Based on our findings, we conclude that this strategy has significant therapeutic potential as an anti-cancer agent. ^

The role of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) in normal human prostate epithelial cells and prostate cancer development

15-Lipoxygenase 2 (15-LOX2) is a recently cloned human lipoxygenase that shows tissue-restricted expression in prostate, lung, skin, and cornea. The protein level and enzymatic activity of 15-LOX2 have been shown to be down-regulated in prostate cancers compared with normal and benign prostate tissues. We report the cloning and functional characterization of 15-LOX2 and its three splice variants (termed 15-LOX2sv-a, 15-LOX2sv-b, and 15-LOX2sv-c) from primary prostate epithelial (NHP) cells. Western blotting with multiple NHP cell strains and prostate cancer (PCa) cell lines reveals that the expression of 15-LOX2 is lost in all PCa cell lines, accompanied by decreased enzymatic activity. 15-LOX2 is expressed at multiple subcellular locations, including cytoplasm, cytoskeleton, cell-cell border, and nucleus. Surprisingly, the three splice variants of 15-LOX2 are mostly excluded from the nucleus. To elucidate the relationship between nuclear localization, enzymatic activity, and tumor suppressive functions, we established PCa cell clones stably expressing 15-LOX2 or 15-LOX2sv-b. The 15-LOX2 clones express 15-LOX2 in the nuclei and possess robust enzymatic activity, whereas 15-LOX2sv-b clones show neither nuclear protein localization nor arachidonic acid-metabolizing activity. Interestingly, both 15-LOX2- and 15-LOX2sv-b-stable clones proliferate much slower in vitro when compared with control clones. When orthotopically implanted in nude mouse prostate, both 15-LOX2 and 15-LOX2sv-b suppress PC3 tumor growth in vivo. Finally, cultured NHP cells lose the expression of putative stem/progenitor cell markers, slow down in proliferation, and enter senescence. Several pieces of evidence implicate 15-LOX2 plays a role in replicative senescence of NHP cells: (1) promoter activity and the mRNA and protein levels of 15-LOX2 and its splice variants are upregulated in serially passaged NHP cells, which precede replicative senescence and occur in a cell-autonomous manner; (2) PCa cells stably expressing 15-LOX2 or 15-LOX2sv-b show a passage-related senescence-like phenotype; (3) enforced expression of 15-LOX2 or 15-LOX2sv-b in young NHP cells induce partial cell-cycle arrest and senescence-like phenotypes. Together, these results suggest that 15-LOX2 suppress prostate tumor development and do not necessarily depend on arachidonic acid-metabolizing activity and nuclear localization. Also, 15-LOX2 may serve as an endogenous prostate senescence gene and its tumor-suppressing functions might be associated with its ability to induce cell senescence. ^

The effects of proteasome inhibition in chronic lymphocytic leukemia and prostate cancer

The use of proteasome inhibitors in cancer has received much attention with the recent FDA approval of bortezomib (Velcade/PS-341). However, in the chronic lymphocytic leukemia (CLL) clinical trial, bortezomib was not as effective as it was in vitro. Accordingly, results in prostate cancer were not remarkable, although regression of lymphadenopathy was observed. This response was also seen in CLL. ^ The proteasome degrades ∼80% of intracellular proteins. Although specific pathways affected by proteasome inhibitors are known, there are still unidentified mechanisms by which they induce apoptosis. The efficacy and mechanism of action of the reversible proteasome inhibitor bortezomib were compared to the novel irreversible inhibitor NPI-0052 in this study, and their mechanisms of action in CLL and prostate cancer were examined. ^ NPI-0052 inhibited proteasome activity and induced apoptosis with more rapid kinetics than bortezomib in CLL. Inhibition of proteasome activity with NPI-0052 was also more durable. Interestingly, bortezomib is cleared from the serum within 15min, which is insufficient time for bortezomib to effectively inhibit the proteasome. However, only 5min exposure was needed for NPI-0052 to produce maximal proteasome inhibition. The data suggest that bortezomib's slow kinetics and reversible nature limit its potential in vivo and the use of NPI-0052 should be considered. ^ In examining the mechanism(s) by which bortezomib and NPI-0052 induce apoptosis in CLL, both were found to elicit the ER stress pathway. A stromal cell co-culture system prevented apoptosis induced by both proteasome inhibitors, suggesting that if such factors in vivo were responsible for reducing bortezomib's efficacy, NPI-0052 would not prove useful either. Finally, Lyn, a Src family kinase (SFK), was decreased in response to bortezomib and NPI-0052 and correlated with apoptosis induction in CLL and prostate cancer. Both proteasome inhibitors specifically targeted Lyn rather than SFKs in general. ^ SFKs are overexpressed in cancer and involved in cell signaling, survival, and metastasis. In prostate cancer cells, both proteasome inhibition and Lyn-silencing significantly inhibited migration. Preliminary evidence also suggested that Lyn downregulation decreases invasion potential. Together, these data suggest that proteasome inhibitors are potential candidates for anti-metastasic therapy and further investigation is warranted for the use of Lyn-targeted therapy to treat metastases. ^

Patient perceptions of balance in prostate cancer screening decision aids

Purpose. Recent reports reveals that studies of decision aids reported concern about the balance and accuracy of information included in decision aids. This study explores measures of balance in patient decision aids through a review of prostate cancer screening decision aid studies and analysis of patients’ rating of a patient decision aid for prostate cancer screening. ^ Methods. A data-abstraction form was used to collect the key characteristics, pertaining to balance, of studies included in the review. The key characteristics included (1) sample characteristics (age, race, family history of prostate cancer, and education), (2) description of the decision aid and how it was implemented, and (3) if a measure of balance was used for process evaluation and the rating. A summary table was used to report the findings. Deidentified data was received from a decision aid control trial and logistic regression analysis was used to test the association between the dependent variable (balance) and the independent variables (age, family history, race, screening preference at baseline, education, health insurance status). ^ Conclusion. Three sociodemographic variables remained significant in the final regression model: African American race, education and PSA history. Further research is needed to determine if these variables can predict a man’s perception of balance in prostate cancer screening decision aids. If a patient’s perceptions of balance can be predicted based on specific characteristics, patient report may not be the most objective method of evaluating the acceptability of a decision.^

The effects of proteasome inhibition on angiogenesis and autophagy in human prostate cancer cells

The proteasome degrades approximately 80% of intracellular proteins to maintain homeostasis. Proteasome inhibition is a validated therapeutic strategy, and currently, proteasome inhibitor bortezomib is FDA approved for the treatment of MM and MCL. Specific pathways affected by proteasome inhibition have been identified, but mechanisms of the anti-tumor effects of proteasome inhibition are not fully characterized and cancer cells display marked heterogeneity in terms of their sensitivity to proteasome inhibitor induced cell death. ^ The antitumor effects of proteasome inhibition involve suppression of tumor angiogenesis and vascular endothelial growth factor (VEGF) expression, but the mechanisms involved have not been clarified. In this dissertation I investigated the mechanisms underlying the effects of two proteasome inhibitors, bortezomib and NPI-0052, on VEGF expression in human prostate cancer cells. I found that proteasome inhibitors selectively downregulated hypoxia inducible factor 1alpha (HIF-1α) protein and its transcriptional activity to inhibit VEGF expression. Mechanistic studies demonstrated that proteasome inhibitors mediate the induction of the unfolded protein response (UPR) and that downregulation of HIF-1α is caused by eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and translation repression. Importantly, I showed that proteasome inhibitors activated the UPR in some cells but not in others. My observation may have implications for the design of combination regimens that are based on exploiting proteasome inhibitor-induced ER stress.^ Although proteasome inhibitors have shown modest activity on prostate cancer, there is general consensus that no single agent is likely to have significant activity in prostate cancer. In the second part of this dissertation I attempted to exploit the effects of proteasome inhibition on the UPR to design a combination therapy that would enhance cancer cell death. Autophagy is a lysosome dependent degradation pathway that functions to eliminate long-lived protein and subcellular structures. Targeting autophagy has been shown to inhibit tumors in preclinical studies. I found that inhibition of autophagy with chloroquine or 3-methyladenine enhanced proteasome inhibitor induced cell death and the effects were associated with increased intracellular stress as marked by aggresome formation. Multiple cancers appear to be resistant to proteasome inhibition treatment alone. The implications of synergy for the combined inhibition of autophagy and the proteasome would likely apply to other cancers aside from prostate cancer. ^

Proton therapy versus intensity modulated x-ray therapy in the treatment of prostate cancer: Estimating secondary cancer risks

External beam radiation therapy is used to treat nearly half of the more than 200,000 new cases of prostate cancer diagnosed in the United States each year. During a radiation therapy treatment, healthy tissues in the path of the therapeutic beam are exposed to high doses. In addition, the whole body is exposed to a low-dose bath of unwanted scatter radiation from the pelvis and leakage radiation from the treatment unit. As a result, survivors of radiation therapy for prostate cancer face an elevated risk of developing a radiogenic second cancer. Recently, proton therapy has been shown to reduce the dose delivered by the therapeutic beam to normal tissues during treatment compared to intensity modulated x-ray therapy (IMXT, the current standard of care). However, the magnitude of stray radiation doses from proton therapy, and their impact on this incidence of radiogenic second cancers, was not known. ^ The risk of a radiogenic second cancer following proton therapy for prostate cancer relative to IMXT was determined for 3 patients of large, median, and small anatomical stature. Doses delivered to healthy tissues from the therapeutic beam were obtained from treatment planning system calculations. Stray doses from IMXT were taken from the literature, while stray doses from proton therapy were simulated using a Monte Carlo model of a passive scattering treatment unit and an anthropomorphic phantom. Baseline risk models were taken from the Biological Effects of Ionizing Radiation VII report. A sensitivity analysis was conducted to characterize the uncertainty of risk calculations to uncertainties in the risk model, the relative biological effectiveness (RBE) of neutrons for carcinogenesis, and inter-patient anatomical variations. ^ The risk projections revealed that proton therapy carries a lower risk for radiogenic second cancer incidence following prostate irradiation compared to IMXT. The sensitivity analysis revealed that the results of the risk analysis depended only weakly on uncertainties in the risk model and inter-patient variations. Second cancer risks were sensitive to changes in the RBE of neutrons. However, the findings of the study were qualitatively consistent for all patient sizes and risk models considered, and for all neutron RBE values less than 100. ^

Diabetes genes and risk of prostate cancer in the Atherosclerosis Risk in Communities study

Prostate cancer (PrCa) is a leading cause of morbidity and mortality, yet the etiology remains uncertain. Meta-analyses show that PrCa risk is reduced by 16% in men with type 2 diabetes (T2D), but the mechanism is unknown. Recent genome-wide association studies and meta-analyses have found single nucleotide polymorphisms (SNPs) that consistently predict T2D risk. We evaluated associations of incident PrCa with 14 T2D SNPs in the Atherosclerosis Risk in Communities (ARIC) study. From 1987-2000, there were 397 incident PrCa cases ascertained from state or local cancer registries among 6,642 men (1,560 blacks and 5,082 whites) aged 45-64 years at baseline. Genotypes were determined by TaqMan assay. Cox proportional hazards models were used to assess the association between PrCa and increasing number of T2D risk-raising alleles for individual SNPs and for genetic risk scores (GRS) comprised of the number of T2D risk-raising alleles across SNPs. Two-way gene-gene interactions were evaluated with likelihood ratio tests. Using additive genetic models, the T2D risk-raising allele was associated with significantly reduced risk of PrCa for IGF2BP2 rs4402960 (hazard ratio [HR]=0.79; P=0.07 among blacks only), SLC2A2 rs5400 (race-adjusted HR=0.85; P=0.05) and UCP2 rs660339 (race-adjusted HR=0.84; P=0.02), but significantly increased risk of PrCa for CAPN10 rs3792267 (race-adjusted HR=1.20; P=0.05). No other SNPs were associated with PrCa using an additive genetic model. However, at least one copy of the T2D risk-raising allele for TCF7L2 rs7903146 was associated with reduced PrCa risk using a dominant genetic model (race-adjusted HR=0.79; P=0.03). These results imply that the T2D-PrCa association may be partly due to shared genetic variation, but these results should be verified since multiple tests were performed. When the combined, additive effects of these SNPs were tested using a GRS, there was nearly a 10% reduction in risk of PrCa per T2D risk-raising allele (race-adjusted HR=0.92; P=0.02). SNPs in IGF2BP2, KCNJ11 and SLC2A2 were also involved in multiple synergistic gene-gene interactions on a multiplicative scale. In conclusion, it appears that the T2D-PrCa association may be due, in part, to common genetic variation. Further knowledge of T2D gene-PrCa mechanisms may improve understanding of PrCa etiology and may inform PrCa prevention and treatment.^

Sexually transmissible diseases, sexual factors and prostate cancer: A review of literature

A review of literature was carried out regarding sexually related factors, sexually transmissible diseases (STD's) and infections with prostate cancer (PC) development risk. The review of literature, in conjunction with the tabulation of studies, suggested that ejaculation and circumcision may play a protective role in the development of PC and that multiple sex partners and an active sex life may play a causal role in the development of PC which may negate and counteract the protective effects of ejaculation and circumcision. HIV infection may plausibly play a function in deteriorating and compromising immune controls on carcinogenesis. Because of the coexistence of a highly active sexual lifestyle and sexual promiscuity with the growing occurence of STD's, their maybe a correlation with the high incidence of prostate cancer in the United States. Potential multi-institutional studies are warranted to confirm the high incidence of this neoplasm with the increasing cases of STD's and if in fact there is a proportional association to further elucidate the factors responsible for its high incidence.^

The role of SRC family kinase activation in prostate cancer growth and lymph node metastasis

Aberrant expression and/or activation of Src Family of non-receptor protein tyrosine kinases (SFKs) occur frequently during progressive stages of multiple types of human malignancies, including prostate cancer. Two SFKs, Src and Lyn, are expressed and implicated in prostate cancer progression. Work in this dissertation investigated the specific roles of Src and Lyn in the prostate tumor progression, and the effects of SFK inhibition on prostate tumor growth and lymph node metastasis in pre-clinical mouse models. ^ Firstly, using a pharmacological inhibitor of SFKs in clinical trials, dasatinib, I demonstrated that SFK inhibition affects both cellular migration and proliferation in vitro. Systemic administration of dasatinib reduced primary tumor growth, as well as development of lymph node metastases, in both androgen-sensitive and -resistant orthotopic prostate cancer mouse models. Immunohistochemical analysis of the primary tumors revealed that dasatinib treatment decreased SFK phosphorylation but not expression, resulting in decreased cellular proliferation and increased apoptosis. For this analysis of immunohistochemical stained tissues, I developed a novel method of quantifying immunohistochemical stain intensity that greatly reduced the inherent bias in analyzing staining intensity. ^ To determine if Src and Lyn played overlapping or distinct roles in prostate cancer tumor growth and progression, Src expression alone was inhibited by small-interfering RNA. The resulting stable cell lines were decreased in migration, but not substantially affected in proliferation rates. In contrast, an analogous strategy targeting Lyn led to stable cell lines in which proliferation rates were significantly reduced. ^ Lastly, I tested the efficacy of a novel SFK inhibitor (KX2-391) targeting peptide substrate-binding domain, on prostate cancer growth and lymph node metastasis in vivo. I demonstrated that KX2-391 has similar effects as dasatinib, an ATP-competitive small molecular inhibitor, on both the primary tumor growth and development of lymph node metastasis in vivo, work that contributed to the first-in-man Phase I clinical trial of KX2-391. ^ In summary, studies in this dissertation provide the first demonstration that Src and Lyn activities affect different cellular functions required for prostate tumor growth and metastasis, and SFK inhibitors effectively reduce primary tumor growth and lymph node metastasis. Therefore, I conclude that SFKs are promising therapeutic targets for treatment of human prostate cancer. ^

Racial/ethnic differences in factors influencing screening and treatment among prostate cancer patients

Background. Racial/ethnic differences have been found in various aspects of cancer care. But a limited number of studies have examined the racial/ethnic differences in predictors of prostate-specific antigen (PSA) screening in a group of prostate cancer patients and have attempted to identify the racial/ethnic differences in treatment discussions, treatment choice and treatment received for organ-confined localized prostate cancer (PCa) among three major racial/ethnic groups of the USA. This study was conducted to redress this lack of information. ^ Methods. This study was conducted on a group of 935 prostate cancer patients representing all three major race/ethnic groups (Whites, African Americans and Hispanics) who were treated at various medical institutes of the Texas Medical Center, Houston between 1996 and 2004 to identify the racial/ethnic differences in predictors of PSA screening. A subset of 640 patients who had organ-confined localized prostate cancer was selected to examine the racial/ethnic differences in treatment discussions, treatment choice and treatment received for their localized prostate cancer. They were interviewed by trained research interviewers of MD Anderson Cancer Center using a validated structured questionnaire. ^ Results. The results showed that African American (54.4%) and Hispanic patients (42.3%) were significantly less likely (p=0.004 and p<.001, respectively) than White patients (63.2%) to report having had PSA screening before their prostate-cancer diagnosis. Among Whites, only education and annual check-ups predicted the use of PSA screening, whereas in African Americans two more additional factors, marital status and bode-mass index (BMI), significantly predicted PSA screening. Among Hispanics, like two other groups, education and annual check-ups also appeared as a significant predictor of PSA screening. ^ Results from multivariable logistic regression showed that African American patients were 15% less likely (OR=0.85, 95% CI=0.61-1.17, p=0.32) and Hispanics patients were 40% less likely (OR=0.60, 95% CI=0.41-0.87, p=0.008) to undergo PSA screening than Whites after adjusting for education and age at diagnosis for African Americans, and for education, annual check-ups and age at diagnosis for Hispanics. ^ This study revealed that health professionals were less likely to discuss surgery (79.9% vs. 93.2%) and watchful waiting (27.9% vs. 43.9%) with Hispanics compared to Whites. African Americans were more likely to choose (35.1% vs. 27.7%) and receive radiation therapy (38.3% vs.31.4%) than Whites. A comparison of concordance between treatment choice and treatment received showed that the highest concordance was found for watchful waiting and radiation therapy among African Americans (100% and 85.9%, respectively) whereas the highest concordance (96.9%) was found for surgery among Hispanics. ^ Conclusions. In this multiethnic study, the rates of PSA screening and its potential predictors varied by racial/ethnic groups. Substantial racial/ethnic variations were also found in treatment discussion, but the differences were not evident for treatment choice and treatment received. Health-education programs and culturally appropriate educational outreach efforts, especially targeted for high-risk groups, are needed to reduce these disparities. In the current climate of uncertainty about the benefits of PSA screening, or the benefit of one treatment over others, men should have access to information and services regardless of race/ethnicity so that they can make informed decisions. Further in-depth studies are needed in other settings to confirm these findings with the goal of developing an intervention to address these concerns. ^

Affect and cognition measures in preference-based decisions: Validity testing of the Ottawa Decisional Conflict Scale and a decision-specific anxiety measure with men eligible for prostate cancer screening

Background. At present, prostate cancer screening (PCS) guidelines require a discussion of risks, benefits, alternatives, and personal values, making decision aids an important tool to help convey information and to help clarify values. Objective: The overall goal of this study is to provide evidence of the reliability and validity of a PCS anxiety measure and the Decisional Conflict Scale (DCS). Methods. Using data from a randomized, controlled PCS decision aid trial that measured PCS anxiety at baseline and DCS at baseline (T0) and at two-weeks (T2), four psychometric properties were assessed: (1) internal consistency reliability, indicated by factor analysis intraclass correlations and Cronbach's α; (2) construct validity, indicated by patterns of Pearson correlations among subscales; (3) discriminant validity, indicated by the measure's ability to discriminate between undecided men and those with a definite screening intention; and (4) factor validity and invariance using confirmatory factor analyses (CFA). Results. The PCS anxiety measure had adequate internal consistency reliability and good construct and discriminant validity. CFAs indicated that the 3-factor model did not have adequate fit. CFAs for a general PCS anxiety measure and a PSA anxiety measure indicated adequate fit. The general PCS anxiety measure was invariant across clinics. The DCS had adequate internal consistency reliability except for the support subscale and had adequate discriminate validity. Good construct validity was found at the private clinic, but was only found for the feeling informed subscale at the public clinic. The traditional DCS did not have adequate fit at T0 or at T2. The alternative DCS had adequate fit at T0 but was not identified at T2. Factor loadings indicated that two subscales, feeling informed and feeling clear about values, were not distinct factors. Conclusions. Our general PCS anxiety measure can be used in PCS decision aid studies. The alternative DCS may be appropriate for men eligible for PCS. Implications: More emphasis needs to be placed on the development of PCS anxiety items relating to testing procedures. We recommend that the two DCS versions be validated in other samples of men eligible for PCS and in other health care decisions that involve uncertainty. ^

Impact of hormonal therapy on survival and racial disparities in a large community-based cohort of older men with local/regional prostate cancer

Prostate cancer (CaP) is the most diagnosed non-cutaneous malignancy and the second leading cause of cancer mortality among United States males. Major racial disparities in incidence, survival, as well as treatment persist. The mortality is three times higher among African Americans (AAs) compared with Caucasians. Androgen carcinogenesis has been persistently implicated but results are inconsistent; and hormone manipulation has been the main stay of treatment for metastatic disease, supportive of the androgen carcinogenesis. The survival disadvantage of AAs has been attributed to the differences in socioeconomic factors (SES), tumor stage, and treatment. We hypostasized that HT prolongs survival in CaP and that the racial disparities in survival is influenced by variation in HT and primary therapies as well as SES. To address these overall hypothesis, we first utilized a random-effect meta-analytic design to examine evidence from randomized trials on the efficacy of androgen deprivation therapy in localized and metastatic disease, and assessed, using Cox proportional hazards models, the effectiveness of HT in prolonging survival in a large community-based cohort of older males diagnosed with local/regional CaP. Further we examined the role of HT and primary therapies on the racial disparities in CaP survival. The results indicated that adjuvant HT compared with standard care alone is efficacious in improving overall survival, whereas HT has no significant benefit in the real world experience in increasing the overall survival of older males in the community treated for local/regional disease. Further, racial differences in survival persist and were explained to some extent by the differences in the primary therapies (radical prostatectomy, radiation and watchful waiting) and largely by SES. Therefore, given the increased used of hormonal therapy and the cost-effectiveness today, more RCTs are needed to assess whether or not survival prolongation translates to improved quality of life, and to answer the research question on whether or not the decreased use of radical prostatectomy by AAs is driven by the Clinicians bias or AAs's preference of conservative therapy and to encourage AAs to seek curative therapies, thus narrowing to some degree the persistent mortality disparities between AAs and Caucasians. ^

Treatment discontinuation among breast, colorectal, and prostate cancer patients in Alabama

Introduction. Cancer registries provide information about treatment initiation but not the full course of treatment. In an effort to identify patient reported reasons for discontinuing cancer treatment, patients with prostate, breast, and colorectal cancer were identified from Alabama State Cancer Registry (ASCR) -Alabama Medicare linked database for interview. This study has two specific aims: (1) determine whether the ASCR-Medicare database accurately reflects patients’ treatment experiences in terms of whether they started and completed treatment when compared to patient self-report and (2) determine which patient demographic and health care system factors are related to treatment completion as defined by patient self-report. ^ Methods. The ASCR-Medicare claims dataset supplemented patient interview responses to identify treatment initiation and completion among prostate, breast, and colorectal cancer patients in Alabama from 1999-2003. Kappa statistic was used to test for concordance of treatment initiation and completion between patient self-report and Medicare claims data. Patients who reported not completing treatment were asked questions to ascertain reasons for treatment discontinuation. Logistic regression models were constructed to explore the association of patient and tumor characteristics with discontinuation of radiation and chemotherapy. ^ Results. Overall, there was a fair agreement across all cancer sites about whether one had surgery (Kappa=.382). There was fair agreement between self-report and Medicare claims data for starting radiation treatment (Kappa=.278). For starting chemotherapy there was moderate agreement (Kappa=.414). There was no agreement for completing treatment for radiation and chemotherapy between the self-report and claims data. Patients most often reported doctor’s recommendation (40% for radiation treatment and 21.4% for chemotherapy) and side effects (30% for radiation treatment and 42.8% for chemotherapy) for discontinuing treatment. Females were less likely to complete radiation than males (OR=.24, 95% CI=.11–.50). Stage I patients were more likely to drop radiation treatment than stage III patients (OR=3.34, 95% CI=1.12–9.95). Younger patients were more likely to discontinue chemotherapy than older patients (OR=2.84 95%, CI=1.08–7.69) and breast cancer patients were less likely to discontinue chemotherapy than colorectal patients (OR=.13, 95% CI=.04–.46). ^ Conclusion. This study reveals that patients recall starting treatment more accurately than completing treatment and that there are several demographic and tumor characteristics that influence treatment discontinuation. Providing patients with treatment summaries and survivorship plans can help patients their follow-up care when there are gaps in treatment recall and discontinuation of treatment.^