Visalini Nair-Shalliker

BACKGROUND: The aim is to determine the effects of obesity and metformin-use in predicting prostate cancer (PC) risk. METHODS: We used male participants from the Sax Institute's 45 and Up Study (Australia), recruited between 2005-2009. Participants completed a questionnaire at recruitment which included information on self-reported body mass index (BMI; kg/m 2). Participants' baseline data were linked by the Centre for Health Record Linkage to the NSW Cancer Registry and to Services Australia to identify index prescription claims for diabetic medications between January 2012 and December 2019. Multivariable Joint Cox regression analyses were used to examine associations between BMI, diabetic medications, and PC risk by cancer spread. RESULTS: Of the 94,674 eligible participants, there were 5265 incident PC cases (localised n = 2638, regional n = 925, metastatic n = 1514 and unknown; n = 1514) diagnosed between January 2012 and December 2019. BMI ≥ 30 kg/m 2 was associated with increased risk of metastatic PC (versus <30 kg/m 2 ; HR adjusted = 1.67;95%CI:1.10-2.54); metformin-use was associated with reduced risk of localised PC (versus non-users; HR-metformin-only = 0.65;95%CI:0.50-0.84; HR metformin-combination = 0.51;95%CI:0.34-0.77). Reduced risk of localised PC diagnosis in metformin-users (versus non-users) was evident across all BMI categories. CONCLUSION: Metformin-use in obese men is associated with reduced PC risk, if detected early. Further research could inform the repurposing of metformin for PC control.

Background The ProsD trial aimed to determine if oral vitamin D supplementation could prevent prostate cancer (PC) progression in men on active surveillance (AS). Methods ProsD is a phase-II double-blinded randomized trial of newly diagnosed, low-intermediate risk PC cases, aged between 50 and 80 years and on AS. The intervention was a monthly oral dose of cholecalciferol (50,000IU; Vitamin D) or placebo. Primary and secondary endpoints were active therapy-free (ATFS) and progression-free (PFS) survival, respectively. Blood samples were analysed for vitamin D metabolites and cytokinesis-block micronucleus cytome (CBMN) markers for lymphocytic genome damage. Results There were 123 randomised participants (81 vitamin D and 42 placebo) included in this analysis. Mean (SD) for age was 66.5 (6.6) years and for 25(OH)D levels were 72.0 (19.9) and 66.4 (18.4) nmol/L at baseline (p = 0.1), and 91.9 (19.9) and 60.4 (24.4) nmol/L at 24 months, in the vitamin D and placebo arms respectively. There were no appreciable differences in ATFS (p_log-rank = 0.44), PFS (p p_log-rank = 0.60) and occurrence of adverse events, in each trial arm. There were declines in some of the lymphocytic CBMN markers in the vitamin D arm. Conclusion Vitamin D supplementation did not prevent PC progression, although reduced prevalence of CBMN markers may indicate a benefit of vitamin D supplementation. Trial registration Australia New Zealand Clinical Trials Registry (ACTRN12616001707459).

Objective: To describe the patterns of care and factors associated with treatment uptake of localised prostate cancer, using the bi‐national Prostate Cancer Outcomes Registry–Australia and New Zealand (PCOR‐ANZ) database. Methods: Data for 36 504 patients, diagnosed between 2015 and 2018, from New Zealand and seven Australian jurisdictions were evaluated. Multinomial logistic regression was performed to identify factors associated with the likelihood of receiving no active treatment, radiotherapy (RT), androgen deprivation therapy (ADT) and combined ADT + RT, compared to radical prostatectomy (RP). Results: The most common disease risk group and treatment were intermediate‐risk disease (49.2%) and RP (40.3%). Men with low‐risk disease were mostly managed by no active treatment (81.5%). Compared to men treated with RP, the likelihood of receiving other treatments was higher in residents from regional areas, those from lower socio‐economic status (SES) areas and those diagnosed at regional or public hospitals. Being in the lowest SES group was associated with an odds ratio (OR) of 1.84, (95% confidence interval [CI] 1.67–2.02) of having no active treatment, an OR of 1.53 (95% CI 1.32–1.78) for RT, an OR of 2.66 (95% CI 2.10–3.36) for ADT and an OR of 2.56 (95% CI 2.23–2.93) for ADT + RT. Conclusions: Factors related to SES and hospital provider were associated with treatment choices in localised prostate cancer patients, independent of their age or disease risk classification.

Guidelines for prostate specific antigen (PSA) testing in Australia recommend that men at average risk of prostate cancer who have been informed of the benefits and harms, and who decide to undergo regular testing, should be offered testing every 2 years from 50 to 69 years. This study aimed to estimate the benefits and harms of regular testing in this context. We constructed Policy1-Prostate, a discrete event microsimulation platform of the natural history of prostate cancer and prostate cancer survival, and PSA testing patterns and subsequent management in Australia. The model was calibrated to pre-PSA (before 1985) prostate cancer incidence and mortality and validated against incidence and mortality trends from 1985 to 2011 and international trials. The model predictions were concordant with trials and Australian observed incidence and mortality data from 1985 to 2011. Out of 1000 men who choose to test according to the guidelines, 36 [21-41] men will die from prostate cancer and 126 [119-133] men will be diagnosed with prostate cancer, compared with 50 [47-54] and 94 [90-98] men who do not test, respectively. During the 20 years of active PSA testing, 32.3% [25.6%-38.8%] of all PSA-test detected cancers are overdiagnosed cases that is, 30 [21-42] out of 94 [83-107] PSA-test detected cancers. Australian men choosing to test with PSA every two years from 50 to 69 will reduce their risk of ever dying from prostate cancer and incur a risk of overdiagnosis: for every man who avoids dying from prostate cancer, two will be overdiagnosed with prostate cancer between 50 and 69 years of age. Australian men, with health professionals, can use these results to inform decision-making about PSA testing.

Background: The association between cutaneous melanoma and subsequent risk of prostate cancer (PC) was examined in a large population-based cohort study. Methods: Male participants in the Sax Institute’s 45 and Up Study (Australia) were recruited between 2006 and 2009. Questionnaire data and linked administrative health data from the Centre for Health Record Linkage and Services Australia identified melanomas diagnosed between 1/1/1994 and 12 months before Study recruitment (i.e., between 2005 and 2008), incident PCs, primary healthcare utilisation and prostate-specific antigen (PSA) tests. Men were excluded from the current analyses if they had a recorded PC or other cancer diagnosis other than melanoma and non-melanoma skin cancer prior to recruitment. Multivariable Cox regression was used to estimate hazard ratios (HRs) adjusting for PSA-testing frequency before PC diagnosis. Results: Of 96,548 eligible men, 1899 were diagnosed with melanoma during the melanoma diagnosis period and 3677 incident PC diagnosed during follow-up (latest date 31/12/2013). Men with melanoma diagnosis had increased risk of a subsequent PC diagnoses (vs. no melanoma; fully adjusted HR = 1.32; 95% CI: 1.09–1.60). There was weak evidence of higher risks of a subsequent PC diagnosis for men diagnosed with more than one melanoma compared to men diagnosed with only one melanoma (p = 0.077), and if first melanoma diagnosis was 10 to 15 years before Study recruitment (fully adjusted HR = 2.05; 95% CI [1.35, 3.12]). Conclusion: Melanoma diagnosis was associated with increased risk of subsequent PC diagnosis, after adjusting for PSA testing and primary healthcare utilisation. While our ability to adjust for PC screening reduced risk of detection bias, we acknowledge that residual confounding from increased medical surveillance after melanoma diagnoses cannot be entirely ruled out.

Background: Prostate cancer (PC) aetiology is unclear. PC risk was examined in relation to several factors in a large population-based prospective study.Methods: Male participants were from Sax Institute’s 45 and Up Study (Australia) recruited between 2006 and 2009. Questionnaire and linked administrative health data from the Centre for Health Record Linkage and Services Australia were used to identify incident PC, healthcare utilisations, Prostate Specific Antigen (PSA) testing reimbursements and dispensing of metformin and benign prostatic hyperplasia (BPH) prescriptions. Multivariable Cox and Joint Cox regression analyses were used to examine associations by cancer spread, adjusting for various confounders.Results: Of 107,706 eligible men, 4257 developed incident PC up to end 2013. Risk of PC diagnosis increased with: PC family history (versus no family history of cancer; HR_adjusted = 1.36; 95% CI:1.21–1.52); father and brother(s) diagnosed with PC (versus cancer-free family history; HR_adjusted = 2.20; 95% CI:1.61–2.99); severe lower-urinary-tract symptoms (versus mild; HR_adjusted = 1.77; 95% CI:1.53–2.04) and vasectomy (versus none; HR_adjusted = 1.08; 95% CI:1.00–1.16). PC risk decreased with dispensed prescriptions (versus none) for BPH (HR_adjusted = 0.76; 95% CI:0.69–0.85) and metformin (HR_adjusted = 0.57; 95% CI:0.48–0.68). Advanced PC risk increased with vasectomy (HR_adjusted = 1.28; 95% CI:1.06–1.55) and being obese (versus normal weight; HR_adjusted = 1.31; 95% CI:1.01–1.69).Conclusion: Vasectomy and obesity are associated with an increased risk of advanced PC. The reduced risk of localised and advanced PC associated with BPH, and diabetes prescriptions warrants investigation.

Background: Population characteristics associated with the use of prostate biopsy are poorly understood. We described the use of diagnostic prostate biopsy and subsequent biopsy outcomes in a population-based Australian cohort. Methods: A total of 91,764 men from the Sax Institute's 45 and Up Study (New South Wales, Australia) recruited during 2006 to 2009 were included. Self-completed baseline questionnaires and linked administrative health data were used. Study period was from the date of recruitment to December 2013. Cox regression and logistic regression identified factors associated with receipt of biopsy and subsequent prostate cancer diagnosis. Results: During the study period, 5,089 participants had a diagnostic prostate biopsy, and 2,805 men (55.1% of those biopsied) received a cancer diagnosis. Men with a family history of prostate cancer (HR 1.55; 95% confidence interval (CI), 1.43–1.68), severe lower urinary tract symptoms (HR 1.62; 95% CI, 1.41–1.86), or a record of medication for benign prostatic hyperplasia (HR 1.34; 95% CI, 1.23–1.47) had increased risks of receiving a biopsy. Men with a family history of prostate cancer had increased odds of a positive biopsy (OR 1.21; 95% CI, 1.01–1.43). High alcohol consumption (≥21 drinks per week compared with 1–6 drinks per week) was associated with decreased risk of biopsy (HR 0.88; 95% CI, 0.80–0.96) but increased odds of a positive biopsy (OR 1.63; 95% CI, 1.32–2.02). Conclusions: Certain characteristics are associated with both undertaking diagnostic prostate biopsy and positive biopsy outcomes. Impact: This highlights the need to improve management of specific groups of men, especially those with clinical symptoms that overlap with prostate cancer, in their investigation for prostate cancer.

Introduction Active surveillance (AS) for patients with prostate cancer (PC) with low risk of PC death is an alternative to radical treatment. A major drawback of AS is the uncertainty whether a patient truly has low risk PC based on biopsy alone. Multiparametric MRI scan together with biopsy, appears useful in separating patients who need curative therapy from those for whom AS may be safe. Two small clinical trials have shown short-term high-dose vitamin D supplementation may prevent PC progression. There is no substantial evidence for its long-term safety and efficacy, hence its use in the care of men with PC on AS needs assessment. This protocol describes the ProsD clinical trial which aims to determine if oral high-dose vitamin D supplementation taken monthly for 2 years can prevent PC progression in cases with low-to-intermediate risk of progression. Method and analysis This is an Australian national multicentre, 2:1 double-blinded placebo-controlled phase II randomised controlled trial of monthly oral high-dose vitamin D supplementation (50 000 IU cholecalciferol), in men diagnosed with localised PC who have low-to-intermediate risk of disease progression and are being managed by AS. This trial will assess the feasibility, efficacy and safety of supplementing men with an initial oral loading dose of 500 000 IU cholecalciferol, followed by a monthly oral dose of 50 000 IU during the 24 months of AS. The primary trial outcome is the commencement of active therapy for clinical or non-clinical reason, within 2 years of AS. Ethics and dissemination This trial is approved by Bellberry Ethics Committee (2016-06-459). All results will be reported in peer-reviewed journals. Trial registration number ACTRN12616001707459.