F C Hamdy

Quality improvement report: Improving design and conduct of randomised trials by embedding them in qualitative research: ProtecT (prostate testing for cancer and treatment) study. Commentary: presenting unbiased information to patients can be difficult.

PROBLEM: Recruitment to randomised trials is often difficult, and many important trials are not mounted because recruitment is thought to be impossible. DESIGN: Controversial ProtecT (prostate testing for cancer and treatment) trial embedded within qualitative research. BACKGROUND AND SETTING: Screening for prostate cancer is hotly debated, and evidence from trials about the effectiveness of treatments (surgery, radiotherapy, and monitoring) is lacking. Mounting a treatment trial is controversial because of past failures and concerns that differences in complications of treatment but not survival make randomisation unacceptable to patients and clinicians, particularly for a trial including monitoring. STRATEGY FOR CHANGE: In-depth interviews explored interpretation of study information. Audiotape recordings of recruitment appointments enabled scrutiny of content and presentation of study information by recruiters. Initial qualitative findings showed that recruiters had difficulty discussing equipoise and presenting treatments equally; they unknowingly used terminology that was misinterpreted by participants. Findings were used to determine changes to content and presentation of information. EFFECTS OF CHANGE: Changes to the order of presenting treatments encouraged emphasis on equivalence, misinterpreted terms were avoided, the non-radical arm was redefined, and randomisation and clinical equipoise were presented more convincingly. The randomisation rate increased from 40% to 70%, all treatments became acceptable, and the three arm trial became the preferred design. LESSONS LEARNT: Changes to information and presentation resulted in efficient recruitment acceptable to patients and clinicians. Embedding this controversial trial within qualitative research improved recruitment. Such methods probably have wider applicability and may enable even the most difficult evaluative questions to be tackled.PROBLEMnRecruitment to randomised trials is often difficult, and many important trials are not mounted because recruitment is thought to be impossible.nnnDESIGNnControversial ProtecT (prostate testing for cancer and treatment) trial embedded within qualitative research.nnnBACKGROUND AND SETTINGnScreening for prostate cancer is hotly debated, and evidence from trials about the effectiveness of treatments (surgery, radiotherapy, and monitoring) is lacking. Mounting a treatment trial is controversial because of past failures and concerns that differences in complications of treatment but not survival make randomisation unacceptable to patients and clinicians, particularly for a trial including monitoring.nnnSTRATEGY FOR CHANGEnIn-depth interviews explored interpretation of study information. Audiotape recordings of recruitment appointments enabled scrutiny of content and presentation of study information by recruiters. Initial qualitative findings showed that recruiters had difficulty discussing equipoise and presenting treatments equally; they unknowingly used terminology that was misinterpreted by participants. Findings were used to determine changes to content and presentation of information.nnnEFFECTS OF CHANGEnChanges to the order of presenting treatments encouraged emphasis on equivalence, misinterpreted terms were avoided, the non-radical arm was redefined, and randomisation and clinical equipoise were presented more convincingly. The randomisation rate increased from 40% to 70%, all treatments became acceptable, and the three arm trial became the preferred design.nnnLESSONS LEARNTnChanges to information and presentation resulted in efficient recruitment acceptable to patients and clinicians. Embedding this controversial trial within qualitative research improved recruitment. Such methods probably have wider applicability and may enable even the most difficult evaluative questions to be tackled.

Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10−8 to P = 2.7 × 10−24). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ∼25% of the familial risk in this disease, have now been identified.

Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within ProtecT study.

Objectives To measure the effect of the adverse events within 35 days of transrectal ultrasound guided biopsy from the perspective of asymptomatic men having prostate specific antigen (PSA) testing; to assess early attitude to re-biopsy; to estimate healthcare resource use associated with adverse events due to biopsy; and to develop a classification scheme for reporting adverse events after prostate biopsy. Design Prospective cohort study (Prostate Biopsy Effects: ProBE) nested within Prostate Testing for Cancer and Treatment (ProtecT) study. Participants Between 1999 and 2008, 227u2009000 community dwelling men aged 5069 years were identified at 352 practices and invited to counselling about PSA testing. 111u2009148 attended a nurse led clinic in the community, and 10u2009297 with PSA concentrations of 3-20 ng/mL were offered biopsy within ProtecT. Between February 2006 and May 2008, 1147/1753 (65%) eligible men (mean age 62.1 years, mean PSA 5.4 ng/mL) having 10 core transrectal ultrasound guided biopsy under antibiotic cover in the context of ProtecT were recruited to the ProBE study. Outcome measures Purpose designed questionnaire administered at biopsy and 7 and 35 days after the procedure to measure frequency and effect of symptoms related to pain, infection, and bleeding; patients’ attitude to repeat biopsy assessed immediately after biopsy and 7 days later; participants’ healthcare resource use within 35 days of biopsy evaluated by questionnaire, telephone follow-up, and medical note review; each man’s adverse event profile graded according to symptoms and healthcare use. Results Pain was reported by 429/984 (43.6%), fever by 172/985 (17.5%), haematuria by 642/976 (65.8%), haematochezia by 356/967 (36.8%), and haemoejaculate by 605/653 (92.6%) men during the 35 days after biopsy. Fewer men rated these symptoms as a major/moderate problem—71/977 (7.3%) for pain, 54/981 (5.5%) for fever, 59/958 (6.2%) for haematuria, 24/951 (2.5%) for haematochezia, and 172/646 (26.6%) for haemoejaculate. Immediately after biopsy, 124/1142 (10.9%, 95% confidence interval 9.2 to 12.8) men reported that they would consider further biopsy a major or moderate problem: seven days after biopsy, this proportion had increased to 213/1085 (19.6%, 17.4% to 22.1%). A negative attitude to repeat biopsy was associated with unfavourable experience after the first biopsy, particularly pain at biopsy (odds ratio 8.2, P<0.001) and symptoms related to infection (7.9, P<0.001) and bleeding (4.2, P<0.001); differences were evident between centres (P<0.001). 119/1147 (10.4%, 8.7% to 12.3%) men reported consultation with a healthcare professional (usually their general practitioner), most commonly for infective symptoms. Complete data for all index symptoms at all time points were available in 851 participants. Symptoms and healthcare use could be used to grade these men as follows: grade 0 (no symptoms/contact) 18 (2.1%, 1.3% to 3.3%); grade 1 (minor problem/no contact) 550 (64.6%, 61.4% to 67.8%); grade 2 (moderate/major problem or contact) 271 (31.8%, 28.8% to 35.1%); grade 3 (hospital admission) 12 (1.4%, 0.8% to 2.4%); and grade 4 (death) 0. Grade of adverse event was associated with an unfavourable attitude to repeat biopsy (Kendall’s τ-b ordinal by ordinal 0.29, P<0.001). Conclusion This study with a high response rate of 89% at 35 days in men undergoing biopsy in the context of a randomised controlled trial has shown that although prostate biopsy is well tolerated by most men, it is associated with significant symptoms in a minority and affects attitudes to repeat biopsy and primary care resource use. These findings will inform men who seek PSA testing for detection of prostate cancer and assist their physicians during counselling about the potential risks and effect of biopsy. Variability in the adverse event profile between centres suggests that patients’ outcomes could be improved and healthcare use reduced with more effective administration of local anaesthetic and antibiotics. Trial registration Current Controlled Trials ISRCTN20141297.

Improving design and conduct of randomised trials by embedding them in qualitative research: ProtecT (prostate testing for cancer and treatment) study

PROBLEM: Recruitment to randomised trials is often difficult, and many important trials are not mounted because recruitment is thought to be impossible. DESIGN: Controversial ProtecT (prostate testing for cancer and treatment) trial embedded within qualitative research. BACKGROUND AND SETTING: Screening for prostate cancer is hotly debated, and evidence from trials about the effectiveness of treatments (surgery, radiotherapy, and monitoring) is lacking. Mounting a treatment trial is controversial because of past failures and concerns that differences in complications of treatment but not survival make randomisation unacceptable to patients and clinicians, particularly for a trial including monitoring. STRATEGY FOR CHANGE: In-depth interviews explored interpretation of study information. Audiotape recordings of recruitment appointments enabled scrutiny of content and presentation of study information by recruiters. Initial qualitative findings showed that recruiters had difficulty discussing equipoise and presenting treatments equally; they unknowingly used terminology that was misinterpreted by participants. Findings were used to determine changes to content and presentation of information. EFFECTS OF CHANGE: Changes to the order of presenting treatments encouraged emphasis on equivalence, misinterpreted terms were avoided, the non-radical arm was redefined, and randomisation and clinical equipoise were presented more convincingly. The randomisation rate increased from 40% to 70%, all treatments became acceptable, and the three arm trial became the preferred design. LESSONS LEARNT: Changes to information and presentation resulted in efficient recruitment acceptable to patients and clinicians. Embedding this controversial trial within qualitative research improved recruitment. Such methods probably have wider applicability and may enable even the most difficult evaluative questions to be tackled.PROBLEMnRecruitment to randomised trials is often difficult, and many important trials are not mounted because recruitment is thought to be impossible.nnnDESIGNnControversial ProtecT (prostate testing for cancer and treatment) trial embedded within qualitative research.nnnBACKGROUND AND SETTINGnScreening for prostate cancer is hotly debated, and evidence from trials about the effectiveness of treatments (surgery, radiotherapy, and monitoring) is lacking. Mounting a treatment trial is controversial because of past failures and concerns that differences in complications of treatment but not survival make randomisation unacceptable to patients and clinicians, particularly for a trial including monitoring.nnnSTRATEGY FOR CHANGEnIn-depth interviews explored interpretation of study information. Audiotape recordings of recruitment appointments enabled scrutiny of content and presentation of study information by recruiters. Initial qualitative findings showed that recruiters had difficulty discussing equipoise and presenting treatments equally; they unknowingly used terminology that was misinterpreted by participants. Findings were used to determine changes to content and presentation of information.nnnEFFECTS OF CHANGEnChanges to the order of presenting treatments encouraged emphasis on equivalence, misinterpreted terms were avoided, the non-radical arm was redefined, and randomisation and clinical equipoise were presented more convincingly. The randomisation rate increased from 40% to 70%, all treatments became acceptable, and the three arm trial became the preferred design.nnnLESSONS LEARNTnChanges to information and presentation resulted in efficient recruitment acceptable to patients and clinicians. Embedding this controversial trial within qualitative research improved recruitment. Such methods probably have wider applicability and may enable even the most difficult evaluative questions to be tackled.

Latest results from the UK trials evaluating prostate cancer screening and treatment: the CAP and ProtecT studies.

The European Randomised Study of Screening for Prostate Cancer (ERSPC) demonstrated a significant reduction in prostate cancer-specific mortality. The ongoing Comparison Arm for ProtecT (CAP) cluster randomised controlled trial (RCT) evaluates prostate cancer screening effectiveness by comparing primary care centres allocated to a round of prostate specific antigen (PSA) testing (intervention) or standard clinical care. Over 550 centres (around 450,000 men) were randomised in eight United Kingdom areas (2002-2008). Intervention group participants were also eligible for the ProtecT (Prostate testing for cancer and Treatment) RCT evaluating active monitoring, radiotherapy and radical prostatectomy treatments for localised prostate cancer. In ProtecT, over 1500 of around 3000 men with prostate cancer were randomised from over 10,000 with an elevated PSA in around 111,000 attendees at clinics. Investigation of the psychological impact of screening in a sub-sample showed that 10% of men still experienced high distress up to 3 months following prostate biopsies (22/227), although most were relatively unaffected. The risk of prostate cancer with a raised PSA was lower if urinary symptoms were present (frequent nocturia odds ratio (OR) 0.44, 95% confidence interval (CI) 0.22-0.83) or if a repeat PSA decreased by > or = 20% prior to biopsy (OR 0.43, 95% CI 0.35-0.52). Men aged 45-49 years attended PSA clinics less frequently (442/1299, 34%) in a nested cohort with a cancer detection rate of 2.3% (10/442). The CAP and ProtecT trials (ISRCTN92187251 and ISRCTN20141217) will help resolve the prostate cancer screening debate, define the optimum treatment for localised disease and generate evidence to improve mens health.

Are diet-prostate cancer associations mediated by the IGF axis? A cross-sectional analysis of diet, IGF-I and IGFBP-3 in healthy middle-aged men

We examined the association of diet with insulin-like growth factors (IGF) in 344 disease-free men. Raised levels of IGF-1 and/or its molar ratio with IGFBP-3 were associated with higher intakes of milk, dairy products, calcium, carbohydrate and polyunsaturated fat; lower levels with high vegetable consumption, particularly tomatoes. These patterns support the possibility that IGFs may mediate some diet–cancer associations.

A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; Pcombined = 6.2 × 10−34), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r2 ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.

Genetic correction of PSA values using sequence variants associated with PSA levels.

Sequence variants in the human genome are associated with serum levels of prostate-specific antigen. SNPping Away at Prostate Cancer Measuring prostate-specific antigen (PSA) in serum is the only diagnostic test for prostate cancer and is used as a screening tool for deciding whether to perform a biopsy. Yet, this diagnostic test is far from ideal, with more than a third of men with serum PSA levels of 10 ng/ml or greater having no evidence of prostate cancer at biopsy, and some men with very low PSA levels (less than the lower threshold of 2.5 ng/ml), who are not given a biopsy but yet end up having prostate cancer. The lack of specificity and sensitivity of the PSA test and the many confounding factors that influence the test result, including medications, inflammation, and, of course, genotype, have reduced the value of this screening tool. As with most cancers, early detection of prostate cancer leads to a greatly improved chance of survival, so improving the predictive accuracy of this test is of paramount importance. In an effort to investigate whether genome sequence variants can be used to make the PSA test more sensitive, Gudmundsson and colleagues have undertaken a genome-wide association study in 15,757 Icelandic men and 454 British men not yet diagnosed with prostate cancer to see whether they can tie sequence variants [single-nucleotide polymorphisms (SNPs)] to serum PSA levels. The authors identify six loci with SNPs that correlate with PSA levels. They then probed these data more deeply. They looked at these loci in 3834 men who underwent subsequent biopsy of the prostate and demonstrate that three of these loci (10q26, 12q24, and 19q13.33) are associated not only with higher PSA levels but also with a higher probability of a negative biopsy result. The authors suggest that this genotype information should be used to calculate a personalized “cutoff” value for serum PSA levels in each individual to improve the predictive accuracy of the test and to ensure that only men who need a prostate biopsy are subjected to this procedure. Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with Pcombined <3 × 10−10. Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.

An evaluation of urinary microRNA reveals a high sensitivity for bladder cancer.

Background:Urinary biomarkers are needed to improve the care and reduce the cost of managing bladder cancer. Current biomarkers struggle to identify both high and low-grade cancers due to differing molecular pathways. Changes in microRNA (miR) expression are seen in urothelial carcinogenesis in a phenotype-specific manner. We hypothesised that urinary miRs reflecting low- and high-grade pathways could detect bladder cancers and overcome differences in genetic events seen within the disease.Methods:We investigated urinary samples (n=121) from patients with bladder cancer (n=68) and age-matched controls (n=53). Fifteen miRs were quantified using real-time PCR.Results:We found that miR is stable within urinary cells despite adverse handling and detected differential expression of 10 miRs from patients with cancer and controls (miRs−15a/15b/24-1/27b/100/135b/203/212/328/1224, ANOVA P<0.05). Individually, miR-1224-3p had the best individual performance with specificity, positive and negative predictive values and concordance of 83%, 83%, 75% and 77%, respectively. The combination of miRs-135b/15b/1224-3p detected bladder cancer with a high sensitivity (94.1%), sufficient specificity (51%) and was correct in 86% of patients (concordance).Conclusion:The use of this panel in patients with haematuria would have found 94% of urothelial cell carcinoma, while reducing cystoscopy rates by 26%. However, two invasive cancers (3%) would have been missed.

Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Study Type – Diagnostic (validating cohort)u2028Level of Evidenceu20031b