Feasibility randomised controlled trial of face-to-face counselling and mobile phone messages compared to usual care for smokeless tobacco cessation in Indian primary care: Project CERTAIN.

INTRODUCTION: Smokeless tobacco (SLT) use in low- and middle-income countries (LMICs) has adverse health consequences. We hypothesize that it is feasible to test an intervention of mobile phone messages and face-to-face counselling session for SLT cessation in India. METHODS: We conducted an exploratory, individual parallel two group, randomised controlled trial (RCT), with baseline -and end-point (three months from randomisation) assessments in urban primary health centres in Odisha, India. A total of 250 current (i.e., users in the last three months) SLT users or dual users (i.e., smokers and SLT users) were recruited to the trial (125 in each group). Participants were randomised to either routine care, face-to-face counselling, and reminder mobile messages or routine care only. The primary outcomes were to assess the feasibility of running a full RCT including recruitment, compliance, and retention. RESULTS: A total seven (77.8%) out of nine primary care centres took part in the trial. Out of the 315 SLT users invited to participate, 250 provided consent and were randomised [79.4% (95% CI: 74.5, 83.7)]. Out of the 250 randomised SLT users, 238 [95% (95% CI: 91.8, 97.5)] were followed up at three months (117 in the intervention group and 121 in the control group). Of the participants in the intervention group, 74 (63.8%) reported that they received the mobile messages. CONCLUSIONS: This exploratory trial demonstrated the feasibility of delivering and evaluating an intervention of mobile phone messages and face-to-face counselling for SLT users in Indian primary care in a full randomised trial. IMPLICATIONS: This study found that combining mobile messages with face-to-face counselling for smokeless tobacco users visiting primary health care settings in India is feasible in terms of recruitment of users, compliance with the intervention, and retention of study participants within the trial.The biochemically verified smokeless tobacco abstinence rate was higher in the intervention group compared with the control groupThere was poor agreement between self-reported tobacco cessation and the measured salivary cotinine in smokeless tobacco users.The findings support the feasibility and acceptability of the intervention signalling the need for a larger clinical trial to test effectiveness of the intervention.

The Role of Multiparametric MRI and MRI-targeted Biopsy in the Diagnosis of Radiorecurrent Prostate Cancer: An Analysis from the FORECAST Trial.

BACKGROUND: The role of multiparametric magnetic resonance imaging (MRI) for detecting recurrent prostate cancer after radiotherapy is unclear. OBJECTIVE: To evaluate MRI and MRI-targeted biopsies for detecting intraprostatic cancer recurrence and planning for salvage focal ablation. DESIGN, SETTING, AND PARTICIPANTS: FOcal RECurrent Assessment and Salvage Treatment (FORECAST; NCT01883128) was a prospective cohort diagnostic study that recruited 181 patients with suspected radiorecurrence at six UK centres (2014 to 2018); 144 were included here. INTERVENTION: All patients underwent MRI with 5 mm transperineal template mapping biopsies; 84 had additional MRI-targeted biopsies. MRI scans with Likert scores of 3 to 5 were deemed suspicious. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: First, the diagnostic accuracy of MRI was calculated. Second, the pathological characteristics of MRI-detected and MRI-undetected tumours were compared using the Wilcoxon rank sum test and chi-square test for trend. Third, four biopsy strategies involving an MRI-targeted biopsy alone and with systematic biopsies of one to two other quadrants were studied. Fisher's exact test was used to compare MRI-targeted biopsy alone with the best other strategy for the number of patients with missed cancer and the number of patients with cancer harbouring additional tumours in unsampled quadrants. Analyses focused primarily on detecting cancer of any grade or length. Last, eligibility for focal therapy was evaluated for men with localised (≤T3bN0M0) radiorecurrent disease. RESULTS AND LIMITATIONS: Of 144 patients, 111 (77%) had cancer detected on biopsy. MRI sensitivity and specificity at the patient level were 0.95 (95% confidence interval [CI] 0.92 to 0.99) and 0.21 (95% CI 0.07 to 0.35), respectively. At the prostate quadrant level, 258/576 (45%) quadrants had cancer detected on biopsy. Sensitivity and specificity were 0.66 (95% CI 0.59 to 0.73) and 0.54 (95% CI 0.46 to 0.62), respectively. At the quadrant level, compared with MRI-undetected tumours, MRI-detected tumours had longer maximum cancer core length (median difference 3 mm [7 vs 4 mm]; 95% CI 1 to 4 mm, p < 0.001) and a higher grade group (p = 0.002). Of the 84 men who also underwent an MRI-targeted biopsy, 73 (87%) had recurrent cancer diagnosed. Performing an MRI-targeted biopsy alone missed cancer in 5/73 patients (7%; 95% CI 3 to 15%); with additional systematic sampling of the other ipsilateral and contralateral posterior quadrants (strategy 4), 2/73 patients (3%; 95% CI 0 to 10%) would have had cancer missed (difference 4%; 95% CI -3 to 11%, p = 0.4). If an MRI-targeted biopsy alone was performed, 43/73 (59%; 95% CI 47 to 69%) patients with cancer would have harboured undetected additional tumours in unsampled quadrants. This reduced but only to 7/73 patients (10%; 95% CI 4 to 19%) with strategy 4 (difference 49%; 95% CI 36 to 62%, p < 0.0001). Of 73 patients, 43 (59%; 95% CI 47 to 69%) had localised radiorecurrent cancer suitable for a form of focal ablation. CONCLUSIONS: For patients with recurrent prostate cancer after radiotherapy, MRI and MRI-targeted biopsy, with or without perilesional sampling, will diagnose cancer in the majority where present. MRI-undetected cancers, defined as Likert scores of 1 to 2, were found to be smaller and of lower grade. However, if salvage focal ablation is planned, an MRI-targeted biopsy alone is insufficient for prostate mapping; approximately three of five patients with recurrent cancer found on an MRI-targeted biopsy alone harboured further tumours in unsampled quadrants. Systematic sampling of the whole gland should be considered in addition to an MRI-targeted biopsy to capture both MRI-detected and MRI-undetected disease. PATIENT SUMMARY: After radiotherapy, magnetic resonance imaging (MRI) is accurate for detecting recurrent prostate cancer, with missed cancer being smaller and of lower grade. Targeting a biopsy to suspicious areas on MRI results in a diagnosis of cancer in most patients. However, for every five men who have recurrent cancer, this targeted approach would miss cancers elsewhere in the prostate in three of these men. If further focal treatment of the prostate is planned, random biopsies covering the whole prostate in addition to targeted biopsies should be considered so that tumours are not missed.

Safety and Efficacy of Liraglutide, 3.0 mg, Once Daily vs Placebo in Patients With Poor Weight Loss Following Metabolic Surgery: The BARI-OPTIMISE Randomized Clinical Trial.

Importance: Metabolic surgery leads to weight loss and improved health, but these outcomes are highly variable. Poor weight loss is associated with lower circulating levels of glucagon-like peptide-1 (GLP-1). Objective: To assess the efficacy and safety of the GLP-1 receptor agonist, liraglutide, 3.0 mg, on percentage body weight reduction in patients with poor weight loss and suboptimal GLP-1 response after metabolic surgery. Design, Setting, and Participants: The Evaluation of Liraglutide 3.0 mg in Patients With Poor Weight Loss and a Suboptimal Glucagon-Like Peptide-1 Response (BARI-OPTIMISE) randomized placebo-controlled trial recruited adult patients at least 1 year after metabolic surgery who had experienced 20% or less body weight loss from the day of surgery and a suboptimal nutrient-stimulated GLP-1 response from 2 hospitals in London, United Kingdom, between October 2018 and November 2019. Key exclusion criteria were type 1 diabetes; severe concomitant psychiatric, gastrointestinal, cardiac, kidney or metabolic disease; and use of insulin, GLP-1 receptor analogues, and medication that can affect weight. The study period was 24 weeks followed by a 4-week follow-up period. Last participant follow-up was completed in June 2020. All participants and clinical study personnel were blinded to treatment allocation. Of 154 assessed for eligibility, 70 met trial criteria and were included in the study, and 57 completed follow-up. Interventions: Liraglutide, 3.0 mg, once daily or placebo as an adjunct to lifestyle intervention with a 500-kcal daily energy deficit for 24 weeks, on a 1:1 allocation by computer-generated randomization sequence, stratified by surgery type (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy [SG]) and type 2 diabetes status. Main Outcome and Measures: The primary outcome was change in percentage body weight from baseline to the end of the 24-week study period based on an intention-to-treat analysis. Participant safety was assessed through monitoring of biochemical parameters, including kidney and liver function, physical examination, and assessment for adverse events. Results: A total of 70 participants (mean [SD] age, 47.6 [10.7] years; 52 [74%] female) with a poor weight loss response following RYGB or SG were randomized to receive 3.0-mg liraglutide (n = 35) or placebo (n = 35). All participants received at least 1 dose of the trial drug. Eight participants discontinued treatment (4 per group), and 2 in the 3.0-mg liraglutide group and 1 in the placebo group were lost to follow-up. Due to COVID-19 restrictions, 3 participants in the 3.0-mg liraglutide group and 7 in the placebo group were unable to attend their final in-person assessment. Estimated change in mean (SD) percentage body weight from baseline to week 24 was -8.82 (4.94) with liraglutide, 3.0 mg (n = 31), vs -0.54 (3.32) with placebo (n = 26). The mean difference in percentage body weight change for liraglutide, 3.0 mg, vs placebo was -8.03 (95% CI, -10.39 to -5.66; P < .001). Adverse events, predominantly gastrointestinal, were more frequent with liraglutide, 3.0 mg (28 events [80%]), than placebo (20 events [57%]). There were no serious adverse events and no treatment-related deaths. Conclusion and Relevance: These findings support the use of adjuvant liraglutide, 3.0 mg, for weight management in patients with poor weight loss and suboptimal GLP-1 response after metabolic surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT03341429.

External validation of a risk model predicting failure of salvage focal ablation for prostate cancer.

OBJECTIVES: To externally validate a published model predicting failure within 2 years after salvage focal ablation in men with localised radiorecurrent prostate cancer using a prospective, UK multicentre dataset. PATIENTS AND METHODS: Patients with biopsy-confirmed ≤T3bN0M0 cancer after previous external beam radiotherapy or brachytherapy were included from the FOcal RECurrent Assessment and Salvage Treatment (FORECAST) trial (NCT01883128; 2014-2018; six centres), and from the high-intensity focussed ultrasound (HIFU) Evaluation and Assessment of Treatment (HEAT) and International Cryotherapy Evaluation (ICE) UK-based registries (2006-2022; nine centres). Eligible patients underwent either salvage focal HIFU or cryotherapy, with the choice based predominantly on anatomical factors. Per the original multivariable Cox regression model, the predicted outcome was a composite failure outcome. Model performance was assessed at 2 years post-salvage with discrimination (concordance index [C-index]), calibration (calibration curve and slope), and decision curve analysis. For the latter, two clinically-reasonable risk threshold ranges of 0.14-0.52 and 0.26-0.36 were considered, corresponding to previously published pooled 2-year recurrence-free survival rates for salvage local treatments. RESULTS: A total of 168 patients were included, of whom 84/168 (50%) experienced the primary outcome in all follow-ups, and 72/168 (43%) within 2 years. The C-index was 0.65 (95% confidence interval 0.58-0.71). On graphical inspection, there was close agreement between predicted and observed failure. The calibration slope was 1.01. In decision curve analysis, there was incremental net benefit vs a 'treat all' strategy at risk thresholds of ≥0.23. The net benefit was therefore higher across the majority of the 0.14-0.52 risk threshold range, and all of the 0.26-0.36 range. CONCLUSION: In external validation using prospective, multicentre data, this model demonstrated modest discrimination but good calibration and clinical utility for predicting failure of salvage focal ablation within 2 years. This model could be reasonably used to improve selection of appropriate treatment candidates for salvage focal ablation, and its use should be considered when discussing salvage options with patients. Further validation in larger, international cohorts with longer follow-up is recommended.

Outlier identification and monitoring of institutional or clinician performance: an overview of statistical methods and application to national audit data.

BACKGROUND: Institutions or clinicians (units) are often compared according to a performance indicator such as in-hospital mortality. Several approaches have been proposed for the detection of outlying units, whose performance deviates from the overall performance. METHODS: We provide an overview of three approaches commonly used to monitor institutional performances for outlier detection. These are the common-mean model, the 'Normal-Poisson' random effects model and the 'Logistic' random effects model. For the latter we also propose a visualisation technique. The common-mean model assumes that the underlying true performance of all units is equal and that any observed variation between units is due to chance. Even after applying case-mix adjustment, this assumption is often violated due to overdispersion and a post-hoc correction may need to be applied. The random effects models relax this assumption and explicitly allow the true performance to differ between units, thus offering a more flexible approach. We discuss the strengths and weaknesses of each approach and illustrate their application using audit data from England and Wales on Adult Cardiac Surgery (ACS) and Percutaneous Coronary Intervention (PCI). RESULTS: In general, the overdispersion-corrected common-mean model and the random effects approaches produced similar p-values for the detection of outliers. For the ACS dataset (41 hospitals) three outliers were identified in total but only one was identified by all methods above. For the PCI dataset (88 hospitals), seven outliers were identified in total but only two were identified by all methods. The common-mean model uncorrected for overdispersion produced several more outliers. The reason for observing similar p-values for all three approaches could be attributed to the fact that the between-hospital variance was relatively small in both datasets, resulting only in a mild violation of the common-mean assumption; in this situation, the overdispersion correction worked well. CONCLUSION: If the common-mean assumption is likely to hold, all three methods are appropriate to use for outlier detection and their results should be similar. Random effect methods may be the preferred approach when the common-mean assumption is likely to be violated.

The accuracy of clinician predictions of survival in the Prognosis in Palliative care Study II (PiPS2): A prospective observational study.

BACKGROUND: Prognostic information is important for patients with cancer, their families, and clinicians. In practice, survival predictions are made by clinicians based on their experience, judgement, and intuition. Previous studies have reported that clinicians' survival predictions are often inaccurate. This study reports a secondary analysis of data from the Prognosis in Palliative care Study II (PiPS2) to assess the accuracy of survival estimates made by doctors and nurses. METHODS AND FINDINGS: Adult patients (n = 1833) with incurable, locally advanced or metastatic cancer, recently referred to palliative care services (community teams, hospital teams, and inpatient palliative care units) were recruited. Doctors (n = 431) and nurses (n = 777) provided independent prognostic predictions and an agreed multi-professional prediction for each patient. Clinicians provided prognostic estimates in several formats including predictions about length of survival and probability of surviving to certain time points. There was a minimum follow up of three months or until death (whichever was sooner; maximum follow-up 783 days). Agreed multi-professional predictions about whether patients would survive for days, weeks or months+ were accurate on 61.9% of occasions. The positive predictive value of clinicians' predictions about imminent death (within one week) was 77% for doctors and 79% for nurses. The sensitivity of these predictions was low (37% and 35% respectively). Specific predictions about how many weeks patients would survive were not very accurate but showed good discrimination (patients estimated to survive for shorted periods had worse outcomes). The accuracy of clinicians' probabilistic predictions (assessed using Brier's scores) was consistently better than chance, improved with proximity to death and showed good discrimination between groups of patients with different survival outcomes. CONCLUSIONS: Using a variety of different approaches, this study found that clinicians predictions of survival show good discrimination and accuracy, regardless of whether the predictions are about how long or how likely patients are to survive. Accuracy improves with proximity to death. Although the positive predictive value of estimates of imminent death are relatively high, the sensitivity of such predictions is relatively low. Despite limitations, the clinical prediction of survival should remain the benchmark against which any innovations in prognostication are judged. STUDY REGISTRATION: ISRCTN13688211. http://www.isrctn.com/ISRCTN13688211.

Magnetic Resonance Imaging and Targeted Biopsies Compared to Transperineal Mapping Biopsies Before Focal Ablation in Localised and Metastatic Recurrent Prostate Cancer After Radiotherapy.

BACKGROUND: Recurrent prostate cancer after radiotherapy occurs in one in five patients. The efficacy of prostate magnetic resonance imaging (MRI) in recurrent cancer has not been established. Furthermore, high-quality data on new minimally invasive salvage focal ablative treatments are needed. OBJECTIVE: To evaluate the role of prostate MRI in detection of prostate cancer recurring after radiotherapy and the role of salvage focal ablation in treating recurrent disease. DESIGN, SETTING, AND PARTICIPANTS: The FORECAST trial was both a paired-cohort diagnostic study evaluating prostate multiparametric MRI (mpMRI) and MRI-targeted biopsies in the detection of recurrent cancer and a cohort study evaluating focal ablation at six UK centres. A total of 181 patients were recruited, with 155 included in the MRI analysis and 93 in the focal ablation analysis. INTERVENTION: Patients underwent choline positron emission tomography/computed tomography and a bone scan, followed by prostate mpMRI and MRI-targeted and transperineal template-mapping (TTPM) biopsies. MRI was reported blind to other tests. Those eligible underwent subsequent focal ablation. An amendment in December 2014 permitted focal ablation in patients with metastases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcomes were the sensitivity of MRI and MRI-targeted biopsies for cancer detection, and urinary incontinence after focal ablation. A key secondary outcome was progression-free survival (PFS). RESULTS AND LIMITATIONS: Staging whole-body imaging revealed localised cancer in 128 patients (71%), with involvement of pelvic nodes only in 13 (7%) and metastases in 38 (21%). The sensitivity of MRI-targeted biopsy was 92% (95% confidence interval [CI] 83-97%). The specificity and positive and negative predictive values were 75% (95% CI 45-92%), 94% (95% CI 86-98%), and 65% (95% CI 38-86%), respectively. Four cancer (6%) were missed by TTPM biopsy and six (8%) were missed by MRI-targeted biopsy. The overall MRI sensitivity for detection of any cancer was 94% (95% CI 88-98%). The specificity and positive and negative predictive values were 18% (95% CI 7-35%), 80% (95% CI 73-87%), and 46% (95% CI 19-75%), respectively. Among 93 patients undergoing focal ablation, urinary incontinence occurred in 15 (16%) and five (5%) had a grade ≥3 adverse event, with no rectal injuries. Median follow-up was 27 mo (interquartile range 18-36); overall PFS was 66% (interquartile range 54-75%) at 24 mo. CONCLUSIONS: Patients should undergo prostate MRI with both systematic and targeted biopsies to optimise cancer detection. Focal ablation for areas of intraprostatic recurrence preserves continence in the majority, with good early cancer control. PATIENT SUMMARY: We investigated the role of magnetic resonance imaging (MRI) scans of the prostate and MRI-targeted biopsies in outcomes after cancer-targeted high-intensity ultrasound or cryotherapy in patients with recurrent cancer after radiotherapy. Our findings show that these patients should undergo prostate MRI with both systematic and targeted biopsies and then ablative treatment focused on areas of recurrent cancer to preserve their quality of life. This trial is registered at ClinicalTrials.gov as NCT01883128.

Multiparametric ultrasound versus multiparametric MRI to diagnose prostate cancer (CADMUS): a prospective, multicentre, paired-cohort, confirmatory study.

BACKGROUND: Multiparametric MRI of the prostate followed by targeted biopsy is recommended for patients at risk of prostate cancer. However, multiparametric ultrasound is more readily available than multiparametric MRI. Data from paired-cohort validation studies and randomised, controlled trials support the use of multiparametric MRI, whereas the evidence for individual ultrasound methods and multiparametric ultrasound is only derived from case series. We aimed to establish the overall agreement between multiparametric ultrasound and multiparametric MRI to diagnose clinically significant prostate cancer. METHODS: We conducted a prospective, multicentre, paired-cohort, confirmatory study in seven hospitals in the UK. Patients at risk of prostate cancer, aged 18 years or older, with an elevated prostate-specific antigen concentration or abnormal findings on digital rectal examination underwent both multiparametric ultrasound and multiparametric MRI. Multiparametric ultrasound consisted of B-mode, colour Doppler, real-time elastography, and contrast-enhanced ultrasound. Multiparametric MRI included high-resolution T2-weighted images, diffusion-weighted imaging (dedicated high B 1400 s/mm2 or 2000 s/mm2 and apparent diffusion coefficient map), and dynamic contrast-enhanced axial T1-weighted images. Patients with positive findings on multiparametric ultrasound or multiparametric MRI underwent targeted biopsies but were masked to their test results. If both tests yielded positive findings, the order of targeting at biopsy was randomly assigned (1:1) using stratified (according to centre only) block randomisation with randomly varying block sizes. The co-primary endpoints were the proportion of positive lesions on, and agreement between, multiparametric MRI and multiparametric ultrasound in identifying suspicious lesions (Likert score of ≥3), and detection of clinically significant cancer (defined as a Gleason score of ≥4 + 3 in any area or a maximum cancer core length of ≥6 mm of any grade [PROMIS definition 1]) in those patients who underwent a biopsy. Adverse events were defined according to Good Clinical Practice and trial regulatory guidelines. The trial is registered on ISRCTN, 38541912, and ClinicalTrials.gov, NCT02712684, with recruitment and follow-up completed. FINDINGS: Between March 15, 2016, and Nov 7, 2019, 370 eligible patients were enrolled; 306 patients completed both multiparametric ultrasound and multiparametric MRI and 257 underwent a prostate biopsy. Multiparametric ultrasound was positive in 272 (89% [95% CI 85-92]) of 306 patients and multiparametric MRI was positive in 238 patients (78% [73-82]; difference 11·1% [95% CI 5·1-17·1]). Positive test agreement was 73·2% (95% CI 67·9-78·1; κ=0·06 [95% CI -0·56 to 0·17]). Any cancer was detected in 133 (52% [95% CI 45·5-58]) of 257 patients, with 83 (32% [26-38]) of 257 being clinically significant by PROMIS definition 1. Each test alone would result in multiparametric ultrasound detecting PROMIS definition 1 cancer in 66 (26% [95% CI 21-32]) of 257 patients who had biopsies and multiparametric MRI detecting it in 77 (30% [24-36]; difference -4·3% [95% CI -8·3% to -0·3]). Combining both tests detected 83 (32% [95% CI 27-38]) of 257 clinically significant cancers as per PROMIS definition 1; of these 83 cancers, six (7% [95% CI 3-15]) were detected exclusively with multiparametric ultrasound, and 17 (20% [12-31]) were exclusively detected by multiparametric MRI (agreement 91·1% [95% CI 86·9-94·2]; κ=0·78 [95% CI 0·69-0·86]). No serious adverse events were related to trial activity. INTERPRETATION: Multiparametric ultrasound detected 4·3% fewer clinically significant prostate cancers than multiparametric MRI, but it would lead to 11·1% more patients being referred for a biopsy. Multiparametric ultrasound could be an alternative to multiparametric MRI as a first test for patients at risk of prostate cancer, particularly if multiparametric MRI cannot be carried out. Both imaging tests missed clinically significant cancers detected by the other, so the use of both would increase the detection of clinically significant prostate cancers compared with using each test alone. FUNDING: The Jon Moulton Charity Trust, Prostate Cancer UK, and UCLH Charity and Barts Charity.

Exploratory randomised trial of face-to-face and mobile phone counselling against usual care for tobacco cessation in Indian primary care: a randomised controlled trial protocol for project CERTAIN.

INTRODUCTION: Despite widespread use of smokeless tobacco products by people within the Indian subcontinent, there is little awareness among Indians of its health hazards when compared with smoked tobacco. We hypothesise that mobile phone counselling will be feasible and effective for smokeless tobacco cessation intervention in India. This paper presents the protocol of the development and conduct of an exploratory trial before progression to a full randomised controlled trial. METHODS AND ANALYSIS: An exploratory randomised controlled trial will be conducted in urban primary health centres in the state of Odisha, India. A total of 250 smokeless tobacco users will be recruited to the study (125 in each arm). Participants in the intervention arm will receive routine care together with a face-to-face counselling intervention followed by advice and reminder mobile messages. The control arm will receive routine care, delivered by a primary care physician based on 'Ask' and 'Advice'. All participants will be followed up for 3 months from the first counselling session. The primary outcome of this trial is to assess the feasibility to carry out a full randomised controlled trial. ETHICS AND DISSEMINATION: Ethical approvals were obtained from the Institutional Ethics Committee of Public Health Foundation of India, Health Ministry's Screening Committee, Odisha State Ethics Board and also from University College London Research Ethics Committee, UK. The study findings will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: CTRI/2019/05/019484.

Study recruitment factors in advanced cancer: the Prognosis in Palliative care Study II (PiPS2) - a multicentre, prospective, observational cohort project.

OBJECTIVES: The Prognosis in Palliative care Study II (PiPS2) was a large multicentre observational study validating prognostic tools in patients with advanced cancer. Many palliative care studies fail to reach their recruitment target. To inform future studies, PiPS2 rigorously monitored and identified any potential recruitment barriers. METHODS: Key recruitment stages (ie, whether patients were eligible for the study, approached by the researchers and whether consent was obtained for enrolment) were monitored via comprehensive screening logs at participating sites (inpatient hospices, hospitals and community palliative care teams). The reasons for patients' ineligibility, inaccessibility or decision not to consent were documented. RESULTS: 17 014 patients were screened across 27 participating sites over a 20-month recruitment period. Of those, 4642 (27%) were ineligible for participation in the study primarily due to non-cancer diagnoses. Of 12 372 eligible patients, 9073 (73%) were not approached, the most common reason being a clinical decision not to do so. Other reasons included patients' death or discharge before they were approached by the researchers. Of the 3299 approached patients, 1458 (44%) declined participation mainly because of feeling too unwell, experiencing severe distress or having other competing priorities. 11% (n=1841/17 014) of patients screened were enrolled in the study, representing 15% (n=1841/12 372) of eligible patients. Different recruitment patterns were observed across inpatient hospice, hospital and community palliative care teams. CONCLUSIONS: The main barrier to recruitment was 'accessing' potentially eligible patients. Monitoring key recruitment stages may help to identify barriers and facilitators to enrolment and allow results to be put into better context. TRIAL REGISTRATION NUMBER: ISRCTN13688211.

Prognostic models of survival in patients with advanced incurable cancer: the PiPS2 observational study.

BACKGROUND: The Prognosis in Palliative care Study (PiPS) prognostic survival models predict survival in patients with incurable cancer. PiPS-A (Prognosis in Palliative care Study - All), which involved clinical observations only, and PiPS-B (Prognosis in Palliative care Study - Blood), which additionally required blood test results, consist of 14- and 56-day models that combine to create survival risk categories: 'days', 'weeks' and 'months+'. OBJECTIVES: The primary objectives were to compare PIPS-B risk categories against agreed multiprofessional estimates of survival and to validate PiPS-A and PiPS-B. The secondary objectives were to validate other prognostic models, to assess the acceptability of the models to patients, carers and health-care professionals and to identify barriers to and facilitators of clinical use. DESIGN: This was a national, multicentre, prospective, observational, cohort study with a nested qualitative substudy using interviews with patients, carers and health-care professionals. SETTING: Community, hospital and hospice palliative care services across England and Wales. PARTICIPANTS: For the validation study, the participants were adults with incurable cancer, with or without capacity to consent, who had been recently referred to palliative care services and had sufficient English language. For the qualitative substudy, a subset of participants in the validation study took part, along with informal carers, patients who declined to participate in the main study and health-care professionals. MAIN OUTCOME MEASURES: For the validation study, the primary outcomes were survival, clinical prediction of survival and PiPS-B risk category predictions. The secondary outcomes were predictions of PiPS-A and other prognostic models. For the qualitative substudy, the main outcomes were participants' views about prognostication and the use of prognostic models. RESULTS: For the validation study, 1833 participants were recruited. PiPS-B risk categories were as accurate as agreed multiprofessional estimates of survival (61%; p = 0.851). Discrimination of the PiPS-B 14-day model (c-statistic 0.837, 95% confidence interval 0.810 to 0.863) and the PiPS-B 56-day model (c-statistic 0.810, 95% confidence interval 0.788 to 0.832) was excellent. The PiPS-B 14-day model showed some overfitting (calibration in the large -0.202, 95% confidence interval -0.364 to -0.039; calibration slope 0.840, 95% confidence interval 0.730 to 0.950). The PiPS-B 56-day model was well-calibrated (calibration in the large 0.152, 95% confidence interval 0.030 to 0.273; calibration slope 0.914, 95% confidence interval 0.808 to 1.02). PiPS-A risk categories were less accurate than agreed multiprofessional estimates of survival (p < 0.001). The PiPS-A 14-day model (c-statistic 0.825, 95% confidence interval 0.803 to 0.848; calibration in the large -0.037, 95% confidence interval -0.168 to 0.095; calibration slope 0.981, 95% confidence interval 0.872 to 1.09) and the PiPS-A 56-day model (c-statistic 0.776, 95% confidence interval 0.755 to 0.797; calibration in the large 0.109, 95% confidence interval 0.002 to 0.215; calibration slope 0.946, 95% confidence interval 0.842 to 1.05) had excellent or reasonably good discrimination and calibration. Other prognostic models were also validated. Where comparisons were possible, the other prognostic models performed less well than PiPS-B. For the qualitative substudy, 32 health-care professionals, 29 patients and 20 carers were interviewed. The majority of patients and carers expressed a desire for prognostic information and said that PiPS could be helpful. Health-care professionals said that PiPS was user friendly and may be helpful for decision-making and care-planning. The need for a blood test for PiPS-B was considered a limitation. LIMITATIONS: The results may not be generalisable to other populations. CONCLUSIONS: PiPS-B risk categories are as accurate as agreed multiprofessional estimates of survival. PiPS-A categories are less accurate. Patients, carers and health-care professionals regard PiPS as potentially helpful in clinical practice. FUTURE WORK: A study to evaluate the impact of introducing PiPS into routine clinical practice is needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13688211. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 28. See the NIHR Journals Library website for further project information.

A prognosis is a prediction about how long someone will live after a diagnosis of illness. The Prognosis in Palliative care Study (PiPS) tools [PiPS-A (Prognosis in Palliative care Study ­ All) and PiPS-B (Prognosis in Palliative care Study ­ Blood), respectively] were designed to predict survival in patients with incurable cancer. Previously, they were found to be as accurate as health-care professionals. The purpose of this study was to find out whether PiPS was more accurate at prognosticating than health-care professionals, to evaluate other prognostic tools and to ask patients, their carers and health-care professionals what they thought about using them. We studied 1833 patients with advanced cancer and calculated their PiPS score and other prognostic scores. We asked health-care professionals to estimate how long the patients would live. We then followed up the patients to find out how long they actually lived and if the predictions made by health-care professionals were as accurate as the predictions made by the prognostic tools. We interviewed patients, their carers and health-care professionals to ask them what they thought about using these prognostic tools. We found that PiPS-B was as accurate as the combined wisdom of a doctor and a nurse at predicting whether patients would live for 'days', 'weeks' or 'months+'. We found that PiPS-A predictions were not as accurate as predictions made by health-care professionals. We found that (where direct comparisons could be made) PiPS-B was better than other prognostic tools. Finally, we found that patients, carers and health-care professionals thought that PiPS tools could be helpful in clinical practice because they would be less subjective than clinicians' intuition. This means that PiPS-B could be considered as a tool to support clinician predictions of survival and may lead to patients and families being able to take more control at the end of their lives. Further research will be required to investigate whether or not this approach actually leads to improvements in care.

A novel risk calculator to predict outcome after surgery for symptomatic spinal metastases; use of a large prospective patient database to personalise surgical management.

AIM: Surgery for spinal metastases can improve symptoms, but sometimes complications can negate the benefits. Operations may have different indications, complexities and risks, and the choice for an individual is a tailor-made personalised decision. Previous prognostic scoring systems are becoming out of date and inaccurate. We designed a risk calculator to estimate survival after surgery, to inform clinicians and patients when making management decisions. METHODS: A prospective cohort study was performed, including 1430 patients with spinal metastases who underwent surgery. Of them, 1264 patients from 20 centres were used for model development using a Cox frailty model. Calibration slope, D-statistic and C-index were used for model validation based on 166 patients. Follow-up was to death or minimum of 2 years after surgery. Pre-operative indices (examination findings, pain, Karnofsky physical functioning score, and radiology) were assessed. RESULTS: An algorithm to predict survival was constructed including the tumour type, ambulatory status, analgesic use, American Society of Anesthesiologists score, number of spinal metastases, previous radiotherapy or chemotherapy, presence of visceral metastases, cervical or thoracic spine involvement, as predictors. An Internet-based risk calculator was developed based on this algorithm, with similar or improved accuracy compared to other validated prognostic scoring systems (C-index, 0.68; 95% confidence interval, 0.63--0.73, and calibration slope, 1.00; 95% confidence interval, 0.68--1.32). CONCLUSION: A large, prospective, surgical series of patients with symptomatic spinal metastases was used to create a validated risk calculator that can help clinicians to inform patients about the most appropriate treatment plan. The calculator is available at www.spinemet.com.

Acceptance and commitment therapy for adults with advanced cancer (CanACT): A feasibility randomised controlled trial.

OBJECTIVE: To understand the feasibility of recruiting people with advanced cancer into a randomised controlled trial of acceptance and commitment therapy (ACT) vs a standardised talking control (TC) and delivering ACT to this population; to explore the acceptability of outcome measures and generate normative data. METHODS: This was a feasibility two-arm randomised controlled trial. Participants were attendees with advanced cancer at one of three hospice-based day-therapy units in London, United Kingdom, who demonstrated low scores on the Functional Assessment of Cancer Therapies-General (FACT-G). The primary end point was 3 months. RESULTS: The recruitment target was 54 participants; 42 people were recruited and randomised to up to eight individual sessions of ACT (n = 20) or TC (n = 22). Eighteen out of 42 (43%) of participants completed the primary outcome at 3 months, and at least one follow-up was available in 30/42 (71%) participants. An exploratory analysis revealed a non-significant adjusted mean difference after 3 months in the main outcome FACT-G of -3.41 (CI = -18.61-11.79) with TC having better functioning. Over 6 months, the adjusted mean difference between trial arms was 2.25 (CI = -6.03-10.52) in favour of ACT. CONCLUSIONS: It is feasible to recruit people with advanced cancer in a trial of ACT versus TC. Future research should test the effectiveness of ACT in a fully powered trial.

The Prognosis in Palliative care Study II (PiPS2): study protocol for a multi-centre, prospective, observational, cohort study.

BACKGROUND: More accurate methods of prognostication are likely to lead to improvements in the quality of care of patients approaching the ends of their lives. The Prognosis in Palliative care Scales (PiPS) are prognostic models of survival. The scores are calculated using simple clinical data and observations. There are two separate PiPS models; PiPS-A for patients without blood test results and PiPS-B for patients with blood test results. Both models predict whether a patient is likely to live for "days", "weeks" or "months" and have been shown to perform as well as clinicians' estimates of survival. PiPS-B has also been found to be significantly better than doctors' estimates of survival. We report here a protocol for the validation of PiPS and for the evaluation of the accuracy of other prognostic tools in a new, larger cohort of patients with advanced cancer. METHODS: This is a national, multi-centre, prospective, observational cohort study, aiming to recruit 1778 patients via palliative care services across England and Wales. Eligible patients have advanced, incurable cancer and have recently been referred to palliative care services. Patients with or without capacity are included in the study. The primary outcome is the accuracy of PiPS predictions and the difference in accuracy between these predictions and the clinicians' estimates of survival; with PiPS-B being the main model of interest. The secondary outcomes include the accuracy of predictions by the Palliative Prognostic Index (PPI), Palliative Performance Scale (PPS), Palliative Prognostic score (PaP) and the Feliu Prognostic Nomogram (FPN) compared with actual patient survival and clinicians' estimates of survival. A nested qualitative sub-study using face-to-face interviews with patients, carers and clinicians is also being undertaken to assess the acceptability of the prognostic models and to identify barriers and facilitators to clinical use. DISCUSSION: The study closed to recruitment at the end of April 2018 having exceeded the required sample size of 1778 patients. The qualitative sub-study is nearing completion. This demonstrates the feasibility of recruiting large numbers of participants to a prospective palliative care study. TRIAL REGISTRATION: ISRCTN13688211 (registration date: 28/06/2016).

Clinical and cost-effectiveness of an intervention for reducing cholesterol and cardiovascular risk for people with severe mental illness in English primary care: a cluster randomised controlled trial.

BACKGROUND: People with severe mental illnesses, including psychosis, have an increased risk of cardiovascular disease. We aimed to evaluate the effects of a primary care intervention on decreasing total cholesterol concentrations and cardiovascular disease risk in people with severe mental illnesses. METHODS: We did this cluster randomised trial in general practices across England, with general practices as the cluster unit. We randomly assigned general practices (1:1) with 40 or more patients with severe mental illnesses using a computer-generated random sequence with a block size of four. Researchers were masked to allocation, but patients and general practice staff were not. We included participants aged 30-75 years with severe mental illnesses (schizophrenia, bipolar disorder, or psychosis), who had raised cholesterol concentrations (5·0 mmol/L) or a total:HDL cholesterol ratio of 4·0 mmol/L or more and one or more modifiable cardiovascular disease risk factors. Eligible participants were recruited within each practice before randomisation. The Primrose intervention consisted of appointments (≤12) with a trained primary care professional involving manualised interventions for cardiovascular disease prevention (ie, adhering to statins, improving diet or physical activity levels, reducing alcohol, or quitting smoking). Treatment as usual involved feedback of screening results only. The primary outcome was total cholesterol at 12 months and the primary economic analysis outcome was health-care costs. We used intention-to-treat analysis. The trial is registered with Current Controlled Trials, number ISRCTN13762819. FINDINGS: Between Dec 10, 2013, and Sept 30, 2015, we recruited general practices and between May 9, 2014, and Feb 10, 2016, we recruited participants and randomly assigned 76 general practices with 327 participants to the Primrose intervention (n=38 with 155 patients) or treatment as usual (n=38 with 172 patients). Total cholesterol concentration data were available at 12 months for 137 (88%) participants in the Primrose intervention group and 152 (88%) participants in the treatment-as-usual group. The mean total cholesterol concentration did not differ at 12 months between the two groups (5·4 mmol/L [SD 1·1] for Primrose vs 5·5 mmol/L [1·1] for treatment as usual; mean difference estimate 0·03, 95% CI -0·22 to 0·29; p=0·788). This result was unchanged by pre-agreed supportive analyses. Mean cholesterol decreased over 12 months (-0·22 mmol/L [1·1] for Primrose vs -0·36 mmol/L [1·1] for treatment as usual). Total health-care costs (£1286 [SE 178] in the Primrose intervention group vs £2182 [328] in the treatment-as-usual group; mean difference -£895, 95% CI -1631 to -160; p=0·012) and psychiatric inpatient costs (£157 [135] vs £956 [313]; -£799, -1480 to -117; p=0·018) were lower in the Primrose intervention group than the treatment-as-usual group. Six serious adverse events of hospital admission and one death occurred in the Primrose group (n=7) and 23, including three deaths, occurred in the treatment-as-usual group (n=18). INTERPRETATION: Total cholesterol concentration at 12 months did not differ between the Primrose and treatment-as-usual groups, possibly because of the cluster design, good care in the treatment-as-usual group, short duration of the intervention, or suboptimal focus on statin prescribing. The association between the Primrose intervention and fewer psychiatric admissions, with potential cost-effectiveness, might be important. FUNDING: National Institute of Health Research Programme Grants for Applied Research.

Living and dying with advanced dementia: A prospective cohort study of symptoms, service use and care at the end of life.

BACKGROUND: Increasing number of people are dying with advanced dementia. Comfort and quality of life are key goals of care. AIMS: To describe (1) physical and psychological symptoms, (2) health and social care service utilisation and (3) care at end of life in people with advanced dementia. DESIGN: 9-month prospective cohort study. SETTING AND PARTICIPANTS: Greater London, England, people with advanced dementia (Functional Assessment Staging Scale 6e and above) from 14 nursing homes or their own homes. MAIN OUTCOME MEASURES: At study entry and monthly: prescriptions, Charlson Comorbidity Index, pressure sore risk/severity (Waterlow Scale/Stirling Scale, respectively), acute medical events, pain (Pain Assessment in Advanced Dementia), neuropsychiatric symptoms (Neuropsychiatric Inventory), quality of life (Quality of Life in Late-Stage Dementia Scale), resource use (Resource Utilization in Dementia Questionnaire and Client Services Receipt Inventory), presence/type of advance care plans, interventions, mortality, place of death and comfort (Symptom Management at End of Life in Dementia Scale). RESULTS: Of 159 potential participants, 85 were recruited (62% alive at end of follow-up). Pain (11% at rest, 61% on movement) and significant agitation (54%) were common and persistent. Aspiration, dyspnoea, septicaemia and pneumonia were more frequent in those who died. In total, 76% had 'do not resuscitate' statements, less than 40% advance care plans. Most received primary care visits, there was little input from geriatrics or mental health but contact with emergency paramedics was common. CONCLUSION: People with advanced dementia lived with distressing symptoms. Service provision was not tailored to their needs. Longitudinal multidisciplinary input could optimise symptom control and quality of life.

Review and evaluation of performance measures for survival prediction models in external validation settings.

BACKGROUND: When developing a prediction model for survival data it is essential to validate its performance in external validation settings using appropriate performance measures. Although a number of such measures have been proposed, there is only limited guidance regarding their use in the context of model validation. This paper reviewed and evaluated a wide range of performance measures to provide some guidelines for their use in practice. METHODS: An extensive simulation study based on two clinical datasets was conducted to investigate the performance of the measures in external validation settings. Measures were selected from categories that assess the overall performance, discrimination and calibration of a survival prediction model. Some of these have been modified to allow their use with validation data, and a case study is provided to describe how these measures can be estimated in practice. The measures were evaluated with respect to their robustness to censoring and ease of interpretation. All measures are implemented, or are straightforward to implement, in statistical software. RESULTS: Most of the performance measures were reasonably robust to moderate levels of censoring. One exception was Harrell's concordance measure which tended to increase as censoring increased. CONCLUSIONS: We recommend that Uno's concordance measure is used to quantify concordance when there are moderate levels of censoring. Alternatively, Gönen and Heller's measure could be considered, especially if censoring is very high, but we suggest that the prediction model is re-calibrated first. We also recommend that Royston's D is routinely reported to assess discrimination since it has an appealing interpretation. The calibration slope is useful for both internal and external validation settings and recommended to report routinely. Our recommendation would be to use any of the predictive accuracy measures and provide the corresponding predictive accuracy curves. In addition, we recommend to investigate the characteristics of the validation data such as the level of censoring and the distribution of the prognostic index derived in the validation setting before choosing the performance measures.

Acceptance and commitment therapy for adults with advanced cancer (CanACT): study protocol for a feasibility randomised controlled trial.

BACKGROUND: One-third of people with cancer experience psychological distress and may suppress distressing thoughts, emotions, and concerns, leading to further problems. Conventional psychological treatments reduce distress by problem solving, but in advanced cancer, when ill health is progressive and death may be approaching, physical and psychological difficulties are complex and have no simple solutions. Acceptance and Commitment Therapy encourages acknowledgement and acceptance of mental experiences, increasing people's ability to work with problems that cannot be solved. Previous pilot work in advanced cancer confirms that distress can be associated with an avoidance of experiencing uncomfortable thoughts and emotions. METHODS/DESIGN: This feasibility randomised controlled trial of Acceptance Commitment Therapy aims to establish parameters for a larger trial. Fifty-four participants with advanced cancer will be randomly allocated to up to eight sessions (each 1 hour) of Acceptance Commitment Therapy or a talking control. Participants will be recruited from those attending outpatient services and hospice day care at three specialist palliative care units in North and East London, United Kingdom. The primary outcome is a measure of functioning in four areas of life (physical, social/family, emotional, and general activity) using the Functional Assessment of Cancer Therapies--General questionnaire at 3 months after randomisation. Secondary outcomes are (i) acceptance using the Acceptance and Action Questionnaire; (ii) psychological distress using the Kessler Psychological Distress Scale; (iii) physical functioning using a timed walk and sit-to-stand test; and (iv) quality of life measures including the Euroqol-5 Dimensions and ICECAP Supportive Care measures. Qualitative data will be collected at 3 months to explore the participants' experiences of the trial and therapy. Data will be collected on the costs of care. DISCUSSION: Data generated on the recruitment, retention, and experience of the interventions and the usefulness of the outcome measures will inform the adaptations required and whether changes in function are consistent with existing data when planning for a sufficiently powered randomised controlled trial. TRIAL REGISTRATION: ISRCTN13841211 (registered 22 July 2015).

Evaluating the clinical and cost effectiveness of a behaviour change intervention for lowering cardiovascular disease risk for people with severe mental illnesses in primary care (PRIMROSE study): study protocol for a cluster randomised controlled trial.

BACKGROUND: People with severe mental illnesses die up to 20 years earlier than the general population, with cardiovascular disease being the leading cause of death. National guidelines recommend that the physical care of people with severe mental illnesses should be the responsibility of primary care; however, little is known about effective interventions to lower cardiovascular disease risk in this population and setting. Following extensive peer review, funding was secured from the United Kingdom National Institute for Health Research (NIHR) to deliver the proposed study. The aim of the trial is to test the effectiveness of a behavioural intervention to lower cardiovascular disease risk in people with severe mental illnesses in United Kingdom General Practices. METHODS/DESIGN: The study is a cluster randomised controlled trial in 70 GP practices for people with severe mental illnesses, aged 30 to 75 years old, with elevated cardiovascular disease risk factors. The trial will compare the effectiveness of a behavioural intervention designed to lower cardiovascular disease risk and delivered by a practice nurse or healthcare assistant, with standard care offered in General Practice. A total of 350 people will be recruited and followed up at 6 and 12 months. The primary outcome is total cholesterol level at the 12-month follow-up and secondary outcomes include blood pressure, body mass index, waist circumference, smoking status, quality of life, adherence to treatments and services and behavioural measures for diet, physical activity and alcohol use. An economic evaluation will be carried out to determine the cost effectiveness of the intervention compared with standard care. DISCUSSION: The results of this pragmatic trial will provide evidence on the clinical and cost effectiveness of the intervention on lowering total cholesterol and addressing multiple cardiovascular disease risk factors in people with severe mental illnesses in GP Practices. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13762819. Date of Registration: 25 February 2013. Date and Version Number: 27 August 2014 Version 5.