Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies

Insulin‐like growth factors (IGFs) and insulin‐like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross‐sectional associations of these exposures with circulating concentrations of IGFs (IGF‐I and IGF‐II) and IGFBPs (IGFBP‐1, IGFBP‐2 and IGFBP‐3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22–89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGF‐I, IGF‐II and IGFBP‐3. Higher body mass index was associated with lower concentrations of IGFBP‐1 and IGFBP‐2. Taller height was associated with higher concentrations of IGF‐I and IGFBP‐3 and lower concentrations of IGFBP‐1. Smokers had higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGFBP‐3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF‐II and lower concentrations of IGF‐I and IGFBP‐2. African Americans had lower concentrations of IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 and Hispanics had lower IGF‐I, IGF‐II and IGFBP‐3 than non‐Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization : Genetic variants as instruments for circulating levels

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker

Circulating insulin-like growth factors and IGF binding proteins in PSA-detected prostate cancer: the large case-control study ProtecT

Circulating insulin-like growth factor-I (IGF-I) has been studied extensively in prostate cancer, but there is still little information about IGFs and IGF binding proteins (IGFBPs) in cancers detected by the prostate-specific antigen (PSA) test. Here we report the findings of a United Kingdom-based case-control study to investigate circulating IGFs and IGFBPs in PSA-detected prostate cancer with regard to their potential associations with different cancer stages or grades. PSA testing was offered to 110,000 men aged 50-69 years from 2002-2009. Participants with an elevated level of PSA (≥ 3.0 ng/ml) underwent prostate biopsy and measurements of blood serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 obtained at recruitment. We found that serum levels of IGF-II (OR per standard deviation increase: 1.16; 95%CI 1.08,1.24;ptrend<0.001), IGFBP-2 (1.18;1.06,1.31;ptrend<0.01) and IGFBP-3 (1.27;1.19,1.36;ptrend<0.001), but not IGF-I (0.99;0.93,1.04;ptrend=0.62), were associated with PSA-detected prostate cancer. After controlling for IGFBP-3, IGF-II was no longer associated (0.99;0.91,1.08;ptrend=0.62) and IGF-I was inversely associated (0.85;0.79,0.91;ptrend<0.001) with prostate cancer. In addition, no strong associations existed with cancer stage or grade. Overall, these findings suggest potentially important roles for circulating IGF-II, IGFBP-2 and IGFBP-3 in PSA-detected prostate cancer, in support of recent in vitro evidence. While our findings for IGF-I agree with previous results from PSA-screening trials, they contrast with positive associations in routinely-detected disease, suggesting that reducing levels of circulating IGF-I might not prevent the initiation of prostate cancer but might nonetheless prevent its progression

Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker