Sensitivity of ocean circulation to warming during the Early Eocene greenhouse.

Multiple abrupt warming events ("hyperthermals") punctuated the Early Eocene and were associated with deep-sea temperature increases of 2 to 4 °C, seafloor carbonate dissolution, and negative carbon isotope (δ13C) excursions. Whether hyperthermals were associated with changes in the global ocean overturning circulation is important for understanding their driving mechanisms and feedbacks and for gaining insight into the circulation's sensitivity to climatic warming. Here, we present high-resolution benthic foraminiferal stable isotope records (δ13C and δ18O) throughout the Early Eocene Climate Optimum (~53.26 to 49.14 Ma) from the deep equatorial and North Atlantic. Combined with existing records from the South Atlantic and Pacific, these indicate consistently amplified δ13C excursion sizes during hyperthermals in the deep equatorial Atlantic. We compare these observations with results from an intermediate complexity Earth system model to demonstrate that this spatial pattern of δ13C excursion size is a predictable consequence of global warming-induced changes in ocean overturning circulation. In our model, transient warming drives the weakening of Southern Ocean-sourced overturning circulation, strengthens Atlantic meridional water mass aging gradients, and amplifies the magnitude of negative δ13C excursions in the equatorial to North Atlantic. Based on model-data consistency, we conclude that Eocene hyperthermals coincided with repeated weakening of the global overturning circulation. Not accounting for ocean circulation impacts on δ13C excursions will lead to incorrect estimates of the magnitude of carbon release driving hyperthermals. Our finding of weakening overturning in response to past transient climatic warming is consistent with predictions of declining Atlantic Ocean overturning strength in our warm future.

Dual-energy x-ray absorptiometry assessment of bone health in Australian men with prostate cancer commencing androgen deprivation therapy.

OBJECTIVE: To determine the prevalence in Australia of bone health assessment of men with prostate cancer by dual-energy x-ray absorptiometry (DXA), from six months before to twelve months after initiation of androgen deprivation therapy (ADT). DESIGN, SETTING: Cross-sectional national study; linkage of de-identified Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) data. PARTICIPANTS: Men (18 years or older) first dispensed PBS-subsidised ADT during 1 May 2017 - 31 July 2020. MAIN OUTCOME MEASURES: Prevalence of MBS-subsidised DXA assessments undertaken from six months before to twelve months after first ADT prescription. RESULTS: Of 33 836 men with prostate cancer commencing ADT therapy during 2017-20, 6683 (19.8%) underwent DXA bone heath assessments between six months before and twelve months after commencing ADT; the mean time from first ADT dispensing to DXA scanning was +90 days (standard deviation, 134 days). The proportion of men aged 54 years or younger who had scans (66 of 639, 10%) was smaller than that of men aged 70-84 years (4528 of 19 378, 23.4%; adjusted odds ratio, 0.36; 95% CI, 0.28-0.47). CONCLUSIONS: For about 80% of men with prostate cancer commencing ADT in Australia, therapy initiation was not accompanied by DXA assessment of bone health. Given the excellent long term prognosis for men with prostate cancer and the availability of bone protective therapy, bone health monitoring should be a routine component of prostate cancer care for men receiving ADT.

Rapid Adaptation of Cancer Education in Response to the COVID-19 Pandemic: Evaluation of a Live Virtual Statistics and Research Skills Workshop for Oncology Trainees.

Due to COVID-19, an annual interactive statistics and research methodology workshop for radiation oncology trainees was adapted at short notice into a live virtual format. This study aimed to evaluate trainee opinions around the educational value of the workshop, logistical aspects and impact on interactivity. A post-course on-line survey was completed by 26/42 trainee attendees (response rate 62%). For five pre-specified learning outcomes (LO), 58 to 69% of trainees agreed that the LO was completely or largely met (Likert scores 6 and 7 on a scale 1 = not met at all; 7 = completely met). All trainees felt that logistical aspects of the workshop including organisation, accessibility to the platform and sound/image quality were good or excellent. With regard to opportunities for interaction and suitability for small-group 'break-out' sessions, the majority felt that interaction could be adequately maintained whilst just under a quarter felt the delivery method was not fit for the purpose. Networking/social engagement with peers and teachers was the factor most impaired using the live virtual delivery format. Over three-quarters of trainees replied they would favour the current event or other educational sessions being offered (at least as an option) in a virtual format in the future. Cost and convenience were given as the major non-COVID-19-related benefits of virtual on-line learning. These preliminary findings provide valuable feedback to help adapt or develop further on-line educational and training initiatives that will be necessary in the COVID-19 pandemic period and beyond.

Junior Doctor Evaluation of Radiation Oncology Education and Training in Medical Schools and Prevocational Training in Australia.

The purpose of this study is to evaluate radiation oncology (RO)-specific education, confidence and knowledge of junior doctors in Australian teaching hospitals. A 38-item web-based survey was emailed to prevocational junior doctors working in Australian hospitals in New South Wales (NSW), Australian Capital Territory (ACT) and Queensland (QLD) between November 2017 and January 2018. The survey evaluated RO educational and clinical exposure of participants during medical school, and prevocational training and their confidence and knowledge of the specialty. A total of 183 respondents across 17 Australian hospital networks completed the survey. During medical school, 53.4% had RO incorporated into their formal curriculum, 19.5% had no formal lectures and 51.7% had never visited a RO department. As a junior doctor, 73.8% of respondents did not receive any formal RO education. When compared with other oncology specialties, fewer junior doctors were confident in consulting the RO team (21.0%) compared with medical oncology (42.0%), palliative care (75.2%) and haematology (40.1%). Majority of respondents (61.6%) showed limited understanding of radiation safety. On multivariate sub-group analysis, both confidence and knowledge in RO improved when RO was incorporated into the formal medical school curriculum. This survey highlights the current low confidence and poor knowledge standard amongst Australian junior doctors on RO due to inadequate teaching during medical school and prevocational training and suggests improvement through standardisation of formal RO curriculum teaching within medical school and prevocational training.

Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial.

BACKGROUND: Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy. METHODS: We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0-1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652. FINDINGS: Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3-7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81-92) in the adjuvant radiotherapy group versus 87% (82-93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65-1·90; pnon-inferiority=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]). INTERPRETATION: Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity. FUNDING: New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.

Oncology and Radiation Oncology Awareness in Final Year Medical Students in Australia and New Zealand.

This study aimed to determine final year students' core oncology and radiation oncology knowledge and attitudes about the quality of teaching in medical programmes delivered in Australia and New Zealand. Does the modern medical programme provide core oncology skills in this leading global cause of mortality and morbidity? An online survey was distributed between April and June 2018 and completed by 316 final year students across all 21 medical schools with final year cohorts in Australia and New Zealand. The survey examined teaching and clinical exposure, attitudes and core knowledge for oncology and radiation oncology. Several questions from a survey done of graduates in 2001 were repeated for comparison. We found that clinical exposure to oncology and its disciplines is low. Students rated oncology and haematology the worst taught medical specialties at medical school. Students reported the most confidence identifying when surgical management of cancer may be indicated and much lower levels of confidence identifying when systemic therapy and radiation therapy may be helpful. The majority of students had no formal course content on radiation therapy and more than one third of final year students erroneously believed that external beam radiation therapy turned patients radioactive. Exposure to oncology practice and the teaching of core oncology knowledge remains low for medical students in Australia and New Zealand. Many areas of oncology teaching and knowledge have worsened for medical students in Australia and New Zealand over the past 20 years. Well-established gaps in the core oncology knowledge of medical graduates must be urgently addressed given the increasing incidence of cancer and ongoing underutilisation of radiation therapy in particular.

Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial.

BACKGROUND: The optimal duration of androgen suppression for men with locally advanced prostate cancer receiving radiotherapy with curative intent is yet to be defined. Zoledronic acid is effective in preventing androgen suppression-induced bone loss, but its role in preventing castration-sensitive bone metastases in locally advanced prostate cancer is unclear. The RADAR trial assessed whether the addition of 12 months of adjuvant androgen suppression, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive 6 months of androgen suppression and prostatic radiotherapy. This report presents 10-year outcomes from this trial. METHODS: For this randomised, phase 3, 2 × 2 factorial trial, eligible men were 18 years or older with locally advanced prostate cancer (either T2b-4, N0 M0 tumours or T2a, N0 M0 tumours provided Gleason score was ≥7 and baseline prostate-specific antigen [PSA] concentration was ≥10 µg/L). We randomly allocated participants in a 2 × 2 factorial design by computer-generated randomisation (using the minimisation technique, and stratified by centre, baseline PSA concentration, clinical tumour stage, Gleason score, and use of a brachytherapy boost) in a 1:1:1:1 ratio to four treatment groups. Patients in the control group received 6 months of neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) and radiotherapy alone (short-term androgen suppression [STAS]); this treatment was either followed by another 12 months of adjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly; intermediate-term androgen suppression [ITAS]), or accompanied by 18 months of zoledronic acid (4 mg every 3 months, intravenously) starting at randomisation (STAS plus zoledronic acid), or both (ITAS plus zoledronic acid). All patients received radiotherapy to the prostate and seminal vesicles, starting from the end of the fifth month of androgen suppression; dosing options were 66, 70, and 74 Gy in 2-Gy fractions per day, or 46 Gy in 2-Gy fractions followed by a high-dose-rate brachytherapy boost dose of 19·5 Gy in 6·5-Gy fractions. Treatment allocation was open label. The primary endpoint was prostate cancer-specific mortality and was analysed according to intention-to-treat using competing-risks methods. The trial is closed to follow-up and this is the final report of the main endpoints. This trial is registered with ClinicalTrials.gov, number NCT00193856. FINDINGS: Between Oct 20, 2003, and Aug 15, 2007, 1071 men were enrolled and randomly assigned to STAS (n=268), ITAS (n=268), STAS plus zoledronic acid (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 10·4 years (IQR 7·9-11·7). At this 10-year follow-up, no interactions were observed between androgen suppression and zoledronic acid so the treatment groups were collapsed to compare treatments according to duration of androgen suppression: 6 months of androgen suppression plus radiotherapy (6AS+RT) versus 18 months of androgen suppression plus radiotherapy (18AS+RT) and to compare treatments according to whether or not patients received zoledronic acid. The total number of deaths was 375 (200 men receiving 6AS+RT and 175 men receiving 18AS+RT), of which 143 (38%) were attributable to prostate cancer (81 men receiving 6AS+RT and 62 men receiving 18AS+RT). When analysed by duration of androgen suppression, the adjusted cumulative incidence of prostate cancer-specific mortality was 13·3% (95% CI 10·3-16·0) for 6AS+RT versus 9·7% (7·3-12·0) for 18AS+RT, representing an absolute difference of 3·7% (95% CI 0·3-7·1; sub-hazard ratio [sHR] 0·70 [95% CI 0·50-0·98], adjusted p=0·035). The addition of zoledronic acid did not affect prostate cancer-specific mortality; the adjusted cumulative incidence of prostate cancer-specific mortality was 11·2% (95% CI 8·7-13·7) with zoledronic acid vs 11·7% (9·2-14·1) without, representing an absolute difference of -0·5% (95% CI -3·8 to 2·9; sHR 0·95 [95% CI 0·69-1·32], adjusted p=0·78). Although safety analysis was not prespecified for this 10-year analysis, one new serious adverse event (osteonecrosis of the mandible, in a patient who received 18 months of androgen suppression plus zoledronic acid) occurred since our previous report, bringing the total number of cases of this serious adverse event to three (<1% out of 530 patients who received zoledronic acid evaluated for safety) and the total number of drug-related serious adverse events to 12 (1% out of all 1065 patients evaluable for safety). No treatment-related deaths occurred during the study. INTERPRETATION: 18 months of androgen suppression plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than 6 months of androgen suppression plus radiotherapy, but the addition of zoledronic acid to this treatment regimen is not beneficial. Evidence from the RADAR and French Canadian Prostate Cancer Study IV trials suggests that 18 months of androgen suppression with moderate radiation dose escalation is an effective but more tolerable option than longer durations of androgen suppression for men with locally advanced prostate cancer including intermediate and high risk elements. FUNDING: National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, AbbVie Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, Cancer Standards Institute New Zealand, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Newcastle Radiation Oncology Fund, and Maitland Cancer Appeal.

Examining trajectories of anxiety in men with prostate cancer faced with complex treatment decisions.

PURPOSE: To examine changes in anxiety over time (trajectories) in men with prostate cancer faced with a decision to participate in a clinical trial and to identify demographic and study variables that predict these trajectories. METHODS: Our data come from a larger study examining the efficacy of a decision aid on decisional conflict in men with prostate cancer who were deciding whether to participate in a prostate cancer clinical trial. We used latent growth mixture models to identify 'classes' (i.e. groups) of participants with different trajectories of anxiety, as assessed by the State-Trait Anxiety Inventory state scale, and binary logistic regression to determine predictors of anxiety 'class'. RESULTS: In 128 men with prostate cancer (mean age = 63), growth mixture modelling identified two classes defined by different anxiety trajectories. One class (n = 27) started with a higher mean anxiety score and did not change over time (stable high), whereas the second class (n = 101) started with lower anxiety and significantly reduced over time (low and recovering). None of the demographic and study variables (including age, education, marital status, and decision to join the trial) was predictive of anxiety class. CONCLUSIONS: Men treated for prostate cancer who have high levels of anxiety after surgery may continue to have persistent high anxiety levels which do not reduce naturally over time. Patient or disease characteristics do not appear to predict anxiety. It is important, therefore, to monitor for anxiety in this population and refer for psychological interventions where required.

Constraints on the onset duration of the Paleocene-Eocene Thermal Maximum.

The Paleocene-Eocene Thermal Maximum (PETM, approx. 56 Ma) provides a test case for investigating how the Earth system responds to rapid greenhouse gas-driven warming. However, current rates of carbon emissions are approximately 10 Pg C yr-1, whereas those proposed for the PETM span orders of magnitude-from ≪1 Pg C yr-1 to greater than the anthropogenic rate. Emissions rate estimates for the PETM are hampered by uncertainty over the total mass of PETM carbon released as well as the PETM onset duration. Here, I review constraints on the onset duration of the carbon isotope excursion (CIE) that is characteristic of the event with a focus on carbon cycle model-based attempts that forgo the need for a traditional sedimentary age model. I also review and compare existing PETM carbon input scenarios employing the Earth system model cGENIE and suggest another possibility-that abrupt input of an isotopically depleted carbon source combined with elevated volcanic outgassing over a longer interval can together account for key features of the PETM CIE.This article is part of a discussion meeting issue 'Hyperthermals: rapid and extreme global warming in our geological past'.

Health-related quality of life for immediate versus delayed androgen-deprivation therapy in patients with asymptomatic, non-curable prostate cancer (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial.

BACKGROUND: Androgen-deprivation therapy in patients with prostate cancer who have relapsed with rising prostate-specific antigen concentration only (PSA-only relapse), or with non-curable but asymptomatic disease at diagnosis, could adversely affect quality of life at a time when the disease itself does not. We aimed to compare the effect of immediate versus delayed androgen-deprivation therapy on health-related quality of life over 5 years in men enrolled in the TOAD (Timing of Androgen Deprivation) trial. METHODS: This randomised, multicentre, open-label, phase 3 trial done in 29 public and private cancer centres across Australia, New Zealand, and Canada compared immediate with delayed androgen-deprivation therapy in men with PSA-only relapse after definitive treatment, or de-novo non-curable disease. Patients were randomly assigned (1:1) with a database-embedded, dynamically balanced algorithm to immediate androgen-deprivation therapy (immediate therapy group) or to delayed androgen-deprivation therapy (delayed therapy group). Any type of androgen-deprivation therapy was permitted, as were intermittent or continuous schedules. The European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaires QLQ-C30 and PR25 were completed before randomisation, every 6 months for 2 years, and annually for a further 3 years. The primary outcome of the trial, reported previously, was overall survival, with global health-related quality of life at 2 years as a secondary endpoint. Here we report prespecified secondary objectives of the quality-of-life endpoint. Analysis was by intention to treat. Statistical significance was set at p=0·0036. The trial was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12606000301561, and ClinicalTrials.gov, number NCT00110162. FINDINGS: Between Sept 3, 2004, and July 13, 2012, 293 men were recruited and randomly assigned; 151 to the delayed therapy group and 142 to the immediate therapy group. There was no difference between the two groups in global health-related quality of life over 2 years from randomisation. There were no statistically significant differences in global quality of life, physical functioning, role functioning, or emotional functioning, fatigue, dyspnoea, insomnia, or feeling less masculine over the entire 5 years after randomisation. Sexual activity was lower in the immediate therapy group than in the delayed group at 6 and 12 months (at 6 months mean score 29·20 [95% CI 24·59-33·80] in the delayed group vs 10·40 [6·87-13·93] in the immediate group, difference 18·80 [95% CI 13·00-24·59], p<0·0001; at 12 months 28·63 [24·07-33·18] vs 13·76 [9·94-17·59], 14·86 [8·95-20·78], p<0·0001), with the differences exceeding the clinically significant threshold of 10 points until beyond 2 years. The immediate therapy group also had more hormone-treatment-related symptoms at 6 and 12 months (at 6 months mean score 8·48 [95% CI 6·89-10·07] in the delayed group vs 15·97 [13·92-18·02] in the immediate group, difference -7·49 [-10·06 to -4·93], p<0·0001; at 12 months 9·32 [7·59-11·05] vs 17·07 [14·75-19·39], -7·75 [-10·62 to -4·89], p<0·0001), but with differences below the threshold of clinical significance. For the individual symptoms, hot flushes were clinically significantly higher in the immediate group (adjusted proportion 0·31 for delayed therapy vs 0·55 for immediate therapy, adjusted odds ratio 2·87 [1·96-4·21], p<0·0001) over the 5-year period, as were nipple or breast symptoms (0·06 vs 0·14, 2·64 [1·61-4·34], p=0·00013). INTERPRETATION: Immediate use of androgen-deprivation therapy was associated with early detriments in specific hormone-treatment-related symptoms, but with no other demonstrable effect on overall functioning or health-related quality of life. This evidence can be used to help decision making about treatment initiation for men at this disease stage. FUNDING: Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia, Tolmar Australia.