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Laparoscopic-assisted surgery for rectal cancer is widely used, however the healthcare costs are thought to be higher than for open resection. This secondary endpoint analysis of a randomized controlled trial aimed to evaluate total healthcare costs of laparoscopic-assisted surgery compared with open resection for rectal cancer over a 12-month period. Patients in the Australasian Laparoscopic Cancer of the Rectum Trial (ALaCaRT) were included in a prospective costing analysis. All healthcare use for the index surgery and hospital admission, readmissions, and follow-up care over 12 months were included. Unit costs were valued in Australian dollars (AUD$) using scheduled Medicare fees and hospital cost weights. The primary outcome was mean per patient cost. Non-parametric bootstrapping with 10,000 replications was undertaken for robustness checks. Data from 468 patients indicated that the laparoscopic-assisted surgical procedure incurred a mean cost of AUD$4542 (standard deviation [SD] AUD$1050)—AUD$521 higher than the open procedure mean cost of AUD$4021 (SD AUD$804) due to longer operative time and involvement of more costly equipment (95% confidence interval [CI] AUD$354–AUD$692). At 12 months, the average cost for the laparoscopic-assisted and open groups was AUD$43,288 (SD AUD$40,883) and AUD$45,384 (SD AUD$38,659), respectively, due to the shorter subsequent hospital stays. No overall significant cost difference between groups was found (95% CI −AUD$9358 to AUD$5003). One-way sensitivity analyses confirmed the robustness of the results. While initially higher, the costs of laparoscopic-assisted surgery for rectal cancer were similar to open resection at 12 months. Clinicians may choose a surgical approach based on clinical need. The Australasian Gastro-Intestinal Trials Group (AGITG) was the legal sponsor and trial coordination was performed by the NHMRC Clinical Trials Centre. The trial was registered with the Australian and New Zealand Clinical Trial Registry (ACTRN12609000663257)

Men who initially present with localized prostate cancer and later develop metachronous metastases have a better prognosis than men with de novo metastatic disease and often have a low burden of disease on conventional imaging. Some have disease amenable to metastasis-directed therapy for lymph node or bone metastases, a strategy used by some because no documented overall survival (OS) benefit of combination systemic therapy in this setting. We report data for patients prospectively classified as "M0" at initial diagnosis from the interim analysis of the ENZAMET trial, with 34 mo of median follow-up for survivors. A total of 312 (28%) of the 1125 enrolled patients were classified as M0 at diagnosis, and 205 (66%) of the 312 patients had low-volume disease at study entry as per the CHAARTED criteria. The hazard ratio for OS, that is, HR(OS), was 0.56 (95% confidence interval [CI]: 0.29-1.06) with the addition of enzalutamide for all patients with metachronous metastatic hormone-sensitive prostate cancer, and for the low-volume subset the HR(OS) was 0.40 (95% CI: 0.16-0.97). The 3-yr OS was 83% without and 89% with enzalutamide for all patients with metachronous metastases, and 83% and 92%, respectively, for the low-volume subset. Intensification of hormonal therapy should strongly be considered for these men. PATIENT SUMMARY: Many men present with prostate cancer that has spread to distant sites beyond the prostate gland years after their initial diagnosis and treatment, while others have distant spread at the time the cancer is diagnosed. On average, men whose cancer comes back years after the initial diagnosis often survive much longer than men whose cancer has been found to spread to distant sites when it is first diagnosed. In this report, we demonstrate strong evidence for the first time that the survival of men whose cancer comes back years later is improved when drugs such as enzalutamide or apalutamide are added to testosterone suppression in this setting.

Purpose Activity estimates should be accurately evaluated in phase 2 clinical trials to ensure appropriate decisions about proceeding to phase 3 trials. RECIST v1.1. progression-free survival (PFS) is a common endpoint in oncology; however, it can be influenced by assessment criteria and trial design. We assessed the value of central adjudication of investigator-assessed PFS times of participants in a double-blind, randomised phase 2 trial evaluating regorafenib versus placebo in advanced gastro-oesophageal cancer (AGITG INTEGRATE) to inform plans for central review in future trials. Methods We calculated the proportion of participants with a disagreement between the site investigator assessment and blinded independent central review and in whom central review resulted in a change, then evaluated the effect of central review on study conclusions by comparing hazard ratios (HRs) for PFS based on site review versus central review. Post-progression unblinding was assessed with similar methods. Simulation studies explored the effect of differential and non-differential measurement error on treatment effect estimation and study power. Results Disagreements between site assessments versus central review occurred in 8/147 (5.4%) participants, 5 resulting in amended date of progression (3.4%). PFS HRs (sites vs central review progression dates) were similar (0.39 vs 0.40). RECIST progression occurred in 82/86 (95%) of cases where post-progression unblinding was requested by the site investigator. Conclusions Blinded independent central review was feasible and supported the reliability of site assessments, trial results, and conclusions. Modelling showed that when treatment effects were large and outcome assessments blinded, central review was unlikely to affect conclusions.

Summary Background Men who are overweight or obese frequently have low serum testosterone concentrations, which are associated with increased risk of type 2 diabetes. We aimed to determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes, beyond the effects of a community-based lifestyle programme. Methods T4DM was a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial done at six Australian tertiary care centres. Men aged 50–74 years, with a waist circumference of 95 cm or higher, a serum testosterone concentration of 14·0 nmol/L or lower but without pathological hypogonadism, and impaired glucose tolerance (oral glucose tolerance test [OGTT] 2-h glucose 7·8–11·0 mmol/L) or newly diagnosed type 2 diabetes (provided OGTT 2-h glucose ≤15·0 mmol/L) were enrolled in a lifestyle programme and randomly assigned (1:1) to receive an intramuscular injection of testosterone undecanoate (1000 mg) or placebo at baseline, 6 weeks, and then every 3 months for 2 years. Randomisation was done centrally, including stratification by centre, age group, waist circumference, 2-h OGTT glucose, smoking, and first-degree family history of type 2 diabetes. The primary outcomes at 2 years were type 2 diabetes (2-h OGTT glucose ≥11·1 mmol/L) and mean change from baseline in 2-h OGTT glucose, assessed by intention to treat. For safety assessment, we did a masked monitoring of haematocrit and prostate-specific antigen, and analysed prespecified serious adverse events. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000287831. Findings Between Feb 5, 2013, and Feb 27, 2017, of 19 022 men who were pre-screened, 1007 (5%) were randomly assigned to the placebo (n=503) and testosterone (n=504) groups. At 2 years, 2-h glucose of 11·1 mmol/L or higher on OGTT was reported in 87 (21%) of 413 participants with available data in the placebo group and 55 (12%) of 443 participants in the testosterone group (relative risk 0·59, 95% CI 0·43 to 0·80; p=0·0007). The mean change from baseline 2-h glucose was −0·95 mmol/L (SD 2·78) in the placebo group and −1·70 mmol/L (SD 2·47) in the testosterone group (mean difference −0·75 mmol/L, −1·10 to −0·40; p Interpretation Testosterone treatment for 2 years reduced the proportion of participants with type 2 diabetes beyond the effects of a lifestyle programme. Increases in haematocrit might be treatment limiting. Longer-term durability, safety, and cardiovascular effects of the intervention remain to be further investigated. Funding Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW (formerly Weight Watchers).

Background Maintaining employment for adults with cancer is important, however, little is known about the impact of surgery for rectal cancer on an individual's capacity to return to work (RTW). This study aimed to determine the impact of laparoscopic vs. open resection on RTW at 12 months. Methods Analyses were undertaken among participants randomized in the Australian Laparoscopic Cancer of the Rectum Trial (ALaCaRT), with work status available at baseline (presurgery), and 12 months. Multivariable logistic regression, adjusted for sociodemographic and clinical characteristics estimated the effect of surgery on RTW in any capacity, or return to preoperative work status at 12 months. Results About 228 of 449 (51%) surviving trial participants at 12 months completed work status questionnaires; mean age was 62 years, 66% males, 117 of these received laparoscopic resection (51%). Of 228, 120 were employed at baseline (90 full‐time, 30 part‐time). Overall RTW in 120 participants in paid work at baseline was 78% (84% laparoscopic, 70% open surgery). Those employed full‐time were more likely to RTW at 12 months (OR, 3.55; 95% CI, 1.02–12.31). Those with distant metastases at baseline were less likely to RTW (OR, 0.07; 95% CI, Rectal cancer patients with laparoscopic‐assisted surgery have a slightly but not significantly higher return to work rate at 12 months than those with open rectal resection. Results of this randomised controlled trial highlight the importance of discussing employment disruption and retention strategies with adults undergoing surgery for rectal cancer

Summary Background Very low birthweight or preterm infants are at increased risk of adverse outcomes including sepsis, necrotising enterocolitis, and death. We assessed whether supplementing the enteral diet of very low-birthweight infants with lactoferrin, an antimicrobial protein, reduces all-cause mortality or major morbidity. Methods We did a multicentre, double-blind, pragmatic, randomised superiority trial in 14 Australian and two New Zealand neonatal intensive care units. Infants born weighing less than 1500 g and aged less than 8 days, were eligible and randomly assigned (1:1) using minimising web-based randomisation to receive once daily 200 mg/kg pasteurised bovine lactoferrin supplements or no lactoferrin supplement added to breast or formula milk until 34 weeks' post-menstrual age (or for 2 weeks, if longer), or until discharge from the study hospital if that occurred first. Designated nurses preparing the daily feeds were not masked to group assignment, but other nurses, doctors, parents, caregivers, and investigators were unaware. The primary outcome was survival to hospital discharge or major morbidity (defined as brain injury, necrotising enterocolitis, late-onset sepsis at 36 weeks' post-menstrual age, or retinopathy treated before discharge) assessed in the intention-to-treat population. Safety analyses were by treatment received. We also did a prespecified, PRISMA-compliant meta-analysis, which included this study and other relevant randomised controlled trials, to estimate more precisely the effects of lactoferrin supplementation on late-onset sepsis, necrotising enterocolitis, and survival. This trial is registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12611000247976. Findings Between June 27, 2014, and Sept 1, 2017, we recruited 1542 infants; 771 were assigned to the intervention group and 771 to the control group. One infant who had consent withdrawn before beginning lactoferrin treatment was excluded from analysis. In-hospital death or major morbidity occurred in 162 (21%) of 770 infants in the intervention group and in 170 (22%) of 771 infants in the control group (relative risk [RR] 0·95, 95% CI 0·79–1·14; p=0·60). Three suspected unexpected serious adverse reactions occurred; two in the lactoferrin group, namely unexplained late jaundice and inspissated milk syndrome, but were not attributed to the intervention and one in the control group had fatal inspissated milk syndrome. Our meta-analysis identified 13 trials completed before Feb 18, 2020, including this Article, in 5609 preterm infants. Lactoferrin supplements significantly reduced late-onset sepsis (RR 0·79, 95% CI 0·71–0·88; p Interpretation Lactoferrin supplementation did not improve death or major morbidity in this trial, but might reduce late-onset sepsis, as found in our meta-analysis of over 5000 infants. Future collaborative studies should use products with demonstrated biological activity, be large enough to detect moderate and clinically important effects reliably, and assess greater doses of lactoferrin in infants at increased risk, such as those not exclusively receiving breastmilk or infants of extremely low birthweight. Funding Australian National Health and Medical Research Council.

Background Elevated plasma cystatin C levels reflect reduced renal function and increased cardiovascular risk. Less is known about whether the increased risk persists long‐term or is independent of renal function and other important biomarkers. Methods and Results Cystatin C and other biomarkers were measured at baseline (in 7863 patients) and 1 year later (in 6106 patients) in participants in the LIPID (Long‐Term Intervention with Pravastatin in Ischemic Disease) study, who had a previous acute coronary syndrome. Outcomes were ascertained during the study (median follow‐up, 6 years) and long‐term (median follow‐up, 16 years). Glomerular filtration rate (GFR) was estimated using Chronic Kidney Disease Epidemiology Collaboration equations (first GFR‐creatinine, then GFR‐creatinine‐cystatin C). Over 6 years, in fully adjusted multivariable time‐to‐event models, with respect to the primary end point of coronary heart disease mortality or nonfatal myocardial infarction, for comparison of Quartile 4 versus 1 of baseline cystatin C, the hazard ratio was 1.37 (95% CI, 1.07–1.74; P =0.01), and for major cardiovascular events was 1.47 (95% CI, 1.19–1.82; P P Conclusions Cystatin C independently predicted major cardiovascular events, development of chronic kidney disease, and cardiovascular and all‐cause mortality. Prediction of long‐term mortality was independent of improved estimation of GFR. Registration URL: https://anzctr.org.au ; Unique identifier: ACTRN12616000535471.

To compare patient-reported urinary, bowel and sexual functioning of ALaCaRT Trial participants randomised to Open or Laparoscopic surgery for rectal cancer.The primary endpoint, non-inferiority of laparoscopic surgical resection adequacy, was not established.Participants completed QLQ-CR29 at baseline, three and 12-months post-surgery. Additionally, women completed Rosen's Female Sexual Functioning Index (FSFI).Men completed the International Index of Erectile Function (IIEF) and QLQ-PR25.We compared the proportions of participants in each group who experienced moderate/severe symptoms/dysfunction at each time-point and compared mean difference scores from baseline to 12 months between groups. All analyses were intention-to-treat. Sexual functioning analyses included only the participants who expressed sexual interest at baseline.Baseline PRO compliance of 475 randomised participants was 88%. At 12 months, a lower proportion of Open surgery participants experienced moderate-severe faecal incontinence and sore skin, compared to Laparoscopic participants, and a lower proportion of men randomised to Open surgery experienced moderate-severe urinary symptoms. There were no differences at three months for bowel or urinary symptoms.Sexual functioning among sexually interested participants was similar between groups at three and 12 months, however a lower proportion of women reported moderate to severe sexual dissatisfaction at three months in the Open (p[Combining Circumflex Accent]1 = 0.31) as compared to the Laparoscopic (p[Combining Circumflex Accent]2 = 0.52) group, (p[Combining Circumflex Accent]2-p[Combining Circumflex Accent]1 = 0.21,95%CI 0.03,0.39).Despite the slightly lower proportions of Open surgery participants self-reporting moderate-severe symptoms for three of 16 urinary/bowel domains, and lack of differences in sexual domains, it remains difficult to recommend one surgical approach over another for rectal resection.

Very preterm infants are at increased risk of adverse outcomes in early childhood. We assessed whether delayed clamping of the umbilical cord reduces mortality or major disability at 2 years in the APTS Childhood Follow Up Study.In this long-term follow-up analysis of the multicentre, randomised APTS trial in 25 centres in seven countries, infants (30 weeks gestation) were randomly assigned before birth (1:1) to have clinicians aim to delay clamping for 60 s or more or clamp within 10 s of birth, both without cord milking. The primary outcome was death or major disability (cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay) at 2 years corrected age, analysed in the intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12610000633088).Between Oct 21, 2009, and Jan 6, 2017, consent was obtained for follow-up for 1531 infants, of whom 767 were randomly assigned to delayed clamping and 764 to immediate clamping. 384 (25%) of 1531 infants were multiple births, 862 (56%) infants were male, and 505 (33%) were born before 27 weeks gestation. 564 (74%) of 767 infants assigned to delayed clamping and 726 (96%) of 764 infants assigned to immediate clamping received treatment that fully adhered to the protocol. Death or major disability was determined in 1419 (93%) infants and occurred in 204 (29%) of 709 infants who were assigned to delayed clamping versus 240 (34%) of 710 assigned to immediate clamping, (relative risk [RR]) 0·83, 95% CI 0·72-0·95; p=0·010). 60 (8%) of 725 infants in the delayed clamping group and 81 (11%) of 720 infants in the immediate clamping group died by 2 years of age (RR 0·70, 95% CI 0·52-0·95); among those who survived, major disability at 2 years occurred in 23% (144/627) versus 26% (159/603) of infants, respectively (RR 0·88, 0·74-1·04).Clamping the umbilical cord at least 60 s after birth reduced the risk of death or major disability at 2 years by 17%, reflecting a 30% reduction in relative mortality with no difference in major disability.Australian National Health and Medical Research Council.

Objectives The aim of the study was to compare the response rates and costs of phone call vs. short message service (SMS) screening reminders to prospective randomized controlled trial (RCT) participants. Study Design and Setting This study was a randomized evaluation within a large Australian diabetes prevention RCT. Participants were men aged 50–74 years, overweight or obese, without a previous type 2 diabetes diagnosis. Those eligible on a prescreening questionnaire who did not attend a further screening assessment within 4 weeks were randomized to receive an SMS or phone call reminder (N = 709). The primary outcome was attendance for further screening assessment within 8 weeks of prescreening. Results Attendance was 18% (62/354) in the SMS reminder group, and 23% (80/355) in the phone reminder group, with no statistically significant difference in response according to reminder type (relative risk = 1.29, 95% confidence interval [CI]: 0.96–1.73, P = 0.09). The lower confidence limits for response to SMS (95% CI: 14–22%) and phone reminders (95% CI: 18–27%) did not include the 8-week attendance rate before this evaluation, 12%. Phone reminders cost substantially more than SMS reminders (AU$6.21 vs. AU$0.53 per reminder). Conclusion SMS reminders were as adequate a method as phone reminders to boost RCT screening uptake and were considerably more affordable.

International collaboration in oncology trials has the potential to enhance clinical trial activity by expediting the recruitment of large patient populations, testing treatments in diverse populations and facilitating the study of rare tumours or specific molecular subtypes. However, a number of challenges continue to hinder the efficient and productive conduct of both commercial and non-commercial international clinical trials. These challenges include complex and burdensome regulatory requirements, the high cost of conducting trials, and logistical challenges associated with ethics review, drug supply and biospecimen collection and management. We propose solutions to promote oncology trial collaboration, such as regulatory reform, harmonisation of trial initiation and management processes and greater recognition and funding of academic (non-commercial) clinical trials. It is only through coordinated effort and leadership from researchers, regulators and those responsible for health systems that the full potential of international trial collaboration can be realised.

Background Effective interventions are required to prevent the current rapid increase in the prevalence of Type 2 diabetes. Clinical trials of large-scale interventions to prevent Type 2 diabetes are essential but recruitment is challenging and expensive, and there are limited data regarding the most cost-effective and efficient approaches to recruitment. This paper aims to evaluate the cost and effectiveness of a range of promotional strategies used to recruit men to a large Type 2 diabetes prevention trial. Methods An observational study was conducted nested within the Testosterone for the Prevention of Type 2 Diabetes (T4DM) study, a large, multi-centre randomised controlled trial (RCT) of testosterone treatment for the prevention of Type 2 diabetes in men aged 50–74 years at high risk of developing diabetes. Study participation was promoted via mainstream media—television, newspaper and radio; direct marketing using mass mail-outs, publicly displayed posters and attendance at local events; digital platforms, including Facebook and Google; and online promotions by community organisations and businesses. For each strategy, the resulting number of participants and the direct cost involved were recorded. The staff effort required for each strategy was estimated based on feedback from staff. Results Of 19,022 men screened for the study, 1007 (5%) were enrolled. The most effective recruitment strategies were targeted radio advertising (accounting for 42% of participants), television news coverage (20%) and mass mail-outs (17%). Other strategies, including radio news, publicly displayed posters, attendance at local events, newspaper advertising, online promotions and Google and Facebook advertising, each accounted for no more than 4% of enrolled participants. Recruitment promotions cost an average of AU$594 per randomised participant. The most cost-effective paid strategy was mass mail-outs by a government health agency (AU$745 per participant). Other paid strategies were more expensive: mail-out by general practitioners (GPs) (AU$1104 per participant), radio advertising (AU$1081) and newspaper advertising (AU$1941). Conclusion Radio advertising, television news coverage and mass mail-outs by a government health agency were the most effective recruitment strategies. Close monitoring of recruitment outcomes and ongoing enhancement of recruitment activities played a central role in recruitment to this RCT. Trial registration ANZCTR, ID: ACTRN12612000287831. Registered on 12 March 2012. Electronic supplementary material The online version of this article (10.1186/s13063-019-3485-2) contains supplementary material, which is available to authorized users.

TPS3646 Background: In retrospective studies statin use during preoperative chemo-radiation (pCRT) for rectal cancer is associated with improved overall survival, pathological tumor response and treatment toxicity. In vivo preclinical studies show that statins radiosensitize cancer cells, with improved tumor control and reduced radiation-induced gastrointestinal (GI) and skin toxicities. A prospective randomized trial is justified to confirm these clinically important benefits. Tumor regression following pCRT has strong prognostic significance, as assessed radiologically (MRI-based tumor regression grading [mrTRG]) prior to, or pathologically (pathTRG) following, surgery. Using mrTRG after each treatment phase in total neoadjuvant therapy (TNT) programs could assess incremental tumor regression and optimize patient management including surgery. Methods: Design: This double-blind phase 2 trial is recruiting 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 17 sites in New Zealand and Australia. Patients are randomized to simvastatin 40mg or placebo daily for 90 days, starting 1 week prior to pCRT, with minimization for major prognostic variables. Pelvic MRI at baseline and 6-8 weeks after pCRT will assess mrTRG. A protocol amendment allows TNT using consolidation chemotherapy after pCRT; MRI timing is unchanged. Primary objective: comparison of rates of grades 1-2 mrTRG following pCRT with simvastatin or placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4-5). Secondary objectives: comparison of rates of grades 1-2 pathTRG in resected tumors; incidence of > grade 2 acute GI and non-GI adverse events (AE); incidence of late GI AE; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection post-pCRT; 3-year local recurrence rate, disease-free and cancer-specific survival; and pathological scores for radiation colitis. Tertiary and correlative objectives: association between mrTRG and pathTRG grouping; inter-observer scoring agreement on mrTRG and pathTRG; comparison of the association between tumor CD3+ and/or CD8+ T-cell infiltrates in diagnostic biopsies and pathTRG; intensity and distribution of subsets of infiltrating T-cells in irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Eligibility criteria exclude statin use within 6 weeks prior to trial entry, patients intolerant of statins, and planned use of oxaliplatin or biological agents during pCRT. Trial recruitment commenced April 2018 and 95 of 222 patients have been recruited as at 21 January 2022. Clinical trial information: ACTRN12617001087347.

Background: The preferred timing of umbilical-cord clamping in preterm infants is unclear. Methods: We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births. Results: Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. Conclusions: Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088. opens in new tab.)

Background Retrospective studies show improved outcomes in colorectal cancer patients if taking statins, including overall survival, pathological response of rectal cancer to preoperative chemoradiotherapy (pCRT), and reduced acute and late toxicities of pelvic radiation. Major tumour regression following pCRT has strong prognostic significance and can be assessed in vivo using MRI-based tumour regression grading (mrTRG) or after surgery using pathological TRG (pathTRG). Methods A double-blind phase 2 trial will randomise 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 18+ sites in New Zealand and Australia. Patients will receive simvastatin 40 mg or placebo daily for 90 days starting 1 week prior to standard pCRT. Pelvic MRI 6 weeks after pCRT will assess mrTRG grading prior to surgery. The primary objective is rates of favourable (grades 1–2) mrTRG following pCRT with simvastatin compared to placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4–5). Secondary objectives include comparison of: rates of favourable pathTRG in resected tumours; incidence of toxicity; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection; cancer outcomes and pathological scores for radiation colitis. Tertiary objectives include: association between mrTRG and pathTRG grouping; inter-observer agreement on mrTRG scoring and pathTRG scoring; studies of T-cell infiltrates in diagnostic biopsies and irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Trial recruitment commenced April 2018. Discussion When completed this study will be able to observe meaningful differences in measurable tumour outcome parameters and/or toxicity from simvastatin. A positive result will require a larger RCT to confirm and validate the merit of statins in the preoperative management of rectal cancer. Such a finding could also lead to studies of statins in conjunction with chemoradiation in a range of other malignancies, as well as further exploration of possible mechanisms of action and interaction of statins with both radiation and chemotherapy. The translational substudies undertaken with this trial will provisionally explore some of these possible mechanisms, and the tissue and data can be made available for further investigations. Trial registration ANZ Clinical Trials Register ACTRN12617001087347. (www.anzctr.org.au, registered 26/7/2017) Protocol Version: 1.1 (June 2017).

Background/aims: Participant recruitment to diabetes prevention randomised controlled trials is challenging and expensive. The T4DM study, a multicentre, Australia-based, Phase IIIb randomised controlled trial of testosterone to prevent Type 2 diabetes in men aged 50–74 years, faced the challenge of screening a large number of prospective participants at a small number of sites, with few staff, and a limited budget for screening activities. This article evaluates a high-volume, low-cost, semi-automated approach to screen and enrol T4DM study participants. Methods: We developed a sequential multi-step screening process: (1) web-based pre-screening, (2) laboratory screening through a network of third-party pathology centres, and (3) final on-site screening, using online data collection, computer-driven eligibility checking, and automated, email-based communication with prospective participants. Phone- and mail-based data collection and communication options were available to participants at their request. The screening process was administered by the central coordinating centre through a central data management system. Results: Screening activities required staffing of approximately 1.6 full-time equivalents over 4 years. Of 19,022 participants pre-screened, 13,108 attended a third-party pathology collection centre for laboratory screening, 1217 received final, on-site screening, and 1007 were randomised. In total, 95% of the participants opted for online pre-screening over phone-based pre-screening. Screening costs, including both direct and staffing costs, totalled AUD1,420,909 (AUD75 per subject screened and AUD1411 per randomised participant). Conclusion: A multi-step, semi-automated screening process with web-based pre-screening facilitated low-cost, high-volume participant enrolment to this large, multicentre randomised controlled trial. Centralisation and automation of screening activities resulted in substantial savings compared to previous, similar studies. Our screening approach could be adapted to other randomised controlled trial settings to minimise the cost of screening large numbers of participants.

Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer.In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events.A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group.Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).

3073 Background: Data on the utility of a PARP inhibitor in combination with a checkpoint inhibitor remain limited, particularly in the histology agnostic setting with homologous recombination deficiency (HRD). This study evaluated the clinical activity of the combination of olaparib and durvalumab with the primary study endpoint of progression-free survival (PFS) at 6 months (PFS6m). Methods: This was a phase II, single-arm, signal-seeking study of the MoST program. Patients were recruited into two cohorts based on HRD genes, agnostic to histology: (1) BRCA 1/2 deficient tumours, excluding breast, prostate, ovarian cancers, and (2) other HRD related genes. Molecular testing was performed using in-house and commercial panels on archival tumour tissue centrally adjudicated by a molecular tumour board. All patients were treated with olaparib 300mg bid for 1 month, followed by combination with durvalumab 1500mg q4 weekly for 13 cycles. Olaparib treatment was then continued until disease progression. Results: Between Nov 2017-Feb 2019, 48 patients were enrolled (16 to BRCA 1/2 cohort 1 and 32 to HRD related genes cohort 2). Most common tumour sites were bone/soft tissue (15%, N=7), pancreas (13%, N=6) and stomach (8%, N=4). Overall best response in cohort 1 was PR (25%, N=4) and SD 4 (25%, N=4), and cohort 2 was PR (6%, N=2) and SD (56%, N=18). Median PFS was 3.65m (Cohort 1) and 3.56m (Cohort 2) respectively. PFS6m was 35% (Cohort 1) and 38% (Cohort 2) respectively. PDL1 status was not predictive of olaparib and durvalumab benefit. The most common grade 3/4 adverse events were anemia (11%%, N=4), abdominal pain (9%, N=3), increased lipase (9%,N=3), increased amylase (9%, N=3), dyspnea (6%, N=2), Hyperglycemia dyspnea (6%, N=2), Pancreatitis dyspnea (6%, N=2) and hematuria (6%, N=2). Conclusions: Olaparib and durvalumab show promising activity in a histology agnostic setting, particularly in BRCA deficient tumours. Further research is needed to identify biomarkers that correlate with treatment benefit. Results from longer clinical follow-up and additional biomarker analyses will be presented. Clinical trial information: ACTRN12617001000392 .

TPS385 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinising hormone releasing hormone analogue (LHRHA) for at least one year, is standard of care for men with very high-risk localised prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of men with very high risk features. Darolutamide is an androgen receptor antagonist with favourable tolerability. Our aim is to determine the efficacy of adding darolutamide to ADT and RT given in the setting of either primary definitive therapy (RP or RT), or adjuvant therapy for very high-risk PC. Methods: This study is a randomised (1:1) phase III placebo-controlled, double-blind trial for men planned for RT who have very high-risk localised PC, or very high-risk features with PSA persistence or rise within one year following RP. The trial will be stratified by: use of adjuvant docetaxel; pelvic nodal involvement; RP. 1100 participants will be randomised to darolutamide 600 mg or placebo twice daily for 96 weeks. Participants will receive LHRHA for 96 weeks, plus RT starting week 8-24 from randomisation. Participants are allowed nonsteroidal antiandrogen (up to 90 days) in addition to LHRHA up until randomisation. Early treatment with 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival, with secondary endpoints overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety and resistance to study treatment. Clinical trial information: NCT04136353.

Background: Low circulating testosterone is associated with an increased risk of developing type 2 diabetes (T2DM) in overweight men with impaired glucose tolerance (IGT). Aims: To determine in a multi-centre, double-blinded placebo-controlled randomized trial whether testosterone treatment combined with lifestyle intervention (Weight Watchers) relative to lifestyle intervention alone reduces T2DM incidence and improves glucose tolerance at 2 years. Study population: Overweight or obese men aged 50-74 years with a serum testosterone of ≤14 nmol/L and IGT or newly diagnosed T2DM established by an oral glucose tolerance test (OGTT). Setting, drug and protocol: Six Australian capital city-based tertiary care centres. Participants were randomized 1:1 and injected with testosterone undecanoate (1000 mg/4 mL) or vehicle (4 mL castor oil), at baseline, 6 weeks and 3-monthly thereafter. Primary endpoints: (a) Proportion of participants with 2-hour OGTT ≥11.1 mmol/L at 2 years, and (b) a difference at 2 years ≥0.6 mmol/L in the mean 2-hour OGTT glucose between treatments. Secondary endpoints: Fasting insulin, HbA1c, body composition, maximal handgrip strength; sexual function and lower urinary tract symptoms; serum sex steroids and sex hormone binding globulin; mood and psychosocial function; adherence to lifestyle intervention; and healthcare utilization and costs. Safety: Overseen by an Independent Data Safety Monitoring Committee. Haematocrit, lipids and prostate-specific antigen (PSA) are assessed 6-monthly and information relating to haematological, urological and cardiovascular adverse events from each clinic visit. Sub-studies: (a) Changes in bone density and micro-architecture, (b) motivation and behaviour, (c) telomere length, (d) extended treatment up to 4 years, and (e) hypothalamo-pituitary testicular axis recovery at treatment end.

The aim of the study was to determine the efficacy of laparoscopic rectal resection (Lap) versus open laparotomy and rectal resection (Open) for rectal cancer on locoregional recurrence (LRR) and disease-free survival (DFS) at 2 years.Although a Lap approach to colon cancer surgery may offer similar oncological outcomes to Open with potentially less morbidity, this remains to be clearly established for the treatment of rectal cancer.A randomized, multicenter noninferiority phase 3 trial of 475 patients with T1 to T3 rectal adenocarcinoma15 cm from anal verge, given Lap or Open and followed for a minimum 2 years to assess LRR, DFS, and overall survival (OS).Secondary endpoint analyses included 450 patients (95%) without metastases at baseline (mean age 64; 34% women) who received Lap (n = 225) or Open (n = 225). Median follow-up was 3.2 years (range: 0.1-5.4 yrs). LRR cumulative incidence at 2 years: Lap 5.4%; Open 3.1% [difference, 2.3%; 95% confidence interval (CI), -1.5% to 6.1%; hazard ratio (HR) 1.7; 95% CI, 0.74-3.9]. DFS at 2 years: Lap 80%; Open 82% (difference, 2.0%; 95% CI, -9.3% to 5.4%; HR for recurrence or death, 1.17; 95% CI, 0.81-1.68; P = 0.41). After adjustment for baseline factors HR = 1.07 (95% CI, 0.7-1.6). OS at 2 years: Lap 94%; Open 93% (difference 0.9%; 95% CI, -3.6% to 5.4%).Laparoscopic surgery for rectal cancer did not differ significantly from open surgery in effects on 2-year recurrence or DFS and OS. Confidence intervals included potentially clinically important differences favoring open resection, so that the combination of primary and secondary study endpoints may not support laparoscopic resection of rectal cancer as a routine standard of care and further follow-up is required.

Background Precision medicine aims to link molecular targets in tumours with corresponding therapies, particularly for patients with rare cancers. Innovative approaches are needed to translate molecular opportunities into clinical care. The Cancer Molecular Screening and Therapeutics (MoST) program employs a molecular screening platform to identify molecular changes of therapeutic relevance (actionable changes) and a master protocol for multiple, parallel signal-seeking clinical substudies, focused on therapies for patients with rare and neglected cancers. Methods and analysis: Archival pathology laboratory samples from patients with treatment-refractory advanced solid cancer of any histologic type undergo molecular tumour profiling. Following review by a Molecular Tumour Board, eligible patients are offered treatment in therapeutic substudies. This novel master protocol allows expedited addition of individual substudies; at least 12 open label, single arm, signal-seeking substudies during the initial 4 years of MoST are planned. The primary objectives are to identify signals of efficacy for developing biomarker-driven therapies and biomarkers that more accurately predict response to therapy, as well as to evaluate the MoST design. Ethics approval: The program has been approved by the St Vincent's Hospital Sydney Human Research Ethics Committee (reference, HREC/16/SVH/23). Dissemination of results: A report summarising and interpreting collected study data will be published. Our findings will be presented at national and international conferences and scientific meetings, and published in peer-reviewed journals. Trial registration Australia New Zealand Clinical Trials Registry: ACTRN12616000908437 (8 July 2016).

Background: D-dimer, a degradation product of cross-linked fibrin, is a marker for hypercoagulability and thrombotic events. Moderately elevated levels of D-dimer are associated with the risk of venous and arterial events in patients with vascular disease. We assessed the role of D-dimer levels in predicting long-term vascular outcomes, cause-specific mortality, and new cancers in the LIPID trial (Long-Term Intervention with Pravastatin in Ischaemic Disease) in the context of other risk factors. Methods: LIPID randomized patients to placebo or pravastatin 40 mg/d 5 to 38 months after myocardial infarction or unstable angina. D-dimer levels were measured at baseline and at 1 year. Median follow-up was 6.0 years during the trial and 16 years in total. Results: Baseline D-dimer levels for 7863 patients were grouped by quartile (≤112, 112–173, 173–273, >273 ng/mL). Higher levels were associated with older age, female sex, history of hypertension, poor renal function, and elevated levels of B-natriuretic peptide, high-sensitivity C-reactive protein, and sensitive troponin I (each P P P P ≤0.01). Higher D-dimer also independently predicted an increase in cancer incidence (HR, 1.16; P =0.02).The D-dimer level increased the net reclassification index for all-cause mortality by 4.0 and venous thromboembolism by 13.6. Conclusions: D-dimer levels predict long-term risk of arterial and venous events, CVD mortality, and non-CVD noncancer mortality independent of other risk factors. D-dimer is also a significant predictor of cancer incidence and mortality. These results support an association of D-dimer with fatal events across multiple diseases and demonstrate that this link extends beyond 10 years’ follow-up.

In patients with stable coronary heart disease (CHD), we aimed to assess 1. the prognostic power of biomarkers reflecting haemodynamics, micronecrosis, inflammation, coagulation, lipids, neurohumoral activity, and renal function; 2. whether changes in concentrations of these biomarkers over 12 months affected subsequent CHD risk; and 3. whether pravastatin modified the change in biomarker concentrations and this influenced the risk of future events.In the LIPID study, 9014 patients were randomised to pravastatin 40 mg or placebo 3-36 months after an acute coronary syndrome. Eight biomarkers were measured at baseline (n=7863) and 12 months later (n=6434).During a median of 6.0 (IQR 5.5-6.5) years follow-up, 1100 CHD-related deaths and nonfatal myocardial infarctions occurred, 694 after biomarker measurement at 12 months. Baseline BNP, CRP, cystatin C, D-dimer, midregional pro-adrenomedullin, and sensitive troponin I predicted recurrent CHD events. In a multivariable model, sensitive troponin I, BNP, and cystatin C had the strongest associations with outcome (P0.001 for trend). The strongest improvement in risk prediction was achieved by including sensitive troponin I (net reclassification improvement (NRI) 5.5%; P=0.003), BNP (4.3%; P=0.02), history of MI (NRI 7.0%; P0.001). In landmark analyses, among biomarkers, changes to 12 months in sensitive troponin I (HR 1.32 (1.03-1.70) for T3/T1), BNP (HR 1.37 (1.10-1.69) for Q4/Q1) and Lp-PLA2 (HR 1.52 (1.16-1.97)) improved CHD risk prediction.Baseline levels and changes in sensitive troponin I, and BNP may have the potential to guide the intensity of secondary prevention therapy.

Systemic reviews have shown that delaying the time of umbilical cord clamping can improve outcomes of preterm newborns. One such study found enhanced placental transfusion through delayed cord clamping, cord-palpation, or a combination of the 2 practices caused a lower infection and mortality rate when compared with immediate clamping. Despite this recent body of evidence, concerns exist about harm from delayed resuscitation and hyperbilirubinemia causing current professional guidelines to vary significantly.

3136 Background: Personalizing therapy will arguably have no greater impact than on patients (pts) with rare (< 6 per 100,000 population) or less common cancers (6-12/100,000). MoST combines a molecular screening platform and biomarker-driven treatments for pts with advanced cancer, with a particular focus on rare and less common cancers (RLC). Methods: Molecular screening was performed using in-house and commercial panels on archival tumor tissue. A Molecular Tumor Board by consensus reported on pathogenic variants with potential therapeutic actionability. Tiers of actionability were defined as: Tier 1–eligible for a MoST substudy; Tier 2–clinical evidence of efficacy in any cancer type, Tier 3—preclinical evidence. The clinical and molecular characteristics of the first 1,000 pts are presented here. Results: Pts were recruited from Sept 2016 to Dec 2018. A report was issued in 94% of cases in a median of 7.7 weeks from consent. In 6%, there was insufficient tissue. The median age at cancer diagnosis was 35 years (range 4-85 years), and 49% were male. Pts had a median of 2 lines of prior systemic therapy (0-11), and a median baseline ECOG performance status of 0 (range 0-3). 82% of pts had RLCs. A total of 2642 pathogenic variants were reported, of which 1144 (43%) were deemed therapeutically actionable. 651(57%) of actionable variants (AVs) occurred in RLC (Table). Most commonly, AVs were found in the cell cycle, homologous recombination repair (HR) and fibroblast growth factor (FGF) pathways. 559(66%) of pts had at least one AV identified, 30% tier 1, 63% tier 2 and 6% tier 3, including 66% of RLC. In 30% of cases, a tumor mutational burden >11 mutations/ megabase was reported. Conclusions: Here we report a high frequency of AVs in RLC, providing a rational basis for assessing the potential of personalized therapy in a population with a historically unmet need for effective treatment. Clinical trial information: ACTRN12616000908437. [Table: see text]

ObjectivesTo identify and review evaluations of strategies to recruit men aged 50 years and over to randomised controlled trials (RCTs).DesignSystematic review and narrative synthesis.Data sourcesMEDLINE, EMBASE, CINAHL and ORRCA databases were searched to 1 December 2017.Eligibility criteriaStudies using quantitative methods to evaluate recruitment strategies to RCTs of men aged 50 years and older.Data extraction and synthesisA single reviewer extracted data (for each strategy, number of participants approached, screened and randomised, and cost). Study quality was assessed using National Heart, Lung and Blood Institute Quality Assessment Tools and considered study design, description of interventions, description and measurement of outcomes, completeness of outcome reporting, performance of statistical testing and consideration of confounders. Recruitment strategies were categorised by the recruitment stage they addressed.ResultsSixteen studies (n >14 000) were included: one good quality, ten fair quality and five poor quality. Studies evaluated strategies to identify prospective participants, and to improve the processes for assessing participant eligibility, providing participant information and seeking consent. In good and fair quality studies, the most effective strategies for identifying participants were referral from an affiliated health service provider (two studies), mass mailing (five studies) and media coverage (two studies). Community outreach activities such as displaying posters and attending local community events were not effective (two studies). Trial-specific training of site recruitment staff, developed using qualitative analysis of recruitment visits (two studies), and provision of study information to prospective participants at a multidisciplinary, group information session (one study) both improved recruitment.ConclusionImproved engagement of men aged 50 years and older in RCTs is needed. A gender-sensitised approach to RCT recruitment may help to address this need. We have identified several promising recruitment strategies that merit further evaluation.PROSPERO registration numberCRD42017060301.

Background Patients who have had a first episode of unprovoked venous thromboembolism have a high risk of recurrence after anticoagulants are discontinued. Aspirin may be effective in preventing a recurrence of venous thromboembolism. Methods We randomly assigned 822 patients who had completed initial anticoagulant therapy after a first episode of unprovoked venous thromboembolism to receive aspirin, at a dose of 100 mg daily, or placebo for up to 4 years. The primary outcome was a recurrence of venous thromboembolism. Results During a median follow-up period of 37.2 months, venous thromboembolism recurred in 73 of 411 patients assigned to placebo and in 57 of 411 assigned to aspirin (a rate of 6.5% per year vs. 4.8% per year; hazard ratio with aspirin, 0.74; 95% confidence interval [CI], 0.52 to 1.05; P = 0.09). Aspirin reduced the rate of the two prespecified secondary composite outcomes: the rate of venous thromboembolism, myocardial infarction, stroke, or cardiovascular death was reduced by 34% (a rate of 8.0% per year with placebo vs. 5.2% per year with aspirin; hazard ratio with aspirin, 0.66; 95% CI, 0.48 to 0.92; P = 0.01), and the rate of venous thromboembolism, myocardial infarction, stroke, major bleeding, or death from any cause was reduced by 33% (hazard ratio, 0.67; 95% CI, 0.49 to 0.91; P = 0.01). There was no significant between-group difference in the rates of major or clinically relevant nonmajor bleeding episodes (rate of 0.6% per year with placebo vs. 1.1% per year with aspirin, P = 0.22) or serious adverse events. Conclusions In this study, aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of venous thromboembolism but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit. These results substantiate earlier evidence of a therapeutic benefit of aspirin when it is given to patients after initial anticoagulant therapy for a first episode of unprovoked venous thromboembolism. (Funded by National Health and Medical Research Council [Australia] and others; Australian New Zealand Clinical Trials Registry number, ACTRN12605000004662.)

Aim The collection of data on longer-term neurodevelopmental outcomes within large neonatal randomized controlled trials by trained assessors can greatly increase costs and present many operational difficulties. The aim of this study was to develop a more practical alternative for identifying major cognitive delay in infants at the age of 24 months, based on parental reports. Method A sample of 476 infants (206 female, 270 male) previously diagnosed with neonatal sepsis (mean birthweight 1329g [SD 865g], mean gestational age at birth 28.7wks [SD 4.5wks]) from the International Neonatal Immunotherapy Study were assessed using the Parent Report of Children’s Abilities – Revised and the Bayley Scales of Infant Development, 2nd edition. Logistic regression was used to model the association between the risk of major cognitive delay (i.e. Bayley Scales of Infant Development Mental Development Index

TPS156 Background: Adjuvant ADT with an LHRH analog (LHRHA) given before, during and after radiotherapy (RT) is standard of care for high risk localised prostate cancer (PC). Enzalutamide improves overall survival (OS) in castration-resistant, metastatic prostate cancer. We hypothesized that the addition of enzalutamide to adjuvant ADT and RT will improve outcomes. The aim is to determine the effects of enzalutamide versus a conventional non-steroidal anti-androgen (NSAA) as part of neoadjuvant and adjuvant ADT in men undergoing RT for high risk, localized PC. Methods: DESIGN: Open label, randomised, phase 3 trial including ANZ, USA, UK, Ireland and Europe. ENDPOINTS: OS (primary), cause-specific survival, PSA progression free survival (PFS), clinical PFS, time to subsequent hormonal therapy, time to castration-resistant disease (PCWG2 criteria), metastasis free survival (MFS), adverse events and health-related quality of life (HRQOL). CORRELATIVE OBJECTIVES: identification of prognostic/predictive biomarkers from archival tumour tissue and serial blood samples. SAMPLE SIZE: 800 participants with a minimum follow-up of 5.5 yrs is designed to give 80% power to detect 33% reduction in the hazard of death assuming 5-year survival rate of 76% amongst controls. TREATMENT: Enzalutamide 160mg daily for 24 months versus conventional NSAA for 6 months. All participants receive LHRHA for 24 months, and RT starting about week 16 delivered as 78Gy in 39#, or 46Gy in 23# plus brachytherapy (nodal RT optional for N0, mandatory for N1). ASSESSMENTS: Baseline, then every 8 weeks until year 2, then 3-4 monthly until year 5, 6-monthly until year 7, then annually. Imaging with CT/MRI and bone scan at baseline, PSA progression, then 6 monthly until re-initiation of ADT, when PCWG2 criteria for CRPC are met and then 3 monthly until evidence of metastases. 623 participants recruited from 61 sites as of 16 October 2017. ENZARAD is an investigator-initiated cooperative group trial led by ANZUP Cancer Trials Group with funds and product from Astellas. Clinical trial information: NCT02446444.

Background— We aimed to assess the long-term effects of treatment with statin therapy on all-cause mortality, cause-specific mortality, and cancer incidence from extended follow-up of the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) trial. Methods and Results— LIPID initially compared pravastatin and placebo over 6 years in 9014 patients with previous coronary heart disease. After the double-blind period, all patients were offered open-label statin therapy. Data were obtained over a further 10 years from 7721 patients, by direct contact for 2 years, by questionnaires thereafter, and from mortality and cancer registries. During extended follow-up, 85% assigned pravastatin and 84% assigned placebo took statin therapy. Patients assigned pravastatin maintained a significantly lower risk of death from coronary heart disease (relative risk [RR] 0.89; 95% confidence interval [CI], 0.81−0.97; P =0.009), from cardiovascular disease (RR, 0.88; 95% CI, 0.81−0.95; P =0.002), and from any cause (RR, 0.91; 95% CI, 0.85−0.97; absolute risk reduction, 2.6%; P =0.003).Cancer incidence was similar by original treatment group during the double-blind period (RR, 0.94; 95% CI, 0.82–1.08; P =0.41), later follow-up (RR, 1.02; 95% CI, 0.91–1.14; P =0.74), and overall (RR, 0.99; 95% CI, 0.91–1.08; P =0.83). There were no significant differences in cancer mortality, or in the incidence of organ-specific cancers. Cancer findings were confirmed in a meta-analysis with other large statin trials with extended follow-up. Conclusions— In LIPID, the absolute survival benefit from 6 years of pravastatin treatment appeared to be maintained for the next 10 years, with a similar risk of death among survivors in both groups after the initial period. Treatment with statins does not influence cancer or death from noncardiovascular causes during long-term follow-up.

OBJECTIVE—Diabetes, a major health problem worldwide, increases the risk of cardiovascular disease and its associated mortality. Evidence of the overall benefits of lipid modification in this area is needed. RESEARCH DESIGN AND METHODS—The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial showed that cholesterol-lowering treatment with pravastatin reduced mortality and coronary heart disease (CHD) events in 9,014 patients aged 31–75 years with CHD and total cholesterol 4.0–7.0 mmol/l. We measured the effects of pravastatin therapy, 40 mg/day over 6.0 years, on the risk of CHD death or nonfatal myocardial infarction and other cardiovascular outcomes in 1,077 LIPID patients with diabetes and 940 patients with impaired fasting glucose (IFG). RESULTS—In patients allocated to placebo, the risk of a major CHD event was 61% higher in patients with diabetes and 23% higher in the IFG group than in patients with normal fasting glucose, and the risk of any cardiovascular event was 37% higher in the diabetic group and 19% higher in the IFG group. Pravastatin therapy reduced the risk of a major CHD event overall from 15.9 to 12.3% (relative risk reduction [RRR] 24%, P < 0.001) and from 23.4 to 19.6% in the diabetic group (19%, P = 0.11); in the diabetic group, the reduction was not significantly different from the reductions in the other groups. Pravastatin reduced the risk of any cardiovascular event from 52.7 to 45.2% (21%, P < 0.008) in patients with diabetes and from 45.7 to 37.1% (26%, P = 0.003) in the IFG group. Pravastatin reduced the risk of stroke from 9.9 to 6.3% in the diabetic group (RRR 39%, CI 7–61%, P = 0.02) and from 5.4 to 3.4% in the IFG group (RRR 42%, CI −9 to 69%, P = 0.09). Pravastatin did not reduce the incidence of diabetes. Over 6 years, pravastatin therapy prevented one major CHD event (CHD death or nonfatal myocardial infarction) in 23 patients with IFG and 18 patients with diabetes. A meta-analysis of other major trials confirmed the high absolute risks of diabetes and IFG and the absolute benefits of statin therapy in these patients. CONCLUSIONS—Cholesterol-lowering treatment with pravastatin therapy prevents cardiovascular events, including stroke, in patients with diabetes or IFG and established CHD.

BACKGROUND: The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study showed that pravastatin therapy over 6 years reduced mortality and cardiovascular events in patients with previous acute coronary syndromes and average cholesterol concentrations. We assessed the longer-term effects of initial treatment with pravastatin on further cardiovascular events and mortality over a total follow-up period of 8 years. METHODS: In the main trial, 9014 patients with previous myocardial infarction or unstable angina and a baseline plasma cholesterol concentration of 4.0-7.0 mmol/L were randomly assigned pravastatin 40 mg daily or placebo and followed up for 6 years. Subsequently, all patients were offered open-label pravastatin for 2 more years. Major cardiovascular events and adverse events were compared according to initial treatment assignment. FINDINGS: 7680 (97% of those still alive) had 2 years of extended follow-up. 3766 (86%) of those assigned placebo and 3914 (88%) assigned pravastatin agreed to take open-label pravastatin. During this period, patients originally assigned pravastatin had almost identical cholesterol concentrations to those assigned placebo, but a lower risk of death from all causes (219 [5.6%] vs 255 [6.8%], p=0.029), coronary heart disease (CHD) death (108 [2.8%] vs 137 [3.6%], p=0.026), and CHD death or non-fatal myocardial infarction (176 [4.5%] vs 196 [5.2%], p=0.08). Over the total 8-year period, all-cause mortality was 888 (19.7%) in the group originally assigned placebo and 717 (15.9%) in the group originally assigned pravastatin, CHD mortality was 510 (11.3%) versus 395 (8.8%), myocardial infarction was 570 (12.7%) versus 435 (9.6%; each p < 0.0001), and stroke was 272 (6.0%) versus 224 (5.0%; p=0.015). Stronger evidence of separate treatment benefits than in the main trial was seen in important prespecified subgroups (women, patients aged > or = 70 years, and those with total cholesterol < 5.5 mmol/L). Pravastatin had no significant adverse effects. INTERPRETATION: The evidence of sustained treatment benefits and safety of long-term pravastatin treatment reinforces the importance of long-term cholesterol-lowering treatment for almost all patients with previous CHD events.

Background — The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial showed that pravastatin significantly reduced mortality and coronary heart disease (CHD) events in 9014 patients with known CHD and total cholesterol 4.0 to 7.0 mmol/L at baseline. Secondary objectives included assessment of CHD event reduction according to lipid levels. Methods and Results — We investigated the relationships of baseline and on-study lipids with subsequent CHD events in separate Cox models. Treatment effect on CHD event reduction was examined by baseline lipids and after adjustment for on-study lipid levels. Baseline lipids were significant predictors of CHD events. The adjusted relative risk per mmol/L (on placebo) was 1.24 ( P =0.004) for total cholesterol, 1.28 ( P =0.002) for low-density lipoprotein cholesterol, and 0.52 ( P =0.004) for high-density lipoprotein cholesterol. Apolipoproteins A1 and B were strong predictors (each P =0.001). Pravastatin reduced the risk of the composite outcome of fatal CHD or nonfatal myocardial infarction by 24% (95% confidence interval [CI], 15% to 32%) and the expanded end point of fatal CHD, nonfatal myocardial infarction, unstable angina, or coronary revascularization by 17% (95% CI, 10% to 24%). Similar relative effects were observed for different categories of baseline lipids. The proportion of treatment effect explained by on-study lipid levels was 67% (95% CI, 27% to 106%) for the composite and 97% (95% CI, 49% to 145%) for the expanded end point. The most important lipids associated with event reduction were apolipoprotein B, low-density lipoprotein cholesterol, and the combination of total and high-density lipoprotein cholesterol. Conclusions — Changes in lipid levels can explain all or most of the observed benefit of pravastatin. Some treatment effect may also be mediated through nonlipid changes.

TPS2621 Background: Precision medicine aims to link molecular targets in tumors to cognate therapies and has the potential to yield new treatments for cancer patients with unmet clinical need. With the accelerating pace of discovery and genomic capacity, innovative approaches are needed to translate molecular opportunities into clinical care. The MoST program tests a novel paradigm for evaluation of biomarker-driven treatment of patients with advanced cancer. The key elements of the design are a molecular screening platform to identify ‘actionable’ variants and an overarching protocol for multiple, parallel, signal-seeking clinical substudies. Methods: 1000 patients with advanced solid cancer of any histologic type, having failed all standard therapies will undergo tumor molecular profiling on archival tissue with a 393-gene panel and other molecular assays. Eligibility for biomarker-driven substudies of targeted treatments is based on tumor variants assessed by a Molecular Tumor Board. A novel framework design allows expedited addition of substudies, with ≥12 open-label, single-arm, signal-seeking substudies planned. The primary objective is to identify signals of clinical activity, as measured by objective tumor response or the ratio of time-to-progression on study treatment over the preceding period. Cohorts of 16 patients will be recruited to each substudy. Substudies with ≥3/16 responding patients will be considered sufficiently interesting to investigate further.As of Feb 2017, 65 patients have been screened, and 8 recruited to 2 open sub-studies: CDK4/6 inhibitor (palbociclib) for Rb pathway defects; CTLA-4 plus PD-L1 checkpoint inhibitors (durvalumab + tremelimumab) for patients with no actionable mutations. Additional substudies under development include: PARP plus PD-L1 inhibitors (olaparib + durvalumab) for HR DNA repair defects; SMO inhibitor (vismodegib) for Hh pathway defects. The modular signal-seeking trial design will be evaluated and is intended to expedite testing of biomarker-based therapies for rare cancers. Clinical trial information: ACTRN12616000908437; ACTRN12616000931471; ACTRN12616001019493.

Summary Background Statins inhibit the same biochemical pathway as aminobisphosphonates, therefore these cholesterol-lowering agents may have a beneficial effect on osteoporosis. This possibility has been supported by the finding that some statins also stimulate bone formation, and by observational studies suggesting that patients using statins have higher bone densities and lower fracture rates than controls. To assess whether statins have clinically significant effects on bone, we studied the frequency of fractures in a large randomised controlled trial of these agents. Methods 9014 patients (17% women, median age 62 years) with ischaemic heart disease were randomly assigned pravastatin 40 mg daily or placebo and followed up for a mean of 6·0 years. Fractures were ascertained from adverse-event reports. Findings 101 patients in the placebo group were admitted to hospital for fracture compared with 107 in the pravastatin group (hazard ratio 1·05 [95% CI 0·80–1·37]). When patients with fractures not necessitating hospital admission were added, the total number of patients having a fracture was 183 in the placebo group and 175 in the pravastatin group (0·94 [0·77–1·16]). Separate analyses for women alone and for individuals aged 65 years and over gave similar results. Interpretation These findings offer no support for the hypothesis that statins have a significant effect on fracture risk. However, this study was not of an osteoporotic population, and fracture rate, although clinically important, is an insensitive index of effects on bone. Statins should not be used to prevent osteoporosis until there is evidence for their efficacy based on randomised controlled trials.

In patients with coronary heart disease and a broad range of cholesterol levels, cholesterol-lowering therapy reduces the risk of coronary events, but the effects on mortality from coronary heart disease and overall mortality have remained uncertain.In a double-blind, randomized trial, we compared the effects of pravastatin (40 mg daily) with those of a placebo over a mean follow-up period of 6.1 years in 9014 patients who were 31 to 75 years of age. The patients had a history of myocardial infarction or hospitalization for unstable angina and initial plasma total cholesterol levels of 155 to 271 mg per deciliter. Both groups received advice on following a cholesterol-lowering diet. The primary study outcome was mortality from coronary heart disease.Death from coronary heart disease occurred in 8.3 percent of the patients in the placebo group and 6.4 percent of those in the pravastatin group, a relative reduction in risk of 24 percent (95 percent confidence interval, 12 to 35 percent; P0.001). Overall mortality was 14.1 percent in the placebo group and 11.0 percent in the pravastatin group (relative reduction in risk, 22 percent; 95 percent confidence interval, 13 to 31 percent; P0.001). The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin; these outcomes included myocardial infarction (reduction in risk, 29 percent; P0.001), death from coronary heart disease or nonfatal myocardial infarction (a 24 percent reduction in risk, P0.001), stroke (a 19 percent reduction in risk, P=0.048), and coronary revascularization (a 20 percent reduction in risk, P0.001). The effects of treatment were similar for all predefined subgroups. There were no clinically significant adverse effects of treatment with pravastatin.Pravastatin therapy reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.

Background The Parent Report of Children’s Abilities-Revised (PARCA-R) assesses cognitive and language development at 24 months. It was validated against the Mental Development Index of the Bayley Scales of Infant Development II (BSID II), but this has now been superseded by BSID III. Objective To compare the PARCA-R against the BSID III. Methods PARCA-R and BSID III assessments scheduled at 24 months of age (corrected for prematurity) were completed in 204 infants with suspected or proven neonatal sepsis in the International Neonatal Immunotherapy Study. Associations between the scales were measured and the predictive accuracy of the PARCA-R for moderate cognitive delay and moderate language delay was assessed using Receiver Operating Characteristic (ROC) analysis. Results Median birthweight was 911 g, median gestational age at birth was 27 weeks and 100 (49.0%) were girls. 4.4% and 8.4% met standard BSID III criteria for cognitive delay and language delay, respectively. These rates increased to 19.6% and 12.6% when an independent sample of normal term infants were used as the reference group suggesting standard BSID III reference norms may tend to underestimate delay. The Spearman correlation between PARCA-R and BSID scales were 0.43 for cognition and 0.71 for language. The PARCA-R successfully predicted cases of cognitive delay and language delay with the area under the ROC curves ranging from 0.83 to 0.97 depending on reference norms used. Conclusions The results support the PARCA-R as a practical tool for the identification of appreciable cognitive and language delay at 24 months among critically ill premature and extremely low birthweight neonates.

TPS5086Background: Adjuvant ADT with an LHRH analog (LHRHA) given before during and after radiotherapy (RT) is standard of care for high risk localised prostate cancer (PC). Enzalutamide is more ef...

TPS5077 Background: Androgen deprivation therapy (ADT) with a luteinising hormone releasing hormone analogue (LHRHA) or surgical castration, either alone or combined with conventional non-steroidal...

The collection of data on longer-term neurodevelopmental outcomes within large neonatal randomized controlled trials by trained assessors can greatly increase costs and present many operational difficulties. The aim of this study was to develop a more practical alternative for identifying major cognitive delay in infants at the age of 24 months, based on parental reports.A sample of 476 infants (206 female, 270 male) previously diagnosed with neonatal sepsis (mean birthweight 1329g [SD 865g], mean gestational age at birth 28.7wks [SD 4.5wks]) from the International Neonatal Immunotherapy Study were assessed using the Parent Report of Children's Abilities - Revised and the Bayley Scales of Infant Development, 2nd edition. Logistic regression was used to model the association between the risk of major cognitive delay (i.e. Bayley Scales of Infant Development Mental Development Index55) and the Parent Report of Children's Abilities - Revised data.The receiver operating characteristic curves for a number of predictive models were constructed - each achieved an area under the curve of at least 90%. The sensitivity, specificity, positive predictive value, and negative predictive value of a number of points on the receiver operating characteristic curves are presented.The Parent Report of Children's Abilities - Revised is a practical tool for identifying major cognitive delay in infants at 24 months.

Importance Laparoscopic procedures are generally thought to have better outcomes than open procedures. Because of anatomical constraints, laparoscopic rectal resection may not be better because of limitations in performing an adequate cancer resection. Objective To determine whether laparoscopic resection is noninferior to open rectal cancer resection for adequacy of cancer clearance. Design, Setting, and Participants Randomized, noninferiority, phase 3 trial (Australasian Laparoscopic Cancer of the Rectum; ALaCaRT) conducted between March 2010 and November 2014. Twenty-six accredited surgeons from 24 sites in Australia and New Zealand randomized 475 patients with T1-T3 rectal adenocarcinoma less than 15 cm from the anal verge. Interventions Open laparotomy and rectal resection (n = 237) or laparoscopic rectal resection (n = 238). Main Outcomes and Measures The primary end point was a composite of oncological factors indicating an adequate surgical resection, with a noninferiority boundary of Δ = −8%. Successful resection was defined as meeting all the following criteria: (1) complete total mesorectal excision, (2) a clear circumferential margin (≥1 mm), and (3) a clear distal resection margin (≥1 mm). Pathologists used standardized reporting and were blinded to the method of surgery. Results A successful resection was achieved in 194 patients (82%) in the laparoscopic surgery group and 208 patients (89%) in the open surgery group (risk difference of −7.0% [95% CI, −12.4% to ∞]; P = .38 for noninferiority). The circumferential resection margin was clear in 222 patients (93%) in the laparoscopic surgery group and in 228 patients (97%) in the open surgery group (risk difference of −3.7% [95% CI, −7.6% to 0.1%]; P = .06), the distal margin was clear in 236 patients (99%) in the laparoscopic surgery group and in 234 patients (99%) in the open surgery group (risk difference of −0.4% [95% CI, −1.8% to 1.0%]; P = .67), and total mesorectal excision was complete in 206 patients (87%) in the laparoscopic surgery group and 216 patients (92%) in the open surgery group (risk difference of −5.4% [95% CI, −10.9% to 0.2%]; P = .06). The conversion rate from laparoscopic to open surgery was 9%. Conclusions and Relevance Among patients with T1-T3 rectal tumors, noninferiority of laparoscopic surgery compared with open surgery for successful resection was not established. Although the overall quality of surgery was high, these findings do not provide sufficient evidence for the routine use of laparoscopic surgery. Longer follow-up of recurrence and survival is currently being acquired. Trial Registration anzctr.org Identifier:ACTRN12609000663257