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Australia's population is ageing and the consequential burden of chronic disease increasingly challenges the health system. This has raised interest in, and awareness of approaches built on multidisciplinary teams and integrated and coordinated care in managing the complex care needs of patient groups such as the chronically ill or frail aged. A systematic investigation of the literature relating to these approaches provided the opportunity to explore the meaning of these terms and their potential application and relevance to the Australian primary health care setting. Five systematic reviews of a sentinel condition and an exemplar approach to coordinated and multidisciplinary care were completed. Common leanings from the individual reviews were identified. The literature suggests that approaches encouraging a coordinated and multidisciplinary plan of care for individual patients and/or particular populations may improve a variety of outcomes. There are many methodological considerations in conducting reviews of complex interventions and in assessing their applicability to the Australian health system. [ABSTRACT FROM AUTHOR]

Objective: To describe the harms in all arms of six consecutive multi-site, double-blind, placebo-controlled randomised clinical trials. Background: Controversies surround conduct of phase III clinical trials in palliative care. Concerns include risks to participants' safety, use of placebo arms, participants' burden, and justification when therapies are already widely used. Methods: This study collates safety data of the first six studies of the Australian national Palliative Care Clinical Studies Collaborative. On an intention-to-treat basis, all harms are described using standard international definitions, their severity, outcomes, and level of attribution. Results: Studies recruited 1,232 participants: 65/1,232 (5.3%) participants had serious adverse events of which none had a definite (blinded) attribution, all of which settled with ceasing the intervention; 49/1,232 (4.0%) participants had adverse events. No participants on placebo arms had adverse or serious adverse events with definite (blinded) attribution. Discussion: These studies are safe for participants and generate knowledge to support informed patient decision making.

Anorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13-24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. Trial registration. The trial has been registered with the Australian New Zealand Clinical Trials Registry [ACTRN12622000129785] and approved by the South Western Sydney Local Health District Human Research Ethics Committee [2021/ETH11339]. https://clin.larvol.com/trial-detail/ACTRN12622000129785., Competing Interests: Prof David Currow is a paid consultant to Helsinn and a member of their Advisory Board. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All the other Authors declare that they have no conflict of interest., (Copyright: © 2023 Sousa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This multi-site, double blind, parallel arm, fixed dose, randomised placebo controlled phase III study compared megestrol acetate 480 mg/day with dexamethasone 4 mg/day for their net effects on appetite in people with cancer anorexia. Patients with advanced cancer and anorexia for ≥ 2 weeks with a score ≤ 4 (0-10 numeric rating scale (NRS) 0 = no appetite, 10 = best possible appetite) were recruited. Participants received megestrol 480 mg or dexamethasone 4 mg or placebo daily for up to 4 weeks. Primary outcomes were at day 7. Responders were defined as having a ≥ 25% improvement in NRS over baseline. There were 190 people randomised (megestrol acetate n = 61; dexamethasone n = 67, placebo n = 62). At week 1 (primary endpoint), 79·3% in the megestrol group, 65·5% in the dexamethasone group and 58·5% in the placebo group (p = 0.067) were responders. No differences in performance status or quality of life were reported. Treatment emergent adverse events were frequent (90·4% of participants), and included altered mood and insomnia. Hyperglycemia and deep vein thromboses were more frequent when on dexamethasone than the other two arms. There was no difference in groups between the three arms, with no benefit seen over placebo with anorexia improving in all arms.Trail registration: The trial was registered on 19/08/2008 with the Australian New Zealand Clinical Trials Registry (ACTRN12608000405314).

Background: Delirium is a common debilitating complication of advanced cancer. Objective: To determine if a multicomponent nonpharmacological delirium prevention intervention was feasible for adult patients with advanced cancer, before a phase III (efficacy) trial. Design: Phase II (feasibility) cluster randomized controlled trial. All sites implemented delirium screening and diagnostic assessment. Strategies within sleep, vision and hearing, hydration, orientation, mobility, and family domains were delivered to enrolled patients at intervention site admission days 1-7. Control sites then implemented the intervention ("waitlist sites"). Setting: Four Australian palliative care units. Measurements: The primary outcome was adherence, with an a priori endpoint of at least 60% patients achieving full adherence. Secondary outcomes were interdisciplinary care delivery, delirium measures, and adverse events, analyzed descriptively and inferentially. Results: Sixty-five enrolled patients (25 control, 20 intervention, and 20 waitlist) had 98% delirium screens and 75% diagnostic assessments completed. Nurses (67%), physicians (16%), allied health (8.4%), family (7%), patients (1%), and volunteers (0.5%) delivered the intervention. There was full adherence for 5% patients at intervention sites, partial for 25%. Both full and partial adherence were higher at waitlist sites: 25% and 45%, respectively. One-third of control site patients (32%) became delirious within seven days of admission compared to one-fifth (20%) at both intervention and waitlist sites ( p  = 0.5). Mean (standard deviation) Delirium Rating Scale-Revised-1998 scores were 16.8 + 12.0 control sites versus 18.4 + 8.2 ( p  = 0.6) intervention and 18.7 + 7.8 ( p  = 0.5) waitlist sites. The intervention caused no adverse events. Conclusion: The intervention requires modification for optimal adherence in a phase III trial.

Context: Chronic breathlessness is a clinical syndrome that results in significant distress and disability. Morphine can reduce chronic breathlessness when the contributing etiologies are optimally treated., Objectives: Does oxycodone reduce chronic breathlessness compared with placebo?, Methods: A multisite, randomized, placebo-controlled, double-blind, parallel-arm, fixed-dose trial of oral controlled-release oxycodone 15 mg (5 mg, eight hourly) or placebo (ACTRN12609000806268 at www.anzctr.org.au). As-needed immediate-release morphine (2.5 mg per dose; six and less doses/day) was available for both arms as required by one ethics committee overseeing the trial. Recruitment occurred from 2010 to 2014 in 14 inpatient and outpatient respiratory, cardiology, and palliative care services across Australia. Participants were adults, with chronic breathlessness (modified Medical Research Council Scale 3 or 4), who were opioid naive. The primary end point was the proportion of people with greater than 15% reduction from baseline in the intensity of breathlessness now (0-100 mm visual analogue scale) comparing arms Days 5-7. Secondary end points were average and worst breathlessness, quality of life, function, and harms., Results: Of 157 participants randomized, 155 were included (74 oxycodone and 81 placebo), but the study did not reach target recruitment. There was difference in neither between groups for the primary outcome (P = 0.489) nor any of the prespecified secondary outcomes. Placebo participants used more as-needed morphine (mean 7.0 vs. 4.2 doses; P ≤ 0.001). Oxycodone participants reported more nausea (P < 0.001)., Conclusion: There was no signal of benefit from oxycodone over placebo. Future research should focus on investigating the existence of an opioid class effect on the reduction of chronic breathlessness., (Copyright © 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Morphine may decrease the intensity of chronic breathlessness but data from a large randomised controlled trial (RCT) are lacking. This first, large, parallel-group trial aimed to test the efficacy and safety of regular, low-dose, sustained-release (SR) morphine compared with placebo for chronic breathlessness., Methods: Multisite (14 inpatient and outpatient cardiorespiratory and palliative care services in Australia), parallel-arm, double-blind RCT. Adults with chronic breathlessness (modified Medical Research Council≥2) were randomised to 20 mg daily oral SR morphine and laxative (intervention) or placebo and placebo laxative (control) for 7 days. Both groups could take ≤6 doses of 2.5 mg, ' as needed ', immediate-release morphine (≤15 mg/24 hours) as required by the ethics review board. The primary endpoint was change from baseline in intensity of breathlessness now (0-100 mm visual analogue scale; two times per day diary) between groups. Secondary endpoints included: worst , best and average breathlessness ; unpleasantness of breathlessness now , fatigue; quality of life; function; and harms., Results: Analysed by intention-to-treat, 284 participants were randomised to morphine (n=145) or placebo (n=139). There was no difference between arms for the primary endpoint (mean difference -0.15 mm (95% CI -4.59 to 4.29; p=0.95)), nor secondary endpoints. The placebo group used more doses of oral morphine solution during the treatment period (mean 8.7 vs 5.8 doses; p=0.001). The morphine group had more constipation and nausea/vomiting. There were no cases of respiratory depression nor obtundation., Conclusion: No differences were observed between arms for breathlessness, but the intervention arm used less rescue immediate-release morphine., Trial Registration Number: ACTRN12609000806268., Competing Interests: Competing interests: DCC has unrestricted research grant from Mundipharma, is an unpaid member of an advisory board for Helsinn Pharmaceuticals, and has consulted to Specialist Therapeutics and Mayne Pharma, and received intellectual property payments from Mayne Pharma. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Head-to-head comparison of reliability, validity and responsiveness of four patient-reported outcome measures (PROMS) suitable for assessing health-related quality of life (HRQOL) in palliative care settings: EORTC QLQ-C15-PAL, FACT-G7, FACIT-Pal and short-form FACIT-Pal-14., Methods: Secondary analysis of two phase III randomised trials: ketamine for chronic cancer pain, octreotide for vomiting in inoperable malignant bowel obstruction. Sub-groups were defined by Australia-modified Karnofsky performance status (AKPS) and participants' global impression of change (GIC). Two aspects of reliability were assessed: internal consistency (Cronbach alpha, α); test-retest reliability (intra-class correlation coefficient (ICC)) of patients with stable AKPS and those who self-reported 'no change' on GIC. Construct validity was assessed via pre-determined hypotheses about sensitivity of PROM scores to AKPS groups and responsiveness of PROM change scores to GIC groups using analysis of variance., Results: FACIT-Pal had better internal consistency (α ranged 0.59-0.80, 15/18 ≥ 0.70) than QLQ-C15-PAL (0.51-0.85, 4/8 ≥ 0.70) and FACT-G7 (0.54-0.64, 0/2 ≥ 0.70). FACIT scales had better test-retest reliability (FACIT-Pal 11/27 ICCs ≥ 0.70, FACT-G7 2/3 ICCs ≥ 0.70) than QLQ-C15-PAL (2/30 ICCs ≥ 0.70, 18/30 ≤ 0.5). Four scales demonstrated sensitivity to AKPS: QLQ-PAL-15 Physical Functioning and Global QOL, FACT-G Functional Wellbeing and FACIT-Pal Trial Outcome Index (TOI). Nine scales demonstrated responsiveness: three in the ketamine trial population (QLQ-C15-PAL Pain, FACIT-Pal-14, FACT-G7), six in the octreotide trial population (QLQ-C15-PAL Fatigue; FACIT-Pal PalCare, TOI, Total; FACT-G Physical Wellbeing and Total)., Conclusions: No PROM was clearly superior, confirming that choosing the best PROM requires careful consideration of the research goals, patient population and the domains of HRQOL targeted by the intervention being investigated.

Introduction: Delirium is a significant medical complication for hospitalised patients. Up to one-third of delirium episodes are preventable in older inpatients through non-pharmacological strategies that support essential human needs, such as physical and cognitive activity, sleep, hydration, vision and hearing. We hypothesised that a multicomponent intervention similarly may decrease delirium incidence, and/or its duration and severity, in inpatients with advanced cancer. Prior to a phase III trial, we aimed to determine if a multicomponent non-pharmacological delirium prevention intervention is feasible and acceptable for this specific inpatient group., Methods and Analysis: The study is a phase II cluster randomised wait-listed controlled trial involving inpatients with advanced cancer at four Australian palliative care inpatient units. Intervention sites will introduce delirium screening, diagnostic assessment and a multicomponent delirium prevention intervention with six domains of care: preserving natural sleep; maintaining optimal vision and hearing; optimising hydration; promoting communication, orientation and cognition; optimising mobility; and promoting family partnership. Interdisciplinary teams will tailor intervention delivery to each site and to patient need. Control sites will first introduce only delirium screening and diagnosis, later implementing the intervention, modified according to initial results. The primary outcome is adherence to the intervention during the first seven days of admission, measured for 40 consecutively admitted eligible patients. Secondary outcomes relate to fidelity and feasibility, acceptability and sustainability of the study intervention, processes and measures in this patient population, using quantitative and qualitative measures. Delirium incidence and severity will be measured to inform power calculations for a future phase III trial., Ethics and Dissemination: Ethical approval was obtained for all four sites. Trial results, qualitative substudy findings and implementation of the intervention will be submitted for publication in peer-reviewed journals, and reported at conferences, to study sites and key peak bodies., Trial Registration Number: ACTRN12617001070325; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)