The effect of osteoprotegerin administration on the intra-tibial growth of the osteoblastic LuCaP 23.1 prostate cancer xenograft

Osteoprotegerin (OPG) plays a central role in controlling bone resorption. Exogenous administration of OPG has been shown to be effective in preventing osteolysis and limiting the growth of osteolytic metastasis. The objective of this study was to investigate the effects of OPG on osteoblastic prostate cancer (CaP) metastases in an animal model. LuCaP 23.1 cells were injected intra-tibially and Fc-OPG (6.0 mg/kg) was administered subcutaneously three times a week starting either 24 hours prior to cell injection (prevention regimen) or at 4 weeks post-injection (treatment regimen). Changes in bone mineral density at the tumor site were determined by dual x-ray absorptiometry. Tumor growth was monitored by evaluating serum prostate specific antigen (PSA). Fc-OPG did not inhibit establishment of osteoblastic bone lesions of LuCaP 23.1, but it decreased growth of the tumor cells, as determined by decreases in serum PSA levels of 73.0 ± 44.3% (P < 0.001) and 78.3 ± 25.3% (P < 0.001) under the treatment and prevention regimens, respectively, compared to the untreated tumor-bearing animals. Administration of Fc-OPG decreased the proliferative index by 35.0% (P = 0.1838) in the treatment group, and 75.2% (P = 0.0358) in the prevention group. The results of this study suggest a potential role for OPG in the treatment of established osteoblastic CaP bone metastases.     

Evidence of prostate cancer screening in a UK region

OBJECTIVE: To examine the pattern of use of prostate-specific antigen (PSA) testing in a UK region, where National Health Service policy does not recommend screening for prostate cancer. SUBJECTS AND METHODS: Data were collected on all PSA tests in Northern Ireland between 1990 and 1999. Annual rates of PSA testing were calculated by age, GP Practice and year. RESULTS: In all, 165 862 PSA tests were performed on 84 669 men, and over a third of men aged > or = 50 years had at least one PSA test. Men aged < 50 years accounted for 12.9% of first tests. The proportion of tests from primary care increased from 47.2% in 1993 to 67.0% in 1999. The mean age of men tested once decreased from 65.6 to 61.9 years (P trend < 0.001) and the proportion with an elevated PSA level also declined during the period. Repeat testing increased with PSA level (P < 0.001) but 29.4% of men with a PSA level of < or = 4 ng/mL also had repeat testing. Raised PSA values were more common from hospital than primary care (32.4% vs 20.6%, P < 0.001) and in older men. Test rates varied 100-fold across general practices, a finding not explained by sociodemographic factors, but one which reflects differential adherence to national guidelines, suggesting that general practitioners are key targets for attempting to rationalise the use of the PSA test. CONCLUSION: These findings suggest that PSA screening is taking place against evidence-based advice and has resulted in over 20 000 men being designated as having a raised PSA level, creating a need for further assessment.     

Capecitabine in hormone-resistant metastatic prostatic carcinoma - a phase II trial

The objective of the trial is to evaluate the efficacy of capecitabine in patients with metastatic hormone-resistant prostate carcinoma (HRPC), in terms of prostate-specific antigen (PSA) response and clinical benefit (decrease of pain or analgesic score) and its safety profile. In all, 25 patients with HRPC were enrolled on a phase II trial of capecitabine (Xeloda) at a dose of 1250 mg m(-2) orally twice daily on days 1-14 every 21 days. The inclusion criteria were PSA serum levels >3 x upper limit of normal, a WHO performance status 0-2, age <85 years and adequate bone marrow, liver and renal function. In patients with grade 2 or higher haematological toxicity on day 1 of the treatment cycle, therapy was first delayed, and then continued at a lower dose. Trial end points were PSA response and clinical benefit defined by quality of life (QL) data and analgesic consumption. The median age of patients was 70 years (range 54-85 years). A median of three cycles of capecitabine was administered (range 1-8). PSA response was observed in three patients (12%, 95% CI 3-31%), with times to tumour progression of 18, 21 and 35 weeks, respectively. In these patients, the response durations were 12, 17 and 32 weeks, respectively. Minor PSA regression was also seen in two further patients. The median time to tumour progression of all patients was 12 weeks (95% CI 9-15 weeks). Haematological toxicity was minor, with leukopenia grade 3 observed in one patient. There were three deaths during trial treatment, respectively, due to sepsis following mucositis and leukopenia, presumed sepsis with mucositis induced by chemotherapy and concomitant radiotherapy and cerebral dysfunction progressing to coma. Hand-foot syndrome grades 2 and 3 were observed in four patients each. Clinical benefit was observed in five patients (20%, CI 7-41%). Based on toxicity data, we recommend a lower starting dose of 1000 mg x m(-2) orally twice daily. While capecitabine has some activity in HRPC, as suggested by observed PSA responses, we conclude that it is not worthwhile to investigate capecitabine monotherapy in a phase III trial. Combinations of capecitabine with other agents, such as vinorelbine or docetaxel, may prove to be more effective.     

International Trends in Prostate-Cancer Mortality: The Decrease is Continuing and Spreading

OBJECTIVE: To measure recent changes in prostate-cancer mortality across 24 developed countries. METHODS: Mortality data for men aged 50-79 years were obtained from the World Health Organisation mortality database and we assessed trends in age-standardised mortality rates using joinpoint regression models. RESULTS: Significant reductions in prostate-cancer mortality were observed in United Kingdom, United States, Austria, Canada, Italy, France, Germany, Australia and Spain, and downward trends were also observable in the Netherlands, Ireland and Sweden. CONCLUSIONS: Mortality declines for prostate cancer are now evident in 12 out of the 24 developed countries considered in this analysis. Increases in PSA screening and better treatment of early-stage disease, possibly acting in combination, remain plausible hypotheses.     

Serum human glandular kallikrein (hK2) and insulin-like growth factor 1 (IGF-1) improve the discrimination between prostate cancer and benign prostatic hyperplasia in combination with total and %free PSA

BACKGROUND: There is growing evidence describing an association of hK2 and IGFs with cancer. The aim of this study is to investigate the differences in serum levels of hK2 and IGFs in a large group of patients with benign prostatic hyperplasia (BPH) or prostatic carcinoma (CaP) and to examine the value of these variables, as well as their various combinations with PSA, for discriminating between these two clinical entities. METHODS: Human glandular kallikrein 2 (hK2), insulin-like growth factor-1 (IGF-1), free and total PSA concentrations were measured with non-competitive immunological procedures. Receiver operating characteristic (ROC) analysis as well as univariate and multivariate logistic regression analysis were performed to investigate the potential utility of the various markers and their combinations for discriminating between BPH and CaP. RESULTS: hK2 and IGF-1 concentrations were increased in CaP patients, in comparison to BPH patients. hK2/free PSA and free/total PSA ratios (area under the curve, AUC = 0.70) were stronger predictors of prostate cancer than the IGF-1/total PSA ratio (AUC = 0.56) in the group of patients with total PSA <4 microg/L. The hK2/free PSA ratio (AUC = 0.74) was found to have significant discriminatory value in patients with total PSA within the "gray zone" (4-10 microg/L). Multivariate logistic regression models confirmed the observed relationships and identified IGF-1/free PSA and hK2/free PSA as independent predictors of CaP. CONCLUSIONS: hK2/free PSA and IGF-1/free PSA ratios may be useful adjuncts in improving patient selection for prostate biopsy.     

Prediction of extraprostatic cancer by prostate specific antigen density,endorectal MRI,and biopsy Gleason score in clinically localized prostate cancer

BACKGROUNDS: The present study was designed to identify the preoperative parameters, including PSA-based parameters, and endorectal MRI, predictive of pathological stage in males who underwent radical prostatectomy. METHODS: We studied 114 patients who underwent radical retropubic prostatectomy and pelvic lymphadenectomy for clinically localized prostate cancer. Clinical stage was assessed by DRE, pelvic CT scan, endorectal MRI, and bone scan. The correlation between the preoperative parameters, including PSA-based parameters, clinical stage, and histological findings of biopsy specimens, and the pathological stage was analyzed. Logistic regression analysis was performed to identify a significant set of independent predictors for local extent of disease. RESULTS: Seventy-six (66.6%) patients had organ confined cancer and 38 (33.4%) patients had extraprostatic cancer. Of the 38 patients with extraprostatic cancer, four had seminal vesicle involvement, while, none had pelvic lymph node involvement. Biopsy Gleason score, PSA, PSA-alpha1-antichymotrypsin (PSA-ACT), PSA-density (PSAD), PSA-transition zone density, PSA-ACT density, and PSA-ACT transition zone (TZ) density were significantly higher and percent free PSA was lower in the patients with organ confined cancer than those with extraprostatic cancer (P < 0.01). PSAD showed the largest area under the ROC curve (AUC) among those parameters (AUC = 0.732). Sixty-eight (74.7%) of 91 patients with T2 on endorectal MRI had organ confined cancer, while 15 (65.2%) of 23 patients with T3 had extraprostatic cancer (P < 0.01). Multivariate logistic regression analysis indicated that Gleason score (> or =7 vs. < or =6), endorectal MRI findings, and PSAD were significant predictors of extraprostatic cancer (P < 0.01). CONCLUSIONS: The present study demonstrated that preoperative PSAD was the most valuable predictor among PSA-based parameters for extraprostatic disease in patients with clinically localized prostate cancer. The combination of PSAD, endorectal MRI findings, and biopsy Gleason score can provide additional information for selecting appropriate candidates for radical prostatectomy.     

Metastatic prostate cancer with normal level of serum prostate-specific antigen

The clinical and pathological features of metastatic prostate cancer with normal level of serum prostate-specific antigen (PSA) were investigated. Four patients with metastatic prostate cancer had serum PSA within the normal range at the diagnosis. All tumors were poorly-differentiated adenocarcinoma. Endocrine therapy was performed as the initial therapy in all patients. Despite subsequently treatment, all cases died of prostate cancer at 2, 8, 9 and 38 months. During disease progression, 3 of 4 patients had elevated serum markers such as carcinoembryonic antigen (CEA), CA19-9, CA15-3, CA125, neuron-specific enolase and pro-gastrin releasing peptide. Immunohistochemical examination of the initial biopsy specimens revealed that 4 and 3 cases were positive for CEA and chromogranin A, respectively. In advanced prostate cancer patients with low PSA level, those markers may aid in the follow up of disease.     

GP and patient predictors of PSA screening in Australian general practice

OBJECTIVE: We determined GP and patient variables associated first with men's prior uptake of prostate-specific antigen (PSA) screening and, subsequently, its initiation during an 'index consultation' in Australian general practice. METHODS: From the practices of 60 GPs, we recruited a sample of 423 male patients aged 40-70 years. In a waiting room questionnaire completed before their 'index consultation' (retrospective component), men reported their previous PSA screening status. We obtained demographic and clinical data, including the presence of lower urinary tract symptoms (LUTS). Men also were mailed a questionnaire 2 days after their 'index consultation' to ascertain whether the GP had discussed PSA screening (prospective component) for prostate cancer and other behaviours. GPs themselves completed questionnaires eliciting demographic and practice characteristics as well as their propensity to screen and understanding of the evidence about PSA testing. GP and patient study variables were modelled simultaneously in analyses. RESULTS: Of those 348 men consulting with their regular GP, 80 (23.0%) reported previously having had a PSA screening test. Men were significantly and independently more likely ever to have had PSA screening if their regular GP reported a propensity to initiate screening [adjusted odds ratio (AOR) = 2.27, 95% confidence interval (CI) 1.23-4.20; P = 0.009]. GP age also was independently associated with men's PSA screening status [chi-squared (3) P < 0.0001] as was men's age and severity of LUTS (AOR = 2.38, 95% CI 1.58-3.57, P < 0.0001 and AOR = 1.79, 95% CI 1.00-3.19, P = 0.004, respectively). Current smokers were less likely ever to have had a PSA screening test (AOR = 0.34, 95% CI 0.16-0.69; P = 0.003). Discussion of PSA screening in their 'index consultation' was recalled independently more often by older men (AOR = 1.46, 95% CI 1.00-2.13; P = 0.04), those with moderate/severe LUTS (AOR = 1.94, 1.07-3.49; P = 0.04), those whose GP had performed or discussed a cholesterol test (AOR = 2.26, 95% CI 1.03-4.92; P = 0.04) and those whose GP had postgraduate training in family medicine (AOR = 3.13, 95% CI 1.23-8.00; P = 0.02). CONCLUSION: In the absence as yet of compelling evidence that PSA screening will prolong life or enhance its quality, our findings identify GP and patient factors that could be targeted to modify PSA screening.     

Promoting better use of the PSA test in general practice: randomized controlled trial of educational strategies based on outreach visits and mailout

BACKGROUND: Prostate-specific antigen (PSA) testing for prostate cancer is controversial. Demand for PSA testing is likely to rise in the UK, Australia and other western countries. Primary care needs to develop appropriate strategies to respond to this demand. OBJECTIVES: Our aim was to compare the effectiveness of educational outreach visits (EOVs) and mailout strategies targeting PSA testing in Australian primary care. METHODS: A randomized controlled trial was conducted in general practices in southern Adelaide. The main outcome measures at baseline, 6 months and 12 months post-intervention were PSA testing rates and GP knowledge in key areas relating to prostate cancer and PSA testing. RESULTS: The interventions were able to demonstrate a change in clinical practice. In the 6 months post-intervention, median PSA testing rate in the EOV group was significantly lower than in the postal group, which in turn was significantly lower than the control group (P < 0.001). Statistically significant differences were not, however, maintained in the 6-12 month post-intervention period. The EOV group, at 6 months follow-up, had a significantly greater proportion of "correct" responses than the control group to questions about prostate cancer treatment effectiveness (P = 0.004) and endorsement of PSA screening by professional bodies (P = 0.041). CONCLUSIONS: Primary care has a central role in PSA testing for prostate cancer. Clinical practice in this area is receptive to evidence-based interventions.     

Statistical validation based on parametric receiver operating characteristic analysis of continuous classification data

Rationale and Objectives. The accuracy of diagnostic test and imaging segmentation is important in clinical practice because it has a direct impact on therapeutic planning. Statistical validations of classification accuracy was conducted based on parametric receiver operating characteristic analysis, illustrated on three radiologic examples.

Materials and Methods. Two parametric models were developed for diagnostic or imaging data. Example 1: A semi-automated fractional segmentation algorithm was applied to magnetic resonance imaging of nine cases of brain tumors. The tumor and background pixel data were assumed to have bi-beta distributions. Fractional segmentation was validated against an estimated composite pixel-wise gold standard based on multi-reader manual segmentations. Example 2: The predictive value of 100 cases of spiral computed tomography of ureteral stone sizes, distributed as bi-normal after a nonlinear transformation, under two treatment options received. Example 3: One hundred eighty cases had prostate-specific antigen levels measured in a prospective clinical trial. Radical prostatectomy was performed in all to provide a binary gold standard of local and advanced cancer stages. Prostate-specific antigen level was transformed and modeled by bi-normal distributions. In all examples, areas under the receiver operating characteristic curves were computed.

Results. The areas under the receiver operating characteristic curves were: Example 1: Fractional segmentation of magnetic resonance imaging of brain tumors: meningiomas (0.924–0.984); astrocytomas (0.786–0.986); and other low-grade gliomas (0.896–0.983). Example 3: Ureteral stone size for treatment planning (0.813). Example 2: Prostate-specific antigen for staging prostate cancer (0.768).

Conclusion. All clinical examples yielded fair to excellent accuracy. The validation metric area under the receiver operating characteristic curves may be generalized to evaluating the performances of several continuous classifiers related to imaging.