A mixed methods approach to developing and evaluating oncology trainee education around minimization of adverse events and improved patient quality and safety

BACKGROUND: Adverse events are a significant quality and safety issue in the hospital setting due to their direct impact on patients. Additionally, such events are often handled by junior doctors due to their direct involvement with patients. As such, it is important for health care organizations to prioritize education and training for junior doctors on identifying adverse events and handling them when they occur. The Cancer Cup Challenge is an educational program focuses on quality improvement and adverse event awareness targeting for junior oncology doctors across three international sites. METHODS: A mixed methodology was used to develop and evaluate the program. The Qstream spaced learning platform was used to disseminate information to participants, as it has been demonstrated to impact on both knowledge and behavior. Eight short case based scenarios with expert feedback were developed by a multidisciplinary advisory committee containing representatives from the international sites. At the conclusion of the course impact on participant knowledge was evaluated using analysis of the metrics collected by the Qstream platform. Additionally, an online survey and semi-structured interviews were used to evaluate engagement and perceived value by participants. RESULTS: A total of 35 junior doctors registered to undertake the Qstream program, with 31 (88.57 %) successfully completing it. Analysis of the Qstream metrics revealed 76.57 % of cases were answered correctly on first attempt. The post-program survey received 17 responses, with 76.47 % indicating cases for the course were interesting and 82.35 % feeling cases were relevant. Finally, 14 participants consented to participate in semi-structured interviews about the program, with feedback towards the course being generally very positive. CONCLUSIONS: Our study demonstrates that an online game is well accepted by junior doctors as a method to increase their quality improvement awareness. Developing effective and sustainable training for doctors is important to ensure positive patient outcomes are maintained in the hospital setting. This is particularly important for junior doctors as they are working closely with patients and learning skills and behaviors, which will influence their practice throughout their careers

Trastuzumab-associated cardiac events in the Persephone trial.

BACKGROUND: We report cardiac events in the Persephone trial which compares 6-12 months of adjuvant trastuzumab in women with confirmed HER2-positive, early-stage breast cancer. METHODS: Clinical cardiac events were defined as any of the following: symptoms and/or signs of congestive heart failure (CHF) and new or altered CHF medication. In addition, left ventricular ejection fraction (LVEF) was measured at baseline and then 3 monthly for 12 months. RESULTS: A total of 2500 patients, aged 22-82, were included: 1251 randomised to 12 months and 1249 to 6 months of trastuzumab treatment. A total of 93% (2335/2500) received anthracyclines, 49% of these (1136/2335) with taxanes. Cardiotoxicity delayed treatment in 6% of 12-month and 4% of 6-month patients (P=0.01), and stopped treatment early in 8% (96/1214) of 12-month and 4% (45/1216) of 6-month patients (P3 cycles of anthracycline was associated with higher risk of cardiac events only for 12-month patients (OR 1.41 (1.04-1.90)), and not for 6-month patients (OR 1.28 (0.91-1.79)). CONCLUSIONS: We demonstrate significantly fewer cardiac events from 6 months of adjuvant trastuzumab compared with that from 12 months. This cardiac signal adds importance to the question of the optimum duration of adjuvant trastuzumab treatment. If 6 months is proven to have non-inferior outcomes to 12 months treatment, these data would support 6 months as the standard of care.National Institute of Health Research Health Technology Assessment (NIHR HTA) Programme UK. Funding reference number - 06/303/98This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/bjc.2016.35

The Parents under Pressure parenting programme for families with fathers receiving treatment for opioid dependency: the PuP4Dads feasibility study

Background: The impact of parental drug use on children is a major public health problem. However, opioid-dependent fathers have been largely ignored in parenting research. Objective: Implement and test the feasibility and acceptability of the ‘Parents under Pressure’ parenting programme for opioid-dependent fathers and their families (PuP4Dads) and determine whether a full scale evaluation could be conducted. Design: Mixed methods feasibility study. Setting: Two non-NHS family support services for parents who use drugs in Scotland. Participants: Fathers prescribed Opioid Substitution Therapy (n=25), their partners (n=17) and children; practitioners; supervisors, service managers; referrers. Intervention: Home-visiting programme, including an integrated theoretical framework, case formulation, collaborative goal setting, and modules designed to improve parenting, the caregiving environment and child welfare. Delivered flexibly over six months by accredited practitioners. Main outcome measures: Feasibility progression criteria: recruitment target (n=24 fathers); acceptability of PUP; father engagement in the study (66% complete programme; minimum 10 complete baseline and post-treatment interviews); engagement in qualitative interviews (fathers n=10 minimum; practitioners 90% uptake; managers 80% uptake); focus groups (referrers 80% uptake); adequate fidelity; no adverse events. Data sources: Researcher administered validated questionnaires: Brief Child Abuse Potential; Parenting Sense of Competence; Difficulties in Emotion Regulation; Paternal/Maternal Antenatal Attachment; Emotional Availability (video); Infant Toddler Social Emotional Assessment/Strengths and Difficulties; Conflict Tactics Scale; Treatment Outcomes Profile; EQ-5D-5L. Other sources: Parent-completed service use (economic measure); Social work child protection data; NHS opioid substitution therapy prescription data. Practitioner reported attendance data. Interviews with fathers, mothers, practitioners (n=8), supervisors (n=2), service managers (n=7); focus groups with referrers (n=28); ‘expert event’ with stakeholders (n=39). Results: PuP was successfully delivered within non-NHS settings and acceptable and suitable for the study population. Referrals (n=44) resulted in 38 (86%) eligible fathers, of whom 25 (66%) fathers and 17 partners/mothers consented to participate. Most fathers reported no previous parenting support. Intervention engagement: 248 sessions delivered to 20 fathers and 14 mothers who started the intervention; 14 fathers (10 mothers) completed ≥ six sessions; six fathers (4 mothers) completed ≤ five sessions. Father and mother attendance rates were equal (mean: 71%). Median length of engagement: fathers 26 weeks, mothers 30 weeks. Research interview completion rates for fathers: 23 at baseline, 16 follow-up one, 13 follow-up two. Measures: well tolerated; suitability of some measures dependent on family circumstances; researcher administered questionnaires resulted in little missing data. Perceived benefits of PuP4Dads from parent, practitioner and manager perspectives: therapeutic focus on fathers, improved parental emotion regulation; understanding and responding to child’s needs; better multi-agency working; programme a good fit with practice ‘ethos’ and policy agenda. Learning highlighted importance of: service-wide adoption and implementation support; strategies to improve recruitment and retention of fathers; managing complex needs of both parents concurrently; understanding contextual factors affecting programme delivery and variables affecting intervention engagement and outcomes. Limitations: Lack of emotional availability and economic (service use) data. Conclusions: A larger evaluation of PuP4Dads is feasible. Future work: Demonstrating the effectiveness of PuP4Dads and the cost implications. Better understanding of how the intervention works, for whom, under what circumstances, and why

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer

Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2, a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 106, empirical P = 1.4 × 10-5), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10-9, empirical P = 1.3 × 10-7). Although requiring further validation, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective, even in relatively small cohorts, and can be adopted in drug development and treatment programs

Key Learning Outcomes for Clinical Pharmacology and Therapeutics Education in Europe: A Modified Delphi Study.

Harmonizing clinical pharmacology and therapeutics (CPT) education in Europe is necessary to ensure that the prescribing competency of future doctors is of a uniform high standard. As there are currently no uniform requirements, our aim was to achieve consensus on key learning outcomes for undergraduate CPT education in Europe. We used a modified Delphi method consisting of three questionnaire rounds and a panel meeting. A total of 129 experts from 27 European countries were asked to rate 307 learning outcomes. In all, 92 experts (71%) completed all three questionnaire rounds, and 33 experts (26%) attended the meeting. 232 learning outcomes from the original list, 15 newly suggested and 5 rephrased outcomes were included. These 252 learning outcomes should be included in undergraduate CPT curricula to ensure that European graduates are able to prescribe safely and effectively. We provide a blueprint of a European core curriculum describing when and how the learning outcomes might be acquired

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

BackgroundAnterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability.MethodsWe did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367.FindingsBetween Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications.InterpretationSurgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management