Michael Davis

Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial

BACKGROUNDnProstate cancer is a major public health problem with considerable uncertainties about the effectiveness of population screening and treatment options. We report the study design, participant sociodemographic and clinical characteristics, and the initial results of the testing and diagnostic phase of the Prostate testing for cancer and Treatment (ProtecT) trial, which aims to investigate the effectiveness of treatments for localised prostate cancer.nnnMETHODSnIn this randomised phase 3 trial, men aged 50-69 years registered at 337 primary care centres in nine UK cities were invited to attend a specialist nurse appointment for a serum prostate-specific antigen (PSA) test. Prostate biopsies were offered to men with a PSA concentration of 3·0 μg/L or higher. Consenting participants with clinically localised prostate cancer were randomly assigned to active monitoring (surveillance strategy), radical prostatectomy, or three-dimensional conformal external-beam radiotherapy by a computer-generated allocation system. Randomisation was stratified by site (minimised for differences in participant age, PSA results, and Gleason score). The primary endpoint is prostate cancer mortality at a median 10-year follow-up, ascertained by an independent committee, which will be analysed by intention to treat in 2016. This trial is registered with ClinicalTrials.gov, number NCT02044172, and as an International Standard Randomised Controlled Trial, number ISRCTN20141297.nnnFINDINGSnBetween Oct 1, 2001, and Jan 20, 2009, 228,966 men were invited to attend an appointment with a specialist nurse. Of the invited men, 100,444 (44%) attended their initial appointment and 82,429 (82%) of attenders had a PSA test. PSA concentration was below the biopsy threshold in 73,538 (89%) men. Of the 8566 men with a PSA concentration of 3·0-19·9 μg/L, 7414 (87%) underwent biopsies. 2896 men were diagnosed with prostate cancer (4% of tested men and 39% of those who had a biopsy), of whom 2417 (83%) had clinically localised disease (mostly T1c, Gleason score 6). With the addition of 247 pilot study participants recruited between 1999 and 2001, 2664 men were eligible for the treatment trial and 1643 (62%) agreed to be randomly assigned (545 to active monitoring, 545 to radiotherapy, and 553 to radical prostatectomy). Clinical and sociodemographic characteristics of randomly assigned participants were balanced across treatment groups.nnnINTERPRETATIONnThe ProtecT trial randomly assigned 1643 men with localised prostate cancer to active monitoring, radiotherapy, or surgery. Participant clinicopathological features are more consistent with contemporary patient characteristics than in previous prostate cancer treatment trials.nnnFUNDINGnUK National Institute for Health Research Health Technology Assessment Programme.

Circulating Folate, Vitamin B12, Homocysteine, Vitamin B12 Transport Proteins, and Risk of Prostate Cancer: a Case-Control Study, Systematic Review, and Meta-analysis

Background: Disturbed folate metabolism is associated with an increased risk of some cancers. Our objective was to determine whether blood levels of folate, vitamin B12, and related metabolites were associated with prostate cancer risk. Methods: Matched case-control study nested within the U.K. population–based Prostate testing for cancer and Treatment (ProtecT) study of prostate-specific antigen–detected prostate cancer in men ages 50 to 69 years. Plasma concentrations of folate, B12 (cobalamin), holo-haptocorrin, holo-transcobalamin total transcobalamin, and total homocysteine (tHcy) were measured in 1,461 cases and 1,507 controls. ProtecT study estimates for associations of folate, B12, and tHcy with prostate cancer risk were included in a meta-analysis, based on a systematic review. Results: In the ProtecT study, increased B12 and holo-haptocorrin concentrations showed positive associations with prostate cancer risk [highest versus lowest quartile of B12 odds ratio (OR) = 1.17 (95% confidence interval, 0.95-1.43); Ptrend = 0.06; highest versus lowest quartile of holo-haptocorrin OR = 1.27 (1.04-1.56); Ptrend = 0.01]; folate, holo-transcobalamin, and tHcy were not associated with prostate cancer risk. In the meta-analysis, circulating B12 levels were associated with an increased prostate cancer risk [pooled OR = 1.10 (1.01-1.19) per 100 pmol/L increase in B12; P = 0.002]; the pooled OR for the association of folate with prostate cancer was positive [OR = 1.11 (0.96-1.28) per 10 nmol/L; P = 0.2) and conventionally statistically significant if ProtecT (the only case-control study) was excluded [OR = 1.18 (1.00-1.40) per 10 nmol/L; P = 0.02]. Conclusion: Vitamin B12 and (in cohort studies) folate were associated with increased prostate cancer risk. Impact: Given current controversies over mandatory fortification, further research is needed to determine whether these are causal associations. Cancer Epidemiol Biomarkers Prev; 19(6); 1632–42. ©2010 AACR.

Association of diabetes mellitus with prostate cancer: nested case-control study (Prostate testing for cancer and treatment study).

Observational studies suggest that diabetes is associated with a decreased risk of prostate cancer, but few are population based or have investigated associations with cancer stage or duration of diabetes. We report a case–control study nested within the population‐based Prostate testing for cancer and Treatment (ProtecT) study ISRCTN20141297. Men aged 50–69 years based around 9 UK cities were invited for a prostate‐specific antigen (PSA) test between June 2002 and November 2006. Amongst 55,215 PSA‐tested men, 1,966 had histologically confirmed prostate cancer; of these, 1,422 (72.3%) completed the questionnaire and 1,291 (65.7%) had complete data for analysis. We randomly selected 6,479 age‐ (within 5 years) and general practice‐matched controls. The prevalence of diabetes was 89/1,291 (6.9%) in cases and 555/6,479 (8.6%) in controls. Diabetes was associated with a reduced risk of prostate cancer (odds ratio = 0.78; 95% confidence interval: 0.61–0.99). There was weak evidence that the inverse association was greater for well‐ versus poorly differentiated cancers (p = 0.07). The magnitude of the inverse association did not change with increasing duration of diabetes (p for trend = 0.95). Diabetes is associated with a decreased risk of PSA‐detected prostate cancer. These data add to the evidence of the association of diabetes with prostate cancer in the PSA era.

Associations between an Obesity Related Genetic Variant (FTO rs9939609) and Prostate Cancer Risk

Observational studies suggest that obese men have a lower risk of incident prostate cancer, but an increased risk of advanced and fatal cancers. These observations could be due to confounding, detection bias, or a biological effect of obesity. Genetic studies are less susceptible to confounding than observational epidemiology and can suggest how associations between phenotypes (such as obesity) and diseases arise. To determine whether the associations between obesity and prostate cancer are causal, we conducted a genetic association study of the relationship between a single nucleotide polymorphism known to be associated with obesity (FTO rs9939609) and prostate cancer. Data are from a population-based sample of 1550 screen-detected prostate cancers, 1815 age- and general practice matched controls with unrestricted prostate specific antigen (PSA) values and 1175 low-PSA controls (PSA <0.5 ng/ml). The rs9939609 A allele, which was associated with higher BMI in the sample, was inversely associated with overall (odds ratio (OR) versus all controls u200a=u200a0.93; 95% confidence interval (CI): 0.85–1.02 pu200a=u200a0.12 per allele) and low-grade (ORu200a=u200a0.90; 0.81–0.99 pu200a=u200a0.03 per allele) prostate cancer risk, but positively associated with high-grade cancer among cases (OR high- versus low-grade cancer u200a=u200a1.16; 0.99–1.37 pu200a=u200a0.07 per allele). Although evidence for these effects was weak, they are consistent with observational data based on BMI phenotypes and suggest that the observed association between obesity and prostate cancer is not due to confounding. Further research should confirm these findings, extend them to other BMI-related genetic variants and determine whether they are due to detection bias or obesity-related hormonal changes. Trial Registration Controlled-Trials.com ISRCTN20141297

Men with prostate cancer make positive dietary changes following diagnosis and treatment.

PurposeFew studies have measured dietary changes made among men diagnosed with prostate cancer (PC) without formal dietary interventions, yet they may offer insight into the needs of PC survivors. This study examined dietary changes in men before and after treatment for PC within the prostate testing for cancer and treatment randomized trial.MethodsThis was a prospective cohort study in community-based men aged 50–69 tested for PC in nine UK areas. 3,935 men completed food frequency questionnaires before diagnosis and 678 with localized PC repeated the questionnaire 1xa0year later (response 82.7xa0%).ResultsMen subsequently diagnosed with or without PC all consumed similar diets before diagnosis. Diagnosis of PC led to dietary changes, with 234 (34.7xa0%) men eating more fresh tomatoes (pxa0<xa00.0001) and 156 (23.5xa0%) more tomato products (pxa0=xa00.01). 271 (40.0xa0%) men consumed more protein (pxa0<xa00.0001) and 193 (28.6xa0%) more fruit/vegetable juice (pxa0<xa00.0001). Fewer macronutrients were obtained from dairy products (pxa0<xa00.01). Men undergoing active monitoring increased their fruit/vegetable juice intake after diagnosis (pxa0=xa00.0023) more than men who had surgery or radiotherapy.ConclusionsAround one-third of men spontaneously adopted a healthier diet and also consumed more ‘prostate-healthy’ foods following a diagnosis of PC. Dietary choices also differed by radical or monitoring treatments, indicating that men undergoing active surveillance may be more likely to pursue dietary changes as an adjunct therapy. PC survivors can adopt healthier diets, thus providing clinicians with opportunities to support PC survivorship by providing targeted advice beneficial to general and potentially prostate-specific health.

Design and preliminary recruitment results of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP)

Background:Screening for prostate cancer continues to generate controversy because of concerns about over-diagnosis and unnecessary treatment. We describe the rationale, design and recruitment of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP) trial, a UK-wide cluster randomised controlled trial investigating the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing.Methods:Seven hundred and eighty-five general practitioner (GP) practices in England and Wales were randomised to a population-based PSA testing or standard care and then approached for consent to participate. In the intervention arm, men aged 50–69 years were invited to undergo PSA testing, and those diagnosed with localised prostate cancer were invited into a treatment trial. Control arm practices undertook standard UK management. All men were flagged with the Health and Social Care Information Centre for deaths and cancer registrations. The primary outcome is prostate cancer mortality at a median 10-year-follow-up.Results:Among randomised practices, 271 (68%) in the intervention arm (198u2009114 men) and 302 (78%) in the control arm (221u2009929 men) consented to participate, meeting pre-specified power requirements. There was little evidence of differences between trial arms in measured baseline characteristics of the consenting GP practices (or men within those practices).Conclusions:The CAP trial successfully met its recruitment targets and will make an important contribution to international understanding of PSA-based prostate cancer screening.

A cross-sectional analysis of the association between diet and insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-2, and IGFBP-3 in men in the United Kingdom

BackgroundThere is evidence of associations between insulin-like growth factor I (IGF-I), IGF-II, insulin-like binding protein-2 (IGFBP-2), IGFBP-3, and prostate cancer risk. This study examines the association between dietary factors associated with prostate cancer and serum levels of these peptides.MethodsA cross-sectional analysis of self-reported 12-month dietary intake with serum IGF and IGFBP levels was performed using data from 1,798 subjects screened negative for prostate cancer as part of a UK multicenter trial comparing treatments for this condition. Multivariable linear regression models tested associations of diet with IGFs and IGFBPs.ResultsFor a one standard deviation (SD) increase in dairy product and dairy protein intake, IGF-I increased by 5.28xa0ng/mL (95xa0% confidence interval: 2.64, 7.92xa0ng/mL) and 6.02xa0ng/mL (3.34, 8.71xa0ng/mL), respectively. A 25xa0% increase in calcium and selenium intake was associated with an increase in IGF-I of 5.92xa0ng/mL (3.77, 8.07xa0ng/mL) and 2.61xa0ng/mL (1.10, 4.13xa0ng/mL), respectively. A one SD increase in animal protein was associated with a decrease in IGFBP-2 of 6.20xa0% (−8.91, −3.41xa0%), and there was some evidence of an inverse association with dairy protein and calcium. There was no evidence of any dietary associations with IGFBP-3 or IGF-II.ConclusionsDiet is associated with IGF-I and IGFBP-2 levels in men in the UK, and these peptides warrant further investigation as part of randomized trials of dietary interventions to reduce the risk or progression of prostate cancer. There is no evidence that IGF-II or IGFBP-3 are mediators of dietary associations with prostate cancer.

Association of obesity with prostate cancer: a case-control study within the population-based PSA testing phase of the ProtecT study

Background:Obesity has been inconsistently linked to prostate cancer, mainly with mortality rather than incidence. Few large-scale studies exist assessing obesity in relation to prostate-specific antigen (PSA)-detected prostate cancer.Methods:We used cases and stratum-matched controls from the population-based PSA-testing phase of the Prostate testing for cancer and Treatment study to examine the hypothesis that obesity as measured by body mass index (BMI), waist circumference and waist-to-hip ratio (WHR) is associated with increased prostate cancer risk, and with higher tumour stage and grade. In all, 2167 eligible cases and 11u2009638 randomly selected eligible controls with PSA values were recruited between 2001 and 2008. A maximum of 960 cases and 4156 controls had measurement data, and also complete data on age and family history, and were included in the final analysis. BMI was categorised as <25.0, 25.0–29.9, ⩾30.0 in kgu2009m−2.Results:Following adjustment for age and family history of prostate cancer, we found little evidence that BMI was associated with total prostate cancer (odds ratio (OR): 0.83, 95% confidence interval (CI): 0.67, 1.03; highest vs lowest tertile; P-trend 0.1). A weak inverse association was evident for low-grade (OR: 0.76, 95% CI: 0.59, 0.97; highest vs lowest tertile; P-trend 0.045) prostate cancer. We found no association of either waist circumference (OR: 0.94, 95% CI: 0.80, 1.12; highest vs lowest tertile) or waist-to-hip ratio (WHR; OR: 0.93, 95% CI: 0.77, 1.11; highest vs lowest tertile) with total prostate cancer, and in analyses stratified by disease stage (all P-trend>0.35) or grade (all P-trend>0.16).Conclusion:General adiposity, as measured by BMI, was associated with a decreased risk of low-grade PSA-detected prostate cancer. However, effects were small and the confidence intervals had limits very close to one. Abdominal obesity (as measured by WHR/waist circumference) was not associated with PSA-detected prostate cancer.

Current strategies for monitoring men with localised prostate cancer lack a strong evidence base: observational longitudinal study.

Background:The UK National Institute for Health and Clinical Excellence (NICE) guidance recommends conservative management of men with ‘low-risk’ localised prostate cancer, monitoring the disease using prostate-specific antigen (PSA) kinetics and re-biopsy. However, there is little evidence of the changes in PSA level that should alert to the need for clinical re-assessment.Methods:This study compares the alerts resulting from PSA kinetics and a novel longitudinal reference range approach, which incorporates age-related changes, during the monitoring of 408 men with localised prostate cancer. Men were monitored by regular PSA tests over a mean of 2.9 years, recording when a mans PSA doubling time fell below 2 years, PSA velocity exceeded 2u2009ngu2009ml–1 per year, or when his upper 10% reference range was exceeded.Results:Prostate-specific antigen doubling time and PSA velocity alerted a high proportion of men initially but became unresponsive to changes with successive tests. Calculating doubling time using recent PSA measurements reduced the decline in response. The reference range method maintained responsiveness to changes in PSA level throughout the monitoring.Conclusion:The increasing unresponsiveness of PSA kinetics is a consequence of the underlying regression model. Novel methods are needed for evaluation in cohorts currently being managed by monitoring. Meanwhile, the NICE guidance should be cautious.

Very Low PSA Concentrations and Deletions of the KLK3 Gene

BACKGROUNDnProstate-specific antigen (PSA), a widely used biomarker for prostate cancer (PCa), is encoded by a kallikrein gene (KLK3, kallikrein-related peptidase 3). Serum PSA concentrations vary in the population, with PCa patients generally showing higher PSA concentrations than control individuals, although a small proportion of individuals in the population display very low PSA concentrations. We hypothesized that very low PSA concentrations might reflect gene-inactivating mutations in KLK3 that lead to abnormally reduced gene expression.nnnMETHODSnWe have sequenced all KLK3 exons and the promoter and searched for gross deletions or duplications in KLK3 in the 30 individuals with the lowest observed PSA concentrations in a sample of approximately 85 000 men from the Prostate Testing for Cancer and Treatment (ProtecT) study. The ProtecT study examines a community-based population of men from across the UK with little prior PSA testing.nnnRESULTSnWe observed no stop codons or frameshift mutations, but we did find 30 single-base genetic variants, including 3 variants not described previously. These variants included missense variants that could be functionally inactivating and splicing variants. At this stage, however, we cannot confidently conclude whether these variants markedly lower PSA concentration or activity. More importantly, we identified 3 individuals with different large heterozygous deletions that encompass all KLK3 exons. The absence of a functional copy of KLK3 in these individuals is consistent with their reduced serum PSA concentrations.nnnCONCLUSIONSnThe clinical interpretation of the PSA test for individuals with KLK3 gene inactivation could lead to false-negative PSA findings used for screening, diagnosis, or monitoring of PCa.