On the receiving end: have patient perceptions of the side-effects of cancer chemotherapy changed since the twentieth century?

BACKGROUND: Studies in 1983 and 1993 identified and ranked symptoms experienced by cancer patients receiving chemotherapy. We repeated the studies to obtain updated information on patient perceptions of chemotherapy-associated symptoms. PATIENTS AND METHODS: A cross-sectional interview and patient-reported outcome questionnaires were administered to out-patients receiving chemotherapy. Patients selected from 124 cards to identify and rank the severity of physical and non-physical symptoms they had experienced and attributed to chemotherapy (primary endpoint). The patient's medical oncologist and primary chemotherapy nurse were invited to rank the five symptoms they believed the patient would rank as their most severe. We analysed the association of symptoms and their severity with patient demographics, chemotherapy regimen, and patient-reported outcomes. Results were compared to the earlier studies. RESULTS: Overall, 302 patients completed the interview: median age 58 years (range 17-85); 56% female; main tumour types colorectal 81 (27%), breast 67 (22%), lung 49 (16%); 45% treated with curative intent. Most common symptoms (reported by >50%) were: alopecia, general weakness, effects on family/partner, loss of taste, nausea, fatigue, difficulty sleeping, effects on work/home duties, and having to put life on hold. The most severe symptoms (ranked by >15% in top five) were: concern about effects on family/partner, nausea, fear of the future, fatigue, not knowing what will happen, putting my life on hold, and general weakness. Perceptions of doctors and nurses of patients' symptom severity closely matched patients' rankings. CONCLUSIONS: Compared to earlier studies, there was an increase in non-physical concerns such as effects on family and future, and a decrease in physical symptoms, particularly vomiting, but nausea, fatigue and general weakness remained bothersome. HIGHLIGHTS: • Symptoms related to chemotherapy have changed over time, likely due to less toxic regimens and improvements in supportive care. • Effects on family/partner, fear of the future, not knowing what will happen, and "life on hold" were major issues for patients. • Vomiting has decreased but nausea, fatigue and general weakness remain common symptoms for chemotherapy patients.

Preferences for life expectancy discussions following diagnosis with a life-threatening illness: a discrete choice experiment.

PURPOSE: To explore in a sample of adult cancer patients: (1) the relative influence of initiation source, information format and consultation format on preferred approach to life expectancy disclosure using a discrete choice experiment (DCE); and (2) whether patient age, cancer type and perceived prognosis were associated with preferences within the three attributes. METHODS: A DCE survey of adult solid tumour and haematological cancer patients. Participants chose between three hypothetical scenarios about life expectancy disclosure consisting of three attributes: initiation source (i.e. doctor versus patient-initiated discussion), information content (i.e. estimate presented as best-worst-typical length of life case scenario versus median survival time) and consultation format (i.e. two 20-min versus one 40-min consultation). Respondents selected their most preferred scenario within each question. RESULTS: Three hundred and two patients completed the DCE (78% consent rate). Initiation source was the most influential predictor of patient choice. More preferred a doctor deliver life expectancy information as soon as it is available rather than waiting for the patient to ask (59% vs 41% z = - 7.396, p < 0.01). More patients preferred the two 20-min rather than the one 40-min consultation format (55% vs 45%, z = 4.284, p < 0.01). Information content did not influence choice. Age, cancer type, and patient-perceived prognosis were not associated with preferences. CONCLUSION: Healthcare professionals should assess cancer patients' preferences for engaging in life expectancy discussions as soon as they have this information, and ensure patients have adequate time to consider the information they receive, seek additional information and involve others if they wish.

FISH analysis of selected soft tissue tumors: Diagnostic experience in a tertiary center.

AIM: Fluorescence in situ hybridization (FISH) is an important ancillary tool for the classification of bone/soft tissue (BST) tumors. The aim of this study was to evaluate the contribution of FISH to the final classification of common BST entities in the molecular pathology department of the Royal Prince Alfred Hospital (RPAH), which is one of the most important referral centers for the management of sarcomas in Australia. METHODS: All routine diagnostic FISH tests performed on BST formalin-fixed paraffin embedded (FFPE) tissue specimens at the RPAH in a 5-year period (February, 2010-November, 2015) were reviewed. FISH analyses presented in this study include commercial break-apart probes (SS18, FUS, DDIT3, FUS, USP6, PDGFB, TFE3 and ALK) and a single enumeration (MDM2) probe. RESULTS: There were 434 interpretable FISH assays on BST samples including MDM2 (n=180), SS18 (n=97), FUS (n=64), DDIT3 (n=37), USP6 (n=30), PDGFB (n=13), TFE3 (n=8) and ALK (n=5). Discrepancies between the histopathological diagnosis and the FISH results were seen in 12% of the cases. In this subset of discordant cases, FISH contributed to the re-classification of 7% of cases originally diagnosed as synovial sarcoma (SS18) and 6% of adipocytic neoplasms (MDM2) based on the presence or absence of the expected gene alteration. CONCLUSION: Our study confirms that paraffin FISH is a sensitive and specific ancillary tool in the diagnosis of BST neoplasms when used in the appropriate clinicopathological context. These findings highlight the need for further ancillary molecular tools in the diagnosis and characterization of challenging cases.

A randomised controlled trial of an advance care planning intervention for patients with incurable cancer.

BACKGROUND: We modified and evaluated an advance care planning (ACP) intervention, which had been shown to improve compliance with patient's end of life (EoL) wishes, in a different patient population. METHODS: Patients with incurable cancer, and a Family Member (FM), were randomised one-to-one to usual care or usual care plus an ACP intervention, between April 2014 and January 2017. Oncologists and participants were non-blinded. ACP was based on the Respecting Patient Choices model, with an offer to provide individualised ranges for typical, best-case and worst-case scenarios for survival time. Seven facilitators (two oncology nurses, two nurses and three allied health professionals) delivered the intervention within 2 weeks of study enrolment. The primary outcome measure, assessed by interviewing the FM 3 months after patient death, was the FM perception that the patient's wishes were discussed, and met. RESULTS: Six hundred and sixty-five patients from seven Australian metropolitan oncology centres were referred for consideration by their oncologists, 444 (67%) met the study inclusion criteria and were approached by a study researcher. Two hundred and eight patients (47%) and their FM entered the trial as dyads. Fifty-three (46%) dyads in the ACP group and 63 (54%) dyads in the usual-care group had complete primary outcome data (p = 0.16). Seventy-nine patients and 53 FMs attended an ACP discussion. Mean length of discussion was 57 min. FMs from 23 (43%) dyads allocated to ACP and 21 (33%) dyads allocated usual care reported the patient's EoL wishes were discussed and met (difference 10%, 95% CI: -2 to 8, p = 0.27). There were no differences in EoL care received, patient satisfaction with care; FM satisfaction with care or with death; or FM well being. Rates of palliative care referral were high in both groups (97% vs 96%). CONCLUSIONS: A formal ACP intervention did not increase the likelihood that EoL care was consistent with patients' preferences.

Supporting doctor-patient communication: Providing a question prompt list and audio recording of the consultation as communication aids to outpatients in a cancer clinic.

OBJECTIVE: To document the effect of a cancer specific question prompt list (QPL) on patients question asking and shared decision-making (SDM), and to evaluate the combined effect of the QPL and consultation audio recording (CAR) on patient outcomes. METHOD: This exploratory study compared two groups of patients receiving either a QPL or combined QPL/CAR, to a control group. Measurements included number/types of questions asked, and physician SDM behavior (OPTION score). Questionnaire data included anxiety/depression and quality of life (QoL). RESULTS: A total of 93 patients participated (31 Control, 30 QPL and 32 Combined). Patients in the intervention groups asked more questions concerning prognosis (p < .0001), the disease (p = .006) and quality of treatment (p < .001) than patients in the control group, but no impact was found on the OPTION score. An increase in mean consultation length was observed in the intervention groups compared to the control group (44 vs. 36 min; p = .028). Patients rated both interventions positively. CONCLUSION: Provision of the QPL facilitates patients to ask a broader range of questions, but does not increase physician SDM behavior. PRACTICAL IMPLEMENTATION: The combination of QPL and CAR seems feasible and should be tested in an implementation study following the disease trajectory.

How Well Do Current Measures Assess the Impact of Advance Care Planning on Concordance Between Patient Preferences for End-of-Life Care and the Care Received: A Methodological Review.

BACKGROUND: Research has begun to focus on whether Advance Care Planning (ACP) has the capacity to influence care, and to examine whether ACP can be effective in meeting patients' wishes at the end of their lives. Little attention has been paid, however, to the validity and clinical relevance of existing measures. METHODS: A search of Medline and CINHAL identified ACP studies measuring concordance between end-of-life (EoL) preferences and the care received. Databases were searched from 2000 to August 2016. We developed a checklist to evaluate the quality of included studies. Data were collected on the proportion of patients who received concordant care, extracted from manuscript tables or calculated from the text. OUTCOMES: Of 2941 papers initially identified, nine eligible studies were included. Proportions of patients who received concordant care varied from 14% to 98%. Studies were heterogeneous and methodologically poor, with limited attention paid to bias/external validity. Studies varied with regards to design of measures, the meaning of relevant terms like "preference" "EoL care" and "concordance," and the completeness of reported data. CONCLUSION: Methodological variations and weaknesses compromise the validity of study results, and prevent meaningful comparisons between studies or synthesis of the results. Effectively evaluating whether ACP interventions enhance a patient's capacity to receive the care they want requires harmonization of research. This demands standardization of methods across studies, validating of instruments, and consensus based on a consistent conceptual framework regarding what constitutes a meaningful outcome measure.

Patient autonomy and advance care planning: a qualitative study of oncologist and palliative care physicians' perspectives.

IMPORTANCE: Patients' are encouraged to participate in advance care planning (ACP) in order to enhance their autonomy. However, controversy exists as to what it means to be autonomous and there is limited understanding of how social and structural factors may influence cancer patients' ability to exercise their autonomy. OBJECTIVE: The objective of this study is to explore oncologists' and palliative care physicians' understanding of patient autonomy, how this influences reported enactment of decision-making at the end of life (EOL), and the role of ACP in EOL care. DESIGN AND SETTING: Qualitative semi-structured interviews were conducted with consultant oncologists (n = 11) and palliative medicine doctors (n = 7) working in oncology centres and palliative care units across Australia. RESULTS: We found that doctors generally conceptualized autonomy in terms of freedom from interference but that there was a profound disconnect between this understanding of autonomy and clinical practice in EOL decision-making. The clinicians in our study privileged care, relationships and a 'good death' above patient autonomy, and in practice were reluctant to 'abandon' their patients to total non-interference in decision-making. Patient autonomy in healthcare is bounded, as while patients were generally encouraged to express their preferences for care, medical norms about the quality and 'reasonableness' of care, the availability of services and the patients' family relationships act to enhance or limit patients' capacity to realize their preferences. While for many, this disconnect between theory and practice did not diminish the rhetorical appeal of ACP; for others, this undermined the integrity of ACP, as well as its relevance to care. For some, ACP had little to do with patient autonomy and served numerous other ethical, practical and political functions. CONCLUSION: The ethical assumptions regarding patient autonomy embedded in academic literature and policy documents relating to ACP are disconnected from the realities of clinical care. Medical norms and professional boundaries surrounding 'good deaths' have a greater influence on care than patient preference. ACP programs, therefore, may be rejected by healthcare professionals as irrelevant to care or may have the unintended consequence of limiting patient autonomy when used as a professional tool to encourage a 'right' way to die. A singular focus on bureaucratic ACP programs, which reduce patient autonomy to a 'tick box' exercise, may fail to enhance EOL care in any meaningful way.

"Standard Care" in Cancer Clinical Trials: An Analysis of Care Provided to Women in the Control Arms of Breast Cancer Clinical Trials.

Background: For trials to validly evaluate new treatments, comparison against the best existing alternative treatment is essential. We reviewed the care provided to women in control arms of breast cancer clinical trials to estimate the proportion consistent with the standard of care as defined in clinical guidelines. Methods: We analyzed phase III randomized controlled breast cancer trials comparing drug treatments with "standard care," enrolling between 2004 and 2014, and registered on ClinicalTrials.gov Our primary outcome was the proportion of trials in which treatment in the control arm was consistent with concurrent NCCN Guidelines. A secondary analysis assessed trials recruiting outside the United States that provided control group therapy not consistent with NCCN Guidelines, comparing them with the German Gynecological Oncology Group (AGO) guidelines. We assessed associations between the primary outcome and a priori selected trial characteristics. Results: This study included 210 trials that recruited 229,182 women worldwide; 29% of trials (60/210) did not provide control group treatment that was consistent with NCCN Guidelines. For trials not recruiting in the United States, results were similar; in 21% of trials, control arm treatment was inconsistent with both AGO and NCCN Guidelines. Factors significantly associated with offering control arm treatment that were inconsistent with guidelines were time period (later trials were less likely to be consistent), breast cancer stage and type (trials in early-stage breast cancer and estrogen receptor-negative disease were less likely consistent), and recruitment in ≥4 countries and recruitment outside the United States. Conclusions: To ensure that clinical trials achieve their goal of obtaining the best information to guide patient treatment, the question of how investigators chose and describe "standard care" for control arm participants warrants further investigation.

Improving hospital-based end of life care processes and outcomes: a systematic review of research output, quality and effectiveness.

BACKGROUND: As in other areas of health delivery, there is a need to ensure that end-of-life care is guided by patient centred research. A systematic review was undertaken to examine the quantity and quality of data-based research aimed at improving the (a) processes and (b) outcomes associated with delivering end-of-life care in hospital settings. METHODS: Medline, EMBASE and Cochrane databases were searched between 1995 and 2015 for data-based papers. Eligible papers were classified as descriptive, measurement or intervention studies. Intervention studies were categorised according to whether the primary aim was to improve: (a) end of life processes (i.e. end-of-life documentation and discussions, referrals); or (b) end-of-life outcomes (i.e. perceived quality of life, health status, health care use, costs). Intervention studies were assessed against the Effective Practice and Organisation of Care methodological criteria for research design, and their effectiveness examined. RESULTS: A total of 416 papers met eligibility criteria. The number increased by 13% each year (p < 0.001). Most studies were descriptive (n = 351, 85%), with fewer measurement (n = 17) and intervention studies (n = 48; 10%). Only 18 intervention studies (4%) met EPOC design criteria. Most reported benefits for end-of-life processes including end-of-life discussions and documentation (9/11). Impact on end-of-life outcomes was mixed, with some benefit for psychosocial distress, satisfaction and concordance in care (3/7). CONCLUSION: More methodologically robust studies are needed to evaluate the impact of interventions on end-of-life processes, including whether changes in processes translate to improved end-of-life outcomes. Interventions which target both the patient and substitute decision maker in an effort to achieve these changes would be beneficial.

Advance Care Planning: is quality end of life care really that simple?

The routine implementation of Advance Care Planning (ACP) is now a prominent feature of policy directed at improving end of life care in Australia. However, while complex ACP interventions may modestly reduce medical care at the end of life and enable more people to die at home or outside of acute hospital settings, existing legal, organisational, cultural and conceptual barriers limit the implementation and utility of ACP. We suggest that meaningful improvements in end of life care will not result from the institutionalisation of ACP but from more significant changes to the design and delivery of care.

Parallel multicentre randomised trial of a clinical trial question prompt list in patients considering participation in phase 3 cancer treatment trials.

OBJECTIVE: To evaluate the effect of a clinical trial question prompt list in patients considering enrolment in cancer treatment trials. SETTING: Tertiary cancer referral hospitals in three state capital cities in Australia. PARTICIPANTS: 88 patients with cancer attending three cancer centres in Australia, who were considering enrolment in phase 3 treatment trials, were invited to enrol in an unblinded randomised trial of provision of a clinical trial question prompt list (QPL) before consenting to enrol in the treatment trial. INTERVENTIONS: We developed and pilot tested a targeted QPL for patients with cancer considering clinical trial participation (the clinical trial QPL). Consenting patients were randomised to receive the clinical trial QPL or not before further discussion with their oncologist and/or trial nurse about the treatment trial. PRIMARY AND SECONDARY OUTCOMES: Questionnaires were completed at baseline and within 3 weeks of deciding on treatment trial participation. MAIN OUTCOME MEASURE: scores on the Quality of Informed Consent questionnaire (QuIC). RESULTS: 88 patients of 130 sought for the study were enrolled (43 males), and 45 received the clinical trial QPL. 49% of trials were chemotherapy interventions for patients with advanced disease, 35% and 16% were surgical adjuvant and radiation adjuvant trials respectively. 70 patients completed all relevant questionnaires. 28 of 43 patients in the control arm compared with 39 of 45 patients receiving the clinical trial QPL completed the QuIC (p=0.0124). There were no significant differences in the QuIC scores between the randomised groups (QuIC part A p=0.08 and QuIC part B p=0.92). There were no differences in patient satisfaction with decisions or in anxiety levels between the randomised groups. CONCLUSIONS: Use of a question prompt list did not significantly change the QuIC scores in this randomised trial. ANZCTR 12606000214538 prospectively registered 31/5/2006. TRIAL REGISTRATION NUMBER: Results, ACTRN12606000214538.

Perceptions of cancer of unknown primary site: a national survey of Australian medical oncologists.

BACKGROUND: Despite being the sixth most common cause of cancer death in Australia, cancer of unknown primary (CUP) site remains poorly understood. AIMS: To describe practices relating to the diagnosis, investigation, classification, communication and management of CUP among medical oncologists. METHODS: We invited all members of the Medical Oncology Group of Australia to participate in a national, anonymous online survey about CUP. The survey collected data regarding diagnosis acceptance, diagnostic tests, treatment protocols and communication practices around the diagnosis of CUP. RESULTS: Three hundred and two oncologists were invited and 86 (28%) completed the survey. Eighty (93%) respondents were directly involved in the assessment of patients with CUP. Eighty-five (99%) respondents were prepared to make a diagnosis of CUP if, after appropriate diagnostic tests, the primary location could not be ascertained. Eighty-three percent would assign a primary site to obtain Pharmaceutical Benefits Schedule funding of medical therapy. Sixty-two percent did not have a specific treatment protocol designed for CUP. The majority of oncologists used serum tumour markers and computed tomography scans in the initial work-up, while 43% indicated they would use a positron emission tomography scan in the majority of cases. The majority would arrange mammography in female patients. Thematic analysis of responses to open-ended questions about how CUP is described identified little consistency in the language being used. CONCLUSION: The approach to diagnosis, investigation and management of CUP by medical oncologists in Australia is variable. Many preferred to estimate the primary site and treat accordingly. Pharmaceutical Benefits Schedule restrictions may encourage the practice of 'best guessing'.

Psychosocial morbidity in TP53 mutation carriers: is whole-body cancer screening beneficial?

Germline TP53 mutation carriers are at high risk of developing a range of cancers. Effective cancer risk management is an important issue for these individuals. We assessed the psychosocial impact in TP53 mutation carriers of WB-MRI screening as part of the Surveillance in Multi-Organ Cancer (SMOC+) protocol, measuring their unmet needs, anxiety and depression levels as well as cancer worry using psychological questionnaires and in-depth interviews about their experiences of screening. We present preliminary psychosocial findings from 17 participants during their first 12 months on the trial. We found a significant reduction in participants' mean anxiety from baseline to two weeks post WB-MRI (1.2, 95% CI 0.17 to 2.23 p = 0.025), indicative of some benefit. Emerging qualitative themes show most participants are emotionally supported and contained by the screening program and are motivated by their immediate concern about staying alive, despite being informed about the current lack of evidence around efficacy of screening for people with TP53 mutations in terms of cancer morbidity or mortality. For those that do gain emotional reassurance from participating in the screening study, feelings of abandonment by the research team are a risk when the study ends. For others, screening was seen as a burden, consistent with the relentless nature of cancer risk associated with Li-Fraumeni syndrome, though these patients still declared they wished to participate due to their concern with staying alive. Families with TP53 mutations need ongoing support due to the impact on the whole family system. These findings suggest a comprehensive multi-organ screening program for people with TP53 mutations provides psychological benefit independent of an impact on cancer morbidity and mortality associated with the syndrome. The benefits of a multi-organ screening program will be greater still if the screening tests additionally reduce the cancer morbidity and mortality associated with the syndrome. These findings may also inform the care of individuals and families with other multi-organ cancer predisposition syndromes.

Encouraging early discussion of life expectancy and end-of-life care: A randomised controlled trial of a nurse-led communication support program for patients and caregivers.

BACKGROUND: Patients are often not given the information needed to understand their prognosis and make informed treatment choices, with many consequently experiencing less than optimal care and quality-of-life at end-of-life. OBJECTIVES: To evaluate the efficacy of a nurse-facilitated communication support program for patients with advanced, incurable cancer to assist them in discussing prognosis and end-of-life care. DESIGN: A parallel-group randomised controlled trial design was used. SETTINGS: This trial was conducted at six cancer treatment centres affiliated with major hospitals in Sydney, Australia. PARTICIPANTS: 110 patients with advanced, incurable cancer participated. METHODS: The communication support program included guided exploration of a question prompt list, communication challenges, patient values and concerns and the value of discussing end-of-life care early, with oncologists cued to endorse question-asking and question prompt list use. Patients were randomised after baseline measure completion, a regular oncology consultation was audio-recorded and a follow-up questionnaire was completed one month later. Communication, health-related quality-of-life and satisfaction measures and a manualised consultation-coding scheme were used. Descriptive, Mixed Modelling and Generalised Linear Mixed Modelling analyses were conducted using SPSS version 22. RESULTS: Communication support program recipients gave significantly more cues for discussion of prognosis, end-of-life care, future care options and general issues not targeted by the intervention during recorded consultations, but did not ask more questions about these issues or overall. Oncologists' question prompt list and question asking endorsement was inconsistent. Communication support program recipients' self-efficacy in knowing what questions to ask their doctor significantly improved at follow-up while control arm patients' self-efficacy declined. The communication support program did not impact patients' health-related quality-of-life or the likelihood that their health information or shared decision-making preferences would be met. Satisfaction with the communication support program was high. CONCLUSIONS: Given the importance of clarifying prognostic expectations and end-of-life care wishes in the advanced cancer context, the communication support program appears to be an effective and well-received solution to encourage early information seeking related to these issues though, its long-term impact remains unclear. The manualised nature of the intervention, designed with existing clinical staff in mind, may make it suited for implementation in a clinical setting, though additional work is needed to identify why question asking was unaffected and establish its impact later in the illness trajectory.

Adapting an Australian question prompt list in oncology to a Norwegian setting-a combined method approach.

PURPOSE: A question prompt list (QPL) is an inexpensive communication aid that has been proved effective in encouraging patients to ask questions during medical consultations. The aim of this project was to develop a QPL for Norwegian cancer patients. METHODS: A multimethod approach was chosen combining literature review, focus groups, and a survey in the process of culturally adjusting an Australian QPL for the Norwegian setting. Participants were recruited from the University Hospital of North Norway. They were asked to review and comment on iterative drafts of the QPL. RESULTS: Eighteen patients, mean age 54, participated in the focus groups, and 31 patients, mean age 55, participated in the survey. Focus groups suggested that topics related to accompanying relatives, children as next of kin, and rehabilitation were important and should be added to the original QPL. The survey revealed that most questions from the original QPL were considered both useful and understandable. Although half of the patients found some questions about prognosis unpleasant, the vast majority considered the same questions useful. Questions regarding clinical studies, multidisciplinary teams, and public versus private hospitals had lower ratings of usefulness. CONCLUSION: QPLs require some adjustment to the local cultural context, and a mixed method approach may provide a useful model for future cultural adaptation of QPLs. The present QPL has been adjusted to the needs of oncology patients in the Norwegian health care setting.

Advance care planning in patients with incurable cancer: study protocol for a randomised controlled trial.

INTRODUCTION: There is limited evidence documenting the effectiveness of Advance Care Planning (ACP) in cancer care. The present randomised trial is designed to evaluate whether the administration of formal ACP improves compliance with patients' end-of-life (EOL) wishes and patient and family satisfaction with care. METHODS AND ANALYSIS: A randomised control trial in eight oncology centres across New South Wales and Victoria, Australia, is designed to assess the efficacy of a formal ACP intervention for patients with cancer. Patients with incurable cancer and an expected survival of 3-12 months, plus a nominated family member or friend will be randomised to receive either standard care or standard care plus a formal ACP intervention. The project sample size is 210 patient-family/friend dyads. The primary outcome measure is family/friend-reported: (1) discussion with the patient about their EOL wishes and (2) perception that the patient's EOL wishes were met. Secondary outcome measures include: documentation of and compliance with patient preferences for medical intervention at the EOL; the family/friend's perception of the quality of the patient's EOL care; the impact of death on surviving family; patient-family and patient-healthcare provider communication about EOL care; patient and family/friend satisfaction with care; quality of life of patient and family/friend subsequent to trial entry, the patient's strength of preferences for quality of life and length of life; the costs of care subsequent to trial entry and place of death. ETHICS AND DISSEMINATION: Ethical approval was received from the Sydney Local Health District (RPA Zone) Human Research Ethical Committee, Australia (Protocol number X13-0064). Study results will be submitted for publication in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: Pre-results; ACTRN12613001288718.