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Screening for Prostate Cancer

Raised levels of prostate-specific antigen (PSA) are a common symptom of prostate cancer, however, it can be caused by other conditions too. Routinely screening of all men to check their levels of PSA is a controversial subject across the international medical community, healthcare providers and advocacy groups. This is because there are many risks (including invasive tests, 'false positives', unnecessary treatment and side effects) as well as potential benefits (earlier detection of disease when it is still curable), and the PSA test does not differentiate between slow growing tumours which may never need treatment and more aggressive prostate cancer. Research into better tests is needed.

Current policies vary between different countries. Some advocates recommend all men over 50 have an annual PSA test, many countries recommend against regular mass screening, but increasingly UK and recent US recommendations are for PSA testing to be a individual's decision to make an informed choice. It is complex and best discussed with your doctor.

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Prostate Cancer
Cancer Screening and Early Detection

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  • PubMed search for publications about Prostate Cancer Screening / PSA test - Limit search to: [Reviews]

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    MeSH term: Prostatic Neoplasms
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Shukla P, Mathur V, Kumar A, et al.
Nanoemulsion based concomitant delivery of curcumin and etoposide: impact on cross talk between prostate cancer cells and osteoblast during metastasis.
J Biomed Nanotechnol. 2014; 10(11):3381-91 [PubMed] Related Publications
An attempt has been made to use curcumin (CUR) in combination with Etoposide (ETP) by encapsulating in nanoemulsion, as two tier approach i.e., to evaluate improvement in efficacy of ETP on prostate cancer cells (PC3 and DU145) and to assess their effect on cross-talk between osteoblast and tumor cells leading to metastatic cascade in bones. Nanoemulsion was developed and evaluated for size, charge, in-vitro drug release and anticancer activity, effect on cross talk between osteoblast and prostate cancer cells and pharmacokinetics in rats. The entrapment efficiency of both ETP and CUR in nanoemulsion was more than 98% while the globule size was less than 150 nm with zeta potential - 29.8 mV. The percent inhibition in case of ETP and ETP: CUR (1:3 w/w) was 55.92 ± 1.2 and 41.13 ± 2.4% (at 5 μM) respectively when tested in PC3 cells. DU-145 seemed to be less responsive in comparison to PC3 cells both in respect of ETP and their mixture (ETP+ CUR). Our data shows that CUR and ETP after encapsulation in nanoemulsion (F5) were effectively delivered intracellularly in PC3 cells and the cytotoxicity of F5 was enhanced by 1.5 fold as compared to ETP + CUR at 5 μM concentration. It has also been observed that mice calvarial osteoblasts cultured and incubated with PC-3 and DU-145 cells conditioned media induces inhibition of osteoblast differentiation event. While this inhibition was significantly reversed by F5 at 5 μM concentration over other treated groups, the pharmacokinetic profile of both ETP and CUR was also significantly improved when administered in nanoemulsion.

McClure P, Elnakib A, Abou El-Ghar M, et al.
In-vitro and in-vivo diagnostic techniques for prostate cancer: a review.
J Biomed Nanotechnol. 2014; 10(10):2747-77 [PubMed] Related Publications
This paper overviews one of the most important, interesting, and challenging problems in oncology, early diagnosis of prostate cancer. Developing effective diagnostic techniques for prostate cancer is of great clinical importance and can improve the effectiveness of treatment and increase the patient's chance of survival. The main focus of this study is to overview the different in-vitro and in-vivo technologies for diagnosing prostate cancer. This review discusses the current clinically used in-vitro cancer diagnostic tools, such as biomarker tests and needle biopsies and including their applications, advantages, and limitations. Moreover, the current in-vitro research tools that focus on the role of nanotechnology in prostate cancer diagnosis have been detailed. In addition to the in-vitro techniques, the current study discusses in detail developed in-vivo non-invasive state-of-the-art Computer-Aided Diagnosis (CAD) systems for prostate cancer based on analyzing Transrectal Ultrasound (TRUS) and different types of magnetic resonance imaging (MRI), e.g., T2-MRI, Diffusion Weighted Imaging (DWI), Dynamic Contrast Enhanced (DCE)-MRI, and multi-parametric MRI, focusing on their implementation, experimental procedures, and reported outcomes. Furthermore, the paper addresses the limitations of the current prostate cancer diagnostic techniques, outlines the challenges that these techniques face, and introduces the recent trends to solve these challenges, which include biomarkers used in in-vitro lab-on-a-chip nanotechnology-based methods.

Galunska B, Gerova D, Kosev P, et al.
Serum 25-hydroxy vitamin D levels in Bulgarian patients with prostate cancer: a pilot study.
Clin Lab. 2015; 61(3-4):329-35 [PubMed] Related Publications
BACKGROUND: The antiproliferative effect of the active form of vitamin D on cancer cells and its ability to induce cell differentiation and suppression of tumor-induced angiogenesis in the last decade has provoked enormous research for the elucidation of its role in the prevention of different types of cancer and in slowing down the malignancy progression. The aim of the present pilot study was to determine the circulating 25-hydroxy vitamin D (25OHD) levels in Bulgarian prostate cancer (PCa) patients and to investigate their relationship with various determinants associated with the severity and progression of the disease.
METHODS: A total of 53 male patients (mean age 67.0 ± 7.1 years) with clinical suspicion for PCa were enrolled in the study. All patients were subjected to systemic transrectal ultrasound-guided tru-cut prostate biopsies (10 cores at least). Detected tumors were graded using the Gleason grading system. Prostate specific antigen (PSA) serum levels were measured immunochemically. The 25OHD assay was performed by a validated HPLC-UV method. Other covariates (BMI, age, family history of PCa) were collected by interview at the time of hospitalization. One-way ANOVA with Kruskal Wallis statistics was used for comparison of medians of different parameters. The level of significance was set at p < 0.05.
RESULTS: Significantly lower 25OHD levels were detected in PCa patients compared to those with benign prostate hyperplasia (BPH) (p < 0.05). Patients with high grade tumors (Gleason score ≥ 7) showed significantly lower 25OHD levels, while those with low grade tumors (Gleason score < 7) revealed better 25OHD status (50.49 vs. 63.17 nmol/L, p < 0.05). A moderate negative correlation between 25OHD levels and the Gleason score was established (Spearman r = -0.46, p < 0.05). Significant seasonal variations in 25OHD levels, both for PCa and BPH patients, were detected (p < 0.01).
CONCLUSIONS: This preliminary study shows an association between 25OHD status and classical markers characterizing the severity of PCa. The results might suggest a potential beneficial role of vitamin D for PCa patients. Further prospective studies are needed to strengthen the interrelationships between 25OHD levels and variables related with PCa and to test them for causality.

Sedelaar JP, Schalken JA
The need for a personalized approach for prostate cancer management.
BMC Med. 2015; 13:109 [PubMed] Free Access to Full Article Related Publications
The stratification of patients for treatment of prostate cancer is based on very general parameters like prostate-specific antigen, Gleason score, and TNM classification. We use these rough parameters for selection of active surveillance, active treatment, and even for the treatment selection in metastasized or castration-resistant prostate cancers. Up to now, we have not used individualized genetic classifiers for detailed sub-stratification, thus treating all patients as equal, and being only moderately successful. With the expected increase in systemic treatments, there is an apparent need for such classifiers. We will address these needs in this short commentary.

Shah M, Denlinger CS
Optimal post-treatment surveillance in cancer survivors: is more really better?
Oncology (Williston Park). 2015; 29(4):230-40 [PubMed] Related Publications
A substantial rise in the number of cancer survivors has led to management questions regarding effective post-treatment surveillance strategies. Although a number of professional societies have proposed surveillance guidelines, clinical practice varies; the general trend is toward more intensive strategies. The evidence supporting intensive surveillance is relatively lacking, with most studies showing that more intense surveillance regimens have minimal, if any, impact on outcomes in terms of survival, quality of life, or overall cost-effectiveness. This has been demonstrated in breast cancer, and data supporting a similar conclusion may be evolving in colorectal cancer, where large prospective studies call into question the utility of intensive surveillance; in prostate cancer, retrospective data suggest a similar trend. In this review, we discuss the established guidelines and current evidence regarding post-treatment surveillance, and we propose general management strategies in prostate, colorectal, and breast cancers.

Raslau D, Summerfield DT, Abu Dabrh AM, et al.
The risk of prostate cancer in pilots: a meta-analysis.
Aerosp Med Hum Perform. 2015; 86(2):112-7 [PubMed] Related Publications
BACKGROUND: Aviation exposes pilots to various occupationally related hazards, including ionizing radiation and chemical combustion. The possible increased risk of prostate cancer among pilots in comparison to the general population is a subject of debate. This systematic review and meta-analysis aimed to determine the quality of supporting evidence and magnitude of this association.
METHODS: All studies pertaining to prostate cancer in pilots were retrieved from multiple databases and from a manual search. Any study that assessed the incidence of prostate cancer relative to the incidence in the general population was included regardless of language or size. A random effect model was used to pool relative risks (RR) across studies. Heterogeneity was assessed using the Q statistic and I².
RESULTS: Eight studies with a low risk of bias were included in the meta-analysis. Pilots had an increased risk of developing prostate cancer compared to the general population [RR 2.0; 95% confidence interval (CI), 1.5-2.7]. The analysis was associated with substantial heterogeneity (I² = 79%). Several subgroups had significantly increased risk, such as African American pilots (RR 10.00; 95% CI, 5.04-19.86) and military pilots (RR 3.30; 95% CI, 2.03-5.39).
CONCLUSION: Pilots are at least twice as likely to develop prostate cancer compared to the general population. The implications of these findings are important considering the high prevalence of prostate cancer and the large number of pilots in the workforce.

Nishikawa M, Miyake H, Fujisawa M
Enhanced Sensitivity to Sunitinib by Inhibition of Akt1 Expression in Human Castration-resistant Prostate Cancer PC3 Cells Both In Vitro and In Vivo.
Urology. 2015; 85(5):1215.e1-7 [PubMed] Related Publications
OBJECTIVE: To investigate whether antitumor activity of sunitinib is enhanced by silencing Akt1 in a human castration-resistant prostate cancer PC3 model.
MATERIALS AND METHODS: We initially established PC3 in which the expression vector containing a short hairpin ribonucleic acid targeting Akt1 was introduced (PC3/sh-Akt1). Changes in various phenotypes of PC3/sh-Akt1 after treatment with sunitinib were compared with those of PC3 transfected with control vector alone (PC3/C) both in vitro and in vivo.
RESULTS: When cultured in the standard medium, in vitro growth of PC3/sh-Akt1 was almost similar to that of PC3/C. However, compared with PC3/C, PC3/sh-Akt1 showed a significantly higher sensitivity to sunitinib, accompanying impaired phosphorylation of p44/42 mitogen-activated protein kinase, downregulation of Bcl-2, and upregulation of Bax. In addition, treatment with sunitinib significantly suppressed the migration ability of PC3/sh-Akt1 compared with that of PC3/C. In vivo, administration of sunitinib induced the significantly marked growth inhibition of PC3/sh-Akt1 compared with that of PC3/C, and apoptotic index in PC3/sh-Akt1 tumor in mice treated with sunitinib was significantly greater than that in PC3/C tumor.
CONCLUSION: Combined treatment with Akt1 inhibitor and sunitinib could be a promising therapeutic approach for men with castration-resistant prostate cancer.

Boniol M, Autier P, Perrin P, Boyle P
Variation of Prostate-specific Antigen Value in Men and Risk of High-grade Prostate Cancer: Analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Study.
Urology. 2015; 85(5):1117-22 [PubMed] Related Publications
OBJECTIVE: To investigate variations in prostate-specific antigen (PSA) levels among men with an initial normal PSA level in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial study.
METHODS: Data were extracted from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial study data set on all men in the interventional arm, with 2 tests performed in a period of < 2 years and with an initial result of the first test <4 ng/mL. The range of variation between first and second tests was computed. Risks of cancer stratified on Gleason score were computed using logistic regression.
RESULTS: A total of 31,286 men had 2 PSA tests within 2 years and with an initial value < 4 ng/mL. From the first to the second test, the median variation of PSA levels was 3.4% (interquartile range, -15% to +26%). The variation in PSA value was not associated with the delay between the first and the second test (P = .36), age (P = .16), body mass index (P = .41), and race (P = .12). A total of 2,781 prostate cancers were diagnosed during follow-up. Adjusting for age and initial PSA level, the risk of prostate cancer increased linearly with increasing PSA level at the second test, with an odds ratio of 1.079 (95% confidence interval, 1.058-1.101) for each percent increase in PSA level. However, the variation in PSA was not associated with a higher Gleason score (P = .95 for level variations in cancer of Gleason score < 7 vs ≥ 7).
CONCLUSION: Although an increase in PSA level over time is associated with increased risk of prostate cancer, this association is not related to more aggressive tumors.

Mok Y, Kimm H, Shin SY, et al.
Screening Prostate-specific Antigen Concentration and Prostate Cancer Mortality: The Korean Heart Study.
Urology. 2015; 85(5):1111-6 [PubMed] Related Publications
OBJECTIVE: To evaluate the association between serum prostate-specific antigen (PSA) concentration from a screening test and prostate cancer mortality in an Asian population.
METHODS: We included 118,665 men in the Korean Heart Study, a large prospective cohort study of participants who voluntarily underwent private health examinations that included PSA-based prostate cancer screening. The baseline visit occurred between January 1994 and December 2004, and follow-up was through December 2011. Deaths from prostate cancer were ascertained from the underlying cause of death from a computerized search of death certificate data from the National Statistical Office in Korea. We used the Cox proportional hazards regression to estimate the association between serum PSA and risk of prostate cancer death adjusting the baseline age, cigarette smoking status, and body mass index.
RESULTS: During 1,381,901 person-years of follow-up, 6036 men died of any cause, and of these, 56 men died of prostate cancer. The multivariate-adjusted hazard ratio for prostate cancer death statistically significantly increased across PSA concentrations (P trend <.0001). The hazard ratio increased 7% per 1-ng/mL increase in PSA. The association between PSA concentration and death from prostate cancer was stronger in younger than in older men and in heavier than leaner men.
CONCLUSION: In conclusion, an increased screening PSA level is associated with an increased risk of prostate cancer death in Korean men. Our findings may have implications for the development of targeted PSA cutpoints for biopsy recommendation.

Karzai FH, Madan RA, Figg WD
Beyond PSA: managing modern therapeutic options in metastatic castration-resistant prostate cancer.
South Med J. 2015; 108(4):224-8 [PubMed] Related Publications
Prostate cancer remains a significant cause of cancer-related deaths in men in the United States. Significant advances in the treatment of metastatic castration-resistant prostate cancer have been made in recent years with the arrival of new therapeutic targets and options. The definition of progression of disease must be thought of in the context of clinical symptoms and radiographic evidence rather than as changes in prostate-specific antigen (PSA). Ultimately, the use of PSA criteria alone should not be used to determine the progression of disease; instead, PSA should be evaluated in combination with other clinical data.

Mahon KL, Lin HM, Castillo L, et al.
Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer.
Br J Cancer. 2015; 112(8):1340-8 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
BACKGROUND: Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ∼50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort.
METHODS: PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response.
RESULTS: PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1β, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002).
CONCLUSIONS: In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.

Wieczorek K, Braczkowski RS, Skrzypek M, et al.
The comparison between vitamin d concentration in upper silesia patients with prostate cancer and with benign prostatic hyperplasia.
J Biol Regul Homeost Agents. 2015 Jan-Mar; 29(1):207-11 [PubMed] Related Publications
A number of studies have shown that vitamin D has a protective effect against the development of cancer, which may also be related to prostate cancer. Low serum vitamin D concentration has also been demonstrated in benign prostate hyperplasia. We compared serum vitamin D concentration in two groups of Polish men with prostate cancer and benign prostate hyperplasia. Each group comprised 30 patients. The concentration was determined by ELISA. To assess the difference between the study population, non-parametric Mann Whitney U test was used. The results revealed that patients with prostate cancer are deficient in vitamin D (median =25.3, quartiles q1 - q3: 13.4 -33.4). The concentration of vitamin D in the group of patients with prostate cancer was lower than in the group of benign prostatic hyperplasia with vitamin D deficiency (median =34.8, quartiles q1 - q3: 17.9 – 44.3). Vitamin D concentration in Polish men with prostate cancer is lower compared to patients with benign prostatic hyperplasia.

Karczmarek-Borowska B, Radziszewska A
Prostate cancer incidence in Podkarpackie province in 2002-2011.
Przegl Epidemiol. 2015; 69(1):65-72, 163-7 [PubMed] Related Publications
INTRODUCTION: Prostate cancer is an important epidemiological problem in Podkarpackie province. A significant rise in the number of new cases was reported. The values of crude and standardized rates, percentage share and cumulative risk also increased.
OBJECTIVE: This article aims at analyzing incidence and mortality rates of prostate cancer in 2002-2011.
MATERIAL AND METHODS: Analysis was based on data retrieved from the Podkarpackie Cancer Registry in Rzeszów. A total of 4 263 prostate cancer cases and 2 032 fatal cases were analyzed from the list of orderly arranged patients. Crude and standardized rates of incidence and mortality, cumulative risk and percentage share of prostate cancer out of all cancers were calculated.
RESULTS: Compared to 2002, the number of cases increased by 150.5% in 2011. Cumulative risk rose from 1.8% in 2002 to 4.7% in 2011. Percentage of prostate cancer cases out of all registered cancers increased more than twofold in the analyzed decade. There was a 22.3% increase in the number of fatal cases due to prostate cancer, accompanied by a slight decrease of standardized mortality rate from 13.2/100 000 in 2002 to 12.6/100 000 in 2011. In the analyzed period, 41.8% of patients were diagnosed with locally adavanced prostate cancer.

Egbers L, Luedeke M, Rinckleb A, et al.
Obesity and Prostate Cancer Risk According to Tumor TMPRSS2:ERG Gene Fusion Status.
Am J Epidemiol. 2015; 181(9):706-13 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
The T2E gene fusion, formed by fusion of the transmembrane protease, serine 2, gene (TMPRSS2) with the erythroblast transformation-specific (ETS)-related gene (ERG), is found in approximately 50% of prostate cancers and may characterize distinct molecular subtypes of prostate cancer with different etiologies. We investigated the relationship between body mass index (BMI; weight (kg)/height (m)(2)) and prostate cancer risk by T2E status. Study participants were residents of King County, Washington, recruited for 2 population-based case-control studies conducted in 1993-1996 and 2002-2005. Tumor T2E status was determined for 563 prostate cancer patients who underwent radical prostatectomy. Information on weight, height, and covariables was obtained through in-person interviews. We performed polytomous logistic regression to calculate odds ratios and 95% confidence intervals for T2E-positive and -negative prostate cancer. Comparing the highest BMI quartile with the lowest, inverse associations were observed between recent (≥29.7 vs. <24.5: odds ratio = 0.66, 95% confidence interval: 0.45, 0.97) and maximum (≥31.8 vs. <25.9: odds ratio = 0.69, 95% confidence interval: 0.47, 1.02) BMI and the risk of T2E-positive prostate cancer. No significant associations were seen for men with T2E-negative tumors. This study provides evidence that obesity is specifically associated with reduced risk of developing androgen-responsive T2E fusion-positive tumors. The altered steroid hormone profile in obese men may contribute to this inverse association.

Guo S, Jiang X, Chen X, et al.
The protective effect of methylenetetrahydrofolate reductase C677T polymorphism against prostate cancer risk: Evidence from 23 case-control studies.
Gene. 2015; 565(1):90-5 [PubMed] Related Publications
Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were considered to have some influence on both folate metabolism and cancer risk. Previous studies on the relation between MTHFR C677T polymorphism and prostate cancer (PCa) risk remained controversial. To derive a more precise estimation of the relationship, we carried out an update comprehensive meta-analysis to assess the associations of the MTHFR C677T polymorphism with the susceptibility of PCa. Twenty-three trials with a total of 24,024 participants on the MTHFR C677T polymorphism that met inclusion criteria were analyzed in the current study. Overall, no statistical relationship was found with any MTHFR C677T genetic model associated with susceptibility to PCa (TT versus CC, OR=0.83, 95% CI 0.68-1.02, P=0.07; CT versus CC, OR=0.95, 95% CI 0.85-1.07, P=0.43; Dominant, OR=0.93, 95% CI 0.83-1.03, P=0.17; Recessive, OR=0.84, 95% CI 0.70-1.02, P=0.09.). Nevertheless, subgroup analysis found a reduced PCa risk associated with polymorphism in Asian population (TT versus CC, CT versus CC, dominant and recessive model). Moreover, the protective effect of polymorphism against PCa risk was also shown upon hospital-based studies (TT versus CC, and recessive model). When benign prostate hyperplasia was chosen as controls, both TT versus CC and recessive model showed significant difference. In addition, the protective effect of homozygote TT against high aggressive PCa was proved to have significant difference. Taken together, the existing evidence indicates the homozygote TT of MTHFR C677T should be viewed as a protective factor against PCa risk for clinical practice with the consideration of different gene background, study design as well as specific controls.

Vorster M, Modiselle M, Ebenhan T, et al.
Fluorine-18-fluoroethylcholine PET/CT in the detection of prostate cancer: a South African experience.
Hell J Nucl Med. 2015 Jan-Apr; 18(1):53-9 [PubMed] Related Publications
OBJECTIVE: Imaging with fluorine-18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) has, until recently provided disappointing results with low sensitivity ranging from 31%-64% in patients with well-differentiated prostate cancer (PC) at all prostatic specific antigen (PSA) levels while fluorine-18-fluoroethylcholine ((18)F-FECh) PET/CT showed about 85% sensitivity in restaging patients after relapse. We present our experience of the sensitivity of (18)F-FECh PET/CT in the early stages of PC.
SUBJECT AND METHODS: Fifty patients were prospectively recruited and imaged, of which 40 fulfilled all inclusion criteria. Our patients had an average age of 65.5 years. Fifteen patients were referred for initial staging, with the remaining 25 referred for restaging and all patients had histologically confirmed adenocarcinoma. Patients were imaged by (18)F-FECh PET/CT. Findings were evaluated qualitatively and quantitatively and compared to the results of histology, PSA, Gleason score and bone scintigraphy. The prostate SUVmax was also used.
RESULTS: Thirty-one patients demonstrated abnormal pelvic- and or extra- pelvic findings on (18)F-FECh PET/CT, which was consistent with malignant or metastatic involvement. The prostate SUVmax could not be used to predict the presence or absence of metastatic disease.
CONCLUSION: Findings of this paper suggest that (18)F-FECh PET/CT in 30/40 cases (estimated as 75%) was helpful in the initial staging, restaging and lymph node detection of patients with PC. The SUVmax was not helpful. We diagnosed more PC cases in our African-American patients as compared to the Caucasian patients.

Clemente S, Nigro R, Oliviero C, et al.
Role of the technical aspects of hypofractionated radiation therapy treatment of prostate cancer: a review.
Int J Radiat Oncol Biol Phys. 2015; 91(1):182-95 [PubMed] Related Publications
The increasing use of moderate (<35 fractions) and extreme (<5 fractions) hypofractionated radiation therapy in prostate cancer is yielding favorable results, both in terms of maintained biochemical response and toxicity. Several hypofractionation (HF) schemes for the treatment of prostate cancer are available, although there is considerable variability in the techniques used to manage intra-/interfraction motion and deliver radiation doses. We performed a review of the published studies on HF regimens as a topic of interest for the Stereotactic Ablative Radiotherapy working group, which is part of the Italian Association of Medical Physics. Aspects of organ motion management (imaging for contouring, target volume definition, and rectum/bladder preparation) and treatment delivery (prostate localization, image guided radiation therapy strategy and frequency) were evaluated and categorized to assess outcome relative to disease control and toxicity. Despite the heterogeneity of the data, some interesting trends that emerged from the review might be useful in identifying an optimum HF strategy.

Fager M, Toma-Dasu I, Kirk M, et al.
Linear energy transfer painting with proton therapy: a means of reducing radiation doses with equivalent clinical effectiveness.
Int J Radiat Oncol Biol Phys. 2015; 91(5):1057-64 [PubMed] Related Publications
PURPOSE: The purpose of this study was to propose a proton treatment planning method that trades physical dose (D) for dose-averaged linear energy transfer (LETd) while keeping the radiobiologically weighted dose (DRBE) to the target the same.
METHODS AND MATERIALS: The target is painted with LETd by using 2, 4, and 7 fields aimed at the proximal segment of the target (split target planning [STP]). As the LETd within the target increases with increasing number of fields, D decreases to maintain the DRBE the same as the conventional treatment planning method by using beams treating the full target (full target planning [FTP]).
RESULTS: The LETd increased 61% for 2-field STP (2STP) compared to FTP, 72% for 4STP, and 82% for 7STP inside the target. This increase in LETd led to a decrease of D with 5.3 ± 0.6 Gy for 2STP, 4.4 ± 0.7 Gy for 4STP, and 5.3 ± 1.1 Gy for 7STP, keeping the Drbe at 90% of the volume (Drbe, 90) constant to FTP.
CONCLUSIONS: LETd painting offers a method to reduce prescribed dose at no cost to the biological effectiveness of the treatment.

Qin A, Sun Y, Liang J, Yan D
Evaluation of online/offline image guidance/adaptation approaches for prostate cancer radiation therapy.
Int J Radiat Oncol Biol Phys. 2015; 91(5):1026-33 [PubMed] Related Publications
PURPOSE: To evaluate online/offline image-guided/adaptive treatment techniques for prostate cancer radiation therapy with daily cone-beam CT (CBCT) imaging.
METHODS AND MATERIALS: Three treatment techniques were evaluated retrospectively using daily pre- and posttreatment CBCT images on 22 prostate cancer patients. Prostate, seminal vesicles (SV), rectal wall, and bladder were delineated on all CBCT images. For each patient, a pretreatment intensity modulated radiation therapy plan with clinical target volume (CTV) = prostate + SV and planning target volume (PTV) = CTV + 3 mm was created. The 3 treatment techniques were as follows: (1) Daily Correction: The pretreatment intensity modulated radiation therapy plan was delivered after online CBCT imaging, and position correction; (2) Online Planning: Daily online inverse plans with 3-mm CTV-to-PTV margin were created using online CBCT images, and delivered; and (3) Hybrid Adaption: Daily Correction plus an offline adaptive inverse planning performed after the first week of treatment. The adaptive plan was delivered for all remaining 15 fractions. Treatment dose for each technique was constructed using the daily posttreatment CBCT images via deformable image registration. Evaluation was performed using treatment dose distribution in target and critical organs.
RESULTS: Treatment equivalent uniform dose (EUD) for the CTV was within [85.6%, 100.8%] of the pretreatment planned target EUD for Daily Correction; [98.7%, 103.0%] for Online Planning; and [99.2%, 103.4%] for Hybrid Adaptation. Eighteen percent of the 22 patients in Daily Correction had a target dose deficiency >5%. For rectal wall, the mean ± SD of the normalized EUD was 102.6% ± 2.7% for Daily Correction, 99.9% ± 2.5% for Online Planning, and 100.6% ± 2.1% for Hybrid Adaptation. The mean ± SD of the normalized bladder EUD was 108.7% ± 8.2% for Daily Correction, 92.7% ± 8.6% for Online Planning, and 89.4% ± 10.8% for Hybrid Adaptation.
CONCLUSIONS: Both Online Planning and Hybrid Adaptation can achieve comparable target coverage and normal tissue sparing and are superior to the Daily Correction technique. The Daily Correction technique using a 3-mm target margin in the pretreatment plan is not appropriate to compensate for residual variations in CBCT image-guided prostate cancer radiation therapy.

Kuang Y, Wu L, Hirata E, et al.
Volumetric modulated arc therapy planning for primary prostate cancer with selective intraprostatic boost determined by 18F-choline PET/CT.
Int J Radiat Oncol Biol Phys. 2015; 91(5):1017-25 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
PURPOSE: This study evaluated expected tumor control and normal tissue toxicity for prostate volumetric modulated arc therapy (VMAT) with and without radiation boosts to an intraprostatically dominant lesion (IDL), defined by (18)F-choline positron emission tomography/computed tomography (PET/CT).
METHODS AND MATERIALS: Thirty patients with localized prostate cancer underwent (18)F-choline PET/CT before treatment. Two VMAT plans, plan79 Gy and plan100-105 Gy, were compared for each patient. The whole-prostate planning target volume (PTVprostate) prescription was 79 Gy in both plans, but plan100-105 Gy added simultaneous boost doses of 100 Gy and 105 Gy to the IDL, defined by 60% and 70% of maximum prostatic uptake on (18)F-choline PET (IDLsuv60% and IDLsuv70%, respectively, with IDLsuv70% nested inside IDLsuv60% to potentially enhance tumor specificity of the maximum point dose). Plan evaluations included histopathological correspondence, isodose distributions, dose-volume histograms, tumor control probability (TCP), and normal tissue complication probability (NTCP).
RESULTS: Planning objectives and dose constraints proved feasible in 30 of 30 cases. Prostate sextant histopathology was available for 28 cases, confirming that IDLsuv60% adequately covered all tumor-bearing prostate sextants in 27 cases and provided partial coverage in 1 case. Plan100-105 Gy had significantly higher TCP than plan79 Gy across all prostate regions for α/β ratios ranging from 1.5 Gy to 10 Gy (P<.001 for each case). There were no significant differences in bladder and femoral head NTCP between plans and slightly lower rectal NTCP (endpoint: grade ≥ 2 late toxicity or rectal bleeding) was found for plan100-105 Gy.
CONCLUSIONS: VMAT can potentially increase the likelihood of tumor control in primary prostate cancer while observing normal tissue tolerances through simultaneous delivery of a steep radiation boost to a (18)F-choline PET-defined IDL.

Wittmann D
Coping with losses, grief, and mourning in prostate cancer.
Adv Psychosom Med. 2015; 34:109-22 [PubMed] Related Publications
Prostate cancer is a highly prevalent disease with a high likelihood of survival. If treated, survivors live with significant and lasting treatment-related side effects. Surgical treatment is associated with urinary incontinence and erectile dysfunction, and radiation leads to urinary and bowel irritability as well as erectile dysfunction. Patients who undergo hormonal treatment cope with sexual dysfunction, bone density loss, hot flashes, mood symptoms, and cardiac and metabolic disorders. Functional losses have a significant impact on patients and their partners' quality of life and are associated with distress and psychosocial morbidity. Psychosocial treatment is largely unavailable in usual care, but has been shown to reduce distress, to increase positive reappraisal of the illness, and to contribute to the recovery of sexual intimacy. Treatment for grief and mourning, typical reactions to loss, has not been introduced into psychosocial interventions but is increasingly recognized as a path toward a 'new normal' after prostate cancer treatment.

Sohail SK, Sarfraz R, Imran M, et al.
Power doppler ultrasonography guided and random prostate biopsy in prostate cancer diagnosis - a comparative study.
J Pak Med Assoc. 2015; 65(1):65-8 [PubMed] Related Publications
OBJECTIVE: To compare the diagnostic accuracy of power Doppler-guided targeted prostate biopsy and random sextant biopsy in the diagnosis of prostate cancer.
METHODS: The prospective study was carried out at the Allama Iqbal Medical College and Jinnah Hospital, Lahore, Pakistan, from January to December, 2012, and comprised clinically suspected cases of carcinoma prostate. Power Doppler-guided biopsies using automatic biopsy gun were obtained from the suspected targeted site. One to three cores per suspected site were obtained. Subsequently random sextant biopsies were performed in the same sitting. Six cores were obtained from 6 random sites using the same gun. Biopsies from both sources were processed for routine haematoxylin and eosin stainstained sections for histopathological examination.
RESULTS: Of the 50 patients in the study, 30(60%) were diagnosed with power Doppler-guided biopsy as malignant, whereas random sextant biopsy could pick up 22(44%) cases. For benign prostatic hyperplasia, random sextant biopsy labelled 28(56%)as benign, whereas only 20 (40%) were labelled as benign with power Doppler-guided biopsy. Discrepancy in the results between the two procedures was observed in 14(28%) cases, and of them, 1 1(22%) were labelled as malignant on power Doppler-guided biopsy while histopathology of sextant biopsies labelled these as benign.The sextant biopsies rendered a specificity, sensitivity, negative predictive value, positive predictive value and diagnostic accuracy of 60.71%, 86.36%, 85%, 63.33% and 72% respectively.
CONCLUSION: Random sextant biopsy in combination with power Doppler-guided targeted biopsy increases the rate of detection of prostate cancer whereas both procedures in isolation have low sensitivity and specificity for cancer detection.

Humm JL, Sartor O, Parker C, et al.
Radium-223 in the treatment of osteoblastic metastases: a critical clinical review.
Int J Radiat Oncol Biol Phys. 2015; 91(5):898-906 [PubMed] Related Publications
The element radium (Ra) was discovered by the Curies in 1898 and within a decade was in broad scientific testing for the management of several forms of cancer. The compound was known to give rise to a series of both high-energy particulate and penetrating γ-emissions. The latter found an important role in early 20th century brachytherapy applications, but the short-range α-particles seemed much less useful. Although highly cytotoxic when released within a few cell diameters of critical cell nuclei, the dense double-strand break damage was poorly repaired, and concerns regarding treatment-related toxicities and secondary malignancies halted clinical development. Moreover, the most common isotope of Ra has an exceptionally long half-life (>1600 years for (226)Ra) that proved daunting when aiming for a systemic cancer therapy. Fortunately, other radium isotopes have more convenient half-lives while still producing cytotoxic α particles. Radium-223 dichloride has a half-life of 11.4 days, and this isotope was identified as an excellent candidate for radionuclide therapy of cancers metastatic to bone. The calcium-mimetic chemical properties of the radium allowed intravenous infusion with rapid uptake to sites of new bone formation. The highly efficient bone localization suggested a potential therapeutic role for osteoblastic bone metastases, and a series of phase 1, 2, and 3 clinical trials was undertaken to explore this possibility. This series of clinical explorations culminated in the ALSYMPCA trial, an international, placebo-controlled, phase 3 study that accrued 921 symptomatic men with bone-metastatic, castrate-resistant prostate cancer. Results of this trial demonstrated a prolongation of overall survival, and regulatory agencies around the world have now approved this product as a treatment for advanced prostate cancer.

Fernandez EV, Reece KM, Ley AM, et al.
Dual targeting of the androgen receptor and hypoxia-inducible factor 1α pathways synergistically inhibits castration-resistant prostate cancer cells.
Mol Pharmacol. 2015; 87(6):1006-12 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and hypoxia inducible factor-1 α (HIF-1α) are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Crosstalk of the AR and HIF-1α signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. HIF-1α inhibition was achieved by siRNA silencing HIF-1α or via chetomin, a disruptor of HIF-1α-p300 interactions. In prostate cancer cells, the gene expression of AR targets (KLK3, FKBP5, TMPRSS2) was repressed by HIF-signaling; conversely, specific HIF-1α target expression was induced by dihydrotestosterone-mediated AR signaling. Treatment of CRPC cells with enzalutamide or HIF-1α inhibition attenuated AR-regulated and HIF-1α-mediated gene transcription. The combination of enzalutamide and HIF-1α inhibition was more effective than either treatment alone. Similarly, the combination also reduced vascular endothelial growth factor protein levels. HIF-1α siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells via increased enzalutamide-induced apoptosis. In conclusion, the combination of enzalutamide with HIF-1α inhibition resulted in synergistic inhibition of AR-dependent and gene-specific HIF-dependent expression and prostate cancer cell growth.

Couper J, Collins A, Bloch S, et al.
Cognitive existential couple therapy (CECT) in men and partners facing localised prostate cancer: a randomised controlled trial.
BJU Int. 2015; 115 Suppl 5:35-45 [PubMed] Related Publications
OBJECTIVES: To assess the efficacy of cognitive existential couple therapy (CECT) for relationship function, coping, cancer distress and mental health in men with localised prostate cancer and in their partners.
PATIENTS SUBJECTS AND METHODS: A randomised controlled trial was conducted with 62 couples randomly assigned to the six-session CECT programme or care as usual. The couple's relationship function (primary outcome), and coping, cancer distress and mental health (secondary outcomes) were evaluated at T0 (baseline), T1 (after treatment) and T2 (9 months from T0). A repeated-measures analysis of covariance model, which incorporated T0 measurements as a covariate, was used to compare treatment groups at T1 and T2.
RESULTS: After CECT, patients reported significantly greater use of adaptive coping (P = 0.03) and problem-focused coping (P = 0.01). These gains were maintained at follow-up, while relationship cohesion had improved (P = 0.03), as had relationship function for younger patients (P = 0.01). Younger partners reported less cancer-specific distress (P = 0.008), avoidance (P = 0.04), intrusive thought (P = 0.006), and hyperarousal (P = 0.01). Gains were maintained at follow-up, while relationship cohesion (P = 0.007), conflict resolution (P = 0.01) and relational function (P = 0.009) all improved.
CONCLUSION: CECT resulted in improved coping for patients and lower cancer-distress for partners. Maintained over time this manifests as improved relationship function. CECT was acceptable to couples, alleviated long-term relationship decline, and is therefore suitable as a preventative mental health intervention for couples facing prostate cancer. Given resourcing demands, we recommend dissemination of CECT be targeted at younger couples, as CECT was more acceptable to the younger group, and they derived greater benefit from it.

Roy J, Nguyen TX, Kanduluru AK, et al.
DUPA conjugation of a cytotoxic indenoisoquinoline topoisomerase I inhibitor for selective prostate cancer cell targeting.
J Med Chem. 2015; 58(7):3094-103 [PubMed] Related Publications
Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancer cells while being present at low or undetectable levels in normal cells. This difference provides an opportunity to selectively deliver cytotoxic drugs to prostate cancer cells while sparing normal cells that lack PSMA, thus improving potencies and reducing toxicities. PSMA has high affinity for 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) (Ki = 8 nM). After binding to a DUPA-drug conjugate, PSMA internalizes, unloads the conjugate, and returns to the surface. In the present studies, an indenoisoquinoline topoisomerase I inhibitor was conjugated to DUPA via a peptide linker and a drug-release segment that facilitates intracellular cleavage to liberate the drug cargo. The DUPA-indenoisoquinoline conjugate exhibited an IC50 in the low nanomolar range in 22RV1 cell cultures and induced a complete cessation of tumor growth with no toxicity, as determined by loss of body weight and death of treated mice.

Malik R, Khan AP, Asangani IA, et al.
Targeting the MLL complex in castration-resistant prostate cancer.
Nat Med. 2015; 21(4):344-52 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.

Wang EH, Yu JB, Gross CP, et al.
Association between surgeon and hospital characteristics and lymph node counts from radical prostatectomy and pelvic lymph node dissection.
Urology. 2015; 85(4):890-5 [PubMed] Related Publications
OBJECTIVE: To assess whether surgical approach and hospital characteristics independently determine the number of lymph nodes (LNs) removed from prostate cancer patients undergoing radical prostatectomy (RP) and pelvic LN dissection (PLND).
METHODS: Using the National Cancer Database, we identified all surgically treated patients diagnosed with pretreatment intermediate- or high-risk prostate cancer from 2010 to 2011. The primary outcome was the number of LNs retrieved at the time of RP. Generalized estimating equations were used to assess for differences in the adjusted number of LNs retrieved after accounting for patient and hospital characteristics and surgical approach.
RESULTS: Overall, 35,876 patients were diagnosed with intermediate-risk (61.2%) and high-risk (38.8%) prostate cancer and underwent RP and PLND.On multivariate analysis, open RP and high-volume and academic hospitals were independently associated with greater LN counts compared with robotic-assisted RP and medium or low and community hospitals, respectively (all P <.001). After adjusting for patient and hospital variables, higher adjusted LN counts were observed for open RP compared with robotic-assisted RP (7.1 vs 6.1; P <.001). Adjusted counts were also higher for high-volume hospitals compared with medium- or low-volume hospitals (7.8 vs 5.9; P <.001), and academic compared with community hospitals (7.3 vs 5.6; P <.001).
CONCLUSION: Among patients with aggressive prostate cancer treated with RP and PLND, retrieval of LN counts varied by surgical approach and hospital characteristics.

Wang J, Li Z, Lin Z, et al.
17-DMCHAG, a new geldanamycin derivative, inhibits prostate cancer cells through Hsp90 inhibition and survivin downregulation.
Cancer Lett. 2015; 362(1):83-96 [PubMed] Related Publications
Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the stability of many client proteins, including androgen receptor (AR) and survivin, making Hsp90 an attractive molecular therapeutic target for prostate cancer. Several Hsp90 inhibitors have shown antitumor activity in various preclinical models and in clinical trials. Geldanamycin is a well-known inhibitor of Hsp90, but its associated liver toxicity limited its clinical development. Here, we report a highly effective and low-hepatotoxic geldanamycin derivative that exhibits antitumor activity against human prostate cancer cells. Treatment of cells with 17-DMCHAG (17-(6-(3,4-dimethoxycinnamamido)hexylamino)-17-demethoxy-geldanamycin) dose-dependently suppressed the proliferation, reduced colony formation and induced apoptosis of human prostate cancer cell lines. 17-DMCHAG exhibits anti-invasive and anti-migratory activities in prostate cancer cells through down-regulating of transcription factors Zeb1, Snail1, Slug, and mesenchymal marker Vimentin, while up-regulating the epithelial marker of E-cadherin. Furthermore, 17-DMCHAG treatment damaged the Hsp90/AR and Hsp90/survivin complexes and induced the proteasome-dependent degradation of AR and survivin, then inhibited the activity of these two proteins. In vivo, we observed that 17-DMCHAG showed strong antitumor effects in LNCaP and DU-145 cell-xenografted nude mice. Thus, 17-DMCHAG is a potential treatment for prostate cancer.

Child CJ, Conroy D, Zimmermann AG, et al.
Incidence of primary cancers and intracranial tumour recurrences in GH-treated and untreated adult hypopituitary patients: analyses from the Hypopituitary Control and Complications Study.
Eur J Endocrinol. 2015; 172(6):779-90 [PubMed] Related Publications
OBJECTIVE: Speculation remains that GH treatment is associated with increased neoplasia risk. Studies in GH-treated childhood cancer survivors suggested higher rates of second neoplasms, while cancer risk data for GH-treated and untreated hypopituitary adults have been variable. We present primary cancer risk data from the Hypopituitary Control and Complications Study (HypoCCS) with a focus on specific cancers, and assessment of recurrence rates for pituitary adenomas (PA) and craniopharyngiomas (CP).
DESIGN: Incident neoplasms during HypoCCS were evaluated in 8418 GH-treated vs 1268 untreated patients for primary malignancies, 3668 GH-treated vs 720 untreated patients with PA history, and 956 GH-treated vs 102 untreated patients with CP history.
METHODS: Using population cancer rates, standardised incidence ratios (SIRs) were calculated for all primary cancers, breast, prostate, and colorectal cancers. Neoplasm rates in GH-treated vs untreated patients were analysed after propensity score adjustment of baseline treatment group imbalances.
RESULTS: During mean follow-up of 4.8 years, 225 primary cancers were identified in GH-treated patients, with SIR of 0.82 (95% CI 0.71-0.93). SIRs (95% CI) for GH-treated patients were 0.59 (0.36-0.90) for breast, 0.80 (0.57-1.10) for prostate, and 0.62 (0.38-0.96) for colorectal cancers. Cancer risk was not statistically different between GH-treated and untreated patients (relative risk (RR)=1.00 (95% CI 0.70-1.41), P=0.98). Adjusted RR for recurrence was 0.91 (0.68-1.22), P=0.53 for PA and 1.32 (0.53-3.31), P=0.55 for CP.
CONCLUSIONS: There was no increased risk for all-site cancers: breast, prostate or colorectal primary cancers in GH-treated patients during HypoCCS. GH treatment did not increase the risk of PA and CP recurrences.

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